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Time dependent directional profit model for financial time series forecasting Goodness-of-fit is the most popular criterion for neural network time series forecasting. In the context of financial time series forecasting, we are not only concerned at how good the forecasts fit their targets, but we are more interested in profits. In order to increase the forecastability in terms of profit earning, we propose a profit based adjusted weight factor for backpropagation network training. Instead of using the traditional least squares error, we add a factor which contains the profit, direction, and time information to the error function. The results show that this new approach does improve the forecastability of neural network models, for the financial application domain. |
/*
* Licensed to the Apache Software Foundation (ASF) under one
* or more contributor license agreements. See the NOTICE file
* distributed with this work for additional information
* regarding copyright ownership. The ASF licenses this file
* to you under the Apache License, Version 2.0 (the
* "License"); you may not use this file except in compliance
* with the License. You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing,
* software distributed under the License is distributed on an
* "AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY
* KIND, either express or implied. See the License for the
* specific language governing permissions and limitations
* under the License.
*/
package org.apache.openwebbeans.junit5.internal;
import org.apache.openwebbeans.junit5.Cdi;
import org.junit.jupiter.api.extension.AfterAllCallback;
import org.junit.jupiter.api.extension.AfterEachCallback;
import org.junit.jupiter.api.extension.BeforeAllCallback;
import org.junit.jupiter.api.extension.BeforeEachCallback;
import org.junit.jupiter.api.extension.ExtensionContext;
import org.junit.platform.commons.util.AnnotationUtils;
import javax.enterprise.context.spi.CreationalContext;
import javax.enterprise.inject.se.SeContainer;
import javax.enterprise.inject.se.SeContainerInitializer;
import javax.enterprise.inject.spi.AnnotatedType;
import javax.enterprise.inject.spi.BeanManager;
import javax.enterprise.inject.spi.InjectionTarget;
import java.lang.reflect.InvocationTargetException;
import java.util.ArrayList;
import java.util.Collection;
import java.util.function.Supplier;
import java.util.stream.Stream;
// todo: enhance the setup to be thread safe? see Meecrowave ClassLoaderLock class and friends
public class CdiExtension extends CdiParametersResolverExtension implements BeforeAllCallback, AfterAllCallback, BeforeEachCallback, AfterEachCallback
{
private static SeContainer reusableContainer;
private SeContainer testInstanceContainer;
private Collection<CreationalContext<?>> creationalContexts = new ArrayList<>();
private AutoCloseable[] onStop;
@Override
public void beforeAll(final ExtensionContext extensionContext)
{
final Cdi config = AnnotationUtils.findAnnotation(extensionContext.getElement(), Cdi.class).orElse(null);
if (config == null)
{
return;
}
final boolean reusable = config.reusable();
if (reusable && reusableContainer != null)
{
return;
}
if (!reusable && reusableContainer != null)
{
throw new IllegalStateException(
"You can't mix @Cdi(reusable=true) and @Cdi(reusable=false) in the same suite");
}
final SeContainerInitializer initializer = SeContainerInitializer.newInstance();
if (config.disableDiscovery())
{
initializer.disableDiscovery();
}
initializer.setClassLoader(Thread.currentThread().getContextClassLoader());
initializer.addBeanClasses(config.classes());
initializer.enableDecorators(config.decorators());
initializer.enableInterceptors(config.interceptors());
initializer.selectAlternatives(config.alternatives());
initializer.selectAlternativeStereotypes(config.alternativeStereotypes());
initializer.addPackages(
Stream.of(config.packages()).map(Class::getPackage).toArray(Package[]::new));
initializer.addPackages(true,
Stream.of(config.recursivePackages()).map(Class::getPackage).toArray(Package[]::new));
Stream.of(config.properties()).forEach(property -> initializer.addProperty(property.name(), property.value()));
onStop = Stream.of(config.onStarts())
.map(it ->
{
try
{
return it.getConstructor().newInstance();
}
catch (final InstantiationException | IllegalAccessException | NoSuchMethodException e)
{
throw new IllegalStateException(e);
}
catch (final InvocationTargetException e)
{
throw new IllegalStateException(e.getTargetException());
}
})
.map(Supplier::get)
.toArray(AutoCloseable[]::new);
SeContainer container = initializer.initialize();
if (reusable)
{
reusableContainer = container;
Runtime.getRuntime().addShutdownHook(new Thread(
() -> doClose(reusableContainer), getClass().getName() + "-shutdown"));
}
else
{
testInstanceContainer = container;
}
}
@Override
public void afterAll(final ExtensionContext extensionContext)
{
if (testInstanceContainer != null)
{
doClose(testInstanceContainer);
testInstanceContainer = null;
}
}
@Override
public void beforeEach(final ExtensionContext extensionContext)
{
final SeContainer container = getContainer();
if (container == null)
{
return;
}
extensionContext.getTestInstances().ifPresent(testInstances ->
{
testInstances.getAllInstances().stream().distinct().forEach(instance ->
{
final BeanManager manager = container.getBeanManager();
final AnnotatedType<?> annotatedType = manager.createAnnotatedType(instance.getClass());
final InjectionTarget injectionTarget = manager.createInjectionTarget(annotatedType);
final CreationalContext<Object> creationalContext = manager.createCreationalContext(null);
creationalContexts.add(creationalContext);
injectionTarget.inject(instance, creationalContext);
});
});
}
@Override
public void afterEach(final ExtensionContext extensionContext)
{
super.afterEach(extensionContext);
if (!creationalContexts.isEmpty())
{
creationalContexts.forEach(CreationalContext::release);
creationalContexts.clear();
}
}
private void doClose(final SeContainer container)
{
container.close();
Stream.of(onStop).forEach(it ->
{
try
{
it.close();
}
catch (final Exception e)
{
throw new IllegalStateException(e);
}
});
}
private SeContainer getContainer()
{
if (testInstanceContainer != null)
{
return testInstanceContainer;
}
else
{
return reusableContainer;
}
}
}
|
package com.fitchle.modelconvertercli;
import com.fitchle.modelconverterapi.ModelConverter;
import java.io.File;
import java.io.IOException;
public final class Main {
public static void main(String[] args) throws IOException {
if (args.length < 2) {
System.out.println(ConsoleColor.TEXT_WHITE.getUnicode() + "-----------------------------------------------");
System.out.println(ConsoleColor.TEXT_RED.getUnicode() + "[FITCHLE-MODEL-CONVERTER/ERROR] " + ConsoleColor.TEXT_WHITE.getUnicode() + "Wrong argument usage!");
System.out.println(ConsoleColor.TEXT_GREEN.getUnicode() + "[FITCHLE-MODEL-CONVERTER/INFO] " + ConsoleColor.TEXT_WHITE.getUnicode() + "Example Usage: java -jar [<jarfile>] [<*.json>] [<texture_location>] [animation_location]");
System.out.println(ConsoleColor.TEXT_WHITE.getUnicode() + "-----------------------------------------------");
return;
}
File f = new File(args[0]);
if (!f.exists()) {
System.out.println("File Not Found!");
return;
}
ModelConverter converter = new ModelConverter(f, args[1]);
if (args.length == 3) {
converter = new ModelConverter(f, args[1], new File(args[2]));
}
converter.convertAndSave();
System.out.println(ConsoleColor.TEXT_WHITE.getUnicode() + "-----------------------------------------------");
System.out.println(ConsoleColor.TEXT_GREEN.getUnicode() + "[FITCHLE-MODEL-CONVERTER/INFO] " + ConsoleColor.TEXT_WHITE.getUnicode() + "Converted succesfully!");
System.out.println(ConsoleColor.TEXT_GREEN.getUnicode() + "[FITCHLE-MODEL-CONVERTER/INFO] " + ConsoleColor.TEXT_WHITE.getUnicode() + "File Location: " + f.getAbsolutePath().replace(".json", "") + ".benchionmodel");
System.out.println(ConsoleColor.TEXT_WHITE.getUnicode() + "-----------------------------------------------");
}
}
|
Production of Bio-Resistant Wood Materials through the Modification of Wood by Boron-Nitrogen Compounds Modifying of the surface of pine wood with aqueous solutions boron-nitrogen compounds was empirically found to provide a 100% biological stability of wood for at least 20 years. Durability of the protective effect of the modifiers developed is due to the formation of hydrolytically stable compounds on the surface of the wood. |
#include "test/test.h"
#include "src/components/buffer.c"
#include "src/components/channel.c"
#include "src/components/input.c"
#include "src/components/mode.c"
#include "src/components/server.c"
#include "src/components/user.c"
#include "src/handlers/irc_recv.c"
#include "src/utils/utils.c"
static char chan_buf[1024];
static char line_buf[1024];
static char send_buf[1024];
/* Mock state.c */
void
newlinef(struct channel *c, enum buffer_line_t t, const char *f, const char *fmt, ...)
{
va_list ap;
int r1;
int r2;
UNUSED(f);
UNUSED(t);
va_start(ap, fmt);
r1 = snprintf(chan_buf, sizeof(chan_buf), "%s", c->name);
r2 = vsnprintf(line_buf, sizeof(line_buf), fmt, ap);
va_end(ap);
assert_gt(r1, 0);
assert_gt(r2, 0);
}
void
newline(struct channel *c, enum buffer_line_t t, const char *f, const char *fmt)
{
int r1;
int r2;
UNUSED(f);
UNUSED(t);
r1 = snprintf(chan_buf, sizeof(chan_buf), "%s", c->name);
r2 = snprintf(line_buf, sizeof(line_buf), "%s", fmt);
assert_gt(r1, 0);
assert_gt(r2, 0);
}
struct channel* current_channel(void) { return NULL; }
void channel_set_current(struct channel *c) { UNUSED(c); }
/* Mock io.c */
const char*
io_err(int err)
{
UNUSED(err);
return "err";
}
int
io_sendf(struct connection *c, const char *fmt, ...)
{
va_list ap;
UNUSED(c);
va_start(ap, fmt);
assert_gt(vsnprintf(send_buf, sizeof(send_buf), fmt, ap), 0);
va_end(ap);
return 0;
}
int
io_dx(struct connection *c)
{
UNUSED(c);
return 0;
}
/* Mock draw.c */
void draw_all(void) { ; }
void draw_bell(void) { ; }
void draw_nav(void) { ; }
void draw_status(void) { ; }
/* Mock irc_ctcp.c */
int
ctcp_request(struct server *s, const char *f, const char *t, char *m)
{
UNUSED(s);
UNUSED(f);
UNUSED(t);
UNUSED(m);
return 0;
}
int
ctcp_response(struct server *s, const char *f, const char *t, char *m)
{
UNUSED(s);
UNUSED(f);
UNUSED(t);
UNUSED(m);
return 0;
}
static void
test_STUB(void)
{
; /* TODO */
}
int
main(void)
{
struct testcase tests[] = {
TESTCASE(test_STUB)
};
return run_tests(tests);
}
|
Dissection of open chromatin domain formation by site-specific recombination in Drosophila ABSTRACT Drosophila polytene interphase chromosomes provide an ideal test system to study the rules that define the structure of chromatin domains. We established a transgenic condensed chromatin domain cassette for the insertion of large pieces of DNA by site-specific recombination. Insertion of this cassette into open chromatin generated a condensed domain, visible as an extra band on polytene chromosomes. Site-specific recombination of DNA sequence variants into this ectopic band allowed us to compare their capacity for open chromatin formation by cytogenetic methods. We demonstrate that the 61C7-8 interband DNA maintains its open chromatin conformation and epigenetic state at an ectopic position. By deletion analysis, we mapped the sequences essential for open chromatin formation to a 490-bp fragment in the proximal part of the 17-kb interband sequence. This fragment overlaps binding sites for the chromatin protein Chriz (also known as Chro), the histone kinase Jil-1 and the boundary element protein CP190. It also overlaps a promoter region that locates between the Rev1 and Med30 transcription units. |
/*
* disptbl
* Display the current fdisk table; determine percentage
* of the disk used for each partition.
*/
static void
disptbl(void)
{
int i;
unsigned int startcyl, endcyl, length, percent, remainder;
char *stat, *type;
int is_pmbr = 0;
if ((heads == 0) || (sectors == 0)) {
(void) printf("WARNING: critical disk geometry information"
" missing!\n");
(void) printf("\theads = %d, sectors = %d\n", heads, sectors);
exit(1);
}
(void) printf(HOME);
(void) printf(T_LINE);
(void) printf(" Total disk size is %d cylinders\n", Numcyl);
(void) printf(" Cylinder size is %d (%d byte) blocks\n\n",
heads * sectors, sectsiz);
(void) printf(
" Cylinders\n");
(void) printf(
" Partition Status Type Start End Length"
" %%\n");
(void) printf(
" ========= ====== ============ ===== === ======"
" ===");
for (i = 0; i < FD_NUMPART; i++) {
if (Table[i].systid == UNUSED) {
continue;
}
if (Table[i].bootid == ACTIVE)
stat = Actvstr;
else
stat = NAstr;
switch (Table[i].systid) {
case UNIXOS:
type = Ustr;
break;
case SUNIXOS:
type = SUstr;
#ifdef i386
if (fdisk_is_linux_swap(epp, Table[i].relsect,
NULL) == 0)
type = LINSWAPstr;
#endif
break;
case SUNIXOS2:
type = SU2str;
break;
case X86BOOT:
type = X86str;
break;
case DOSOS12:
type = Dstr;
break;
case DOSOS16:
type = D16str;
break;
case EXTDOS:
type = EDstr;
break;
case DOSDATA:
type = DDstr;
break;
case DOSHUGE:
type = DBstr;
break;
case PCIXOS:
type = PCstr;
break;
case DIAGPART:
type = DIAGstr;
break;
case FDISK_IFS:
type = IFSstr;
break;
case FDISK_AIXBOOT:
type = AIXstr;
break;
case FDISK_AIXDATA:
type = AIXDstr;
break;
case FDISK_OS2BOOT:
type = OS2str;
break;
case FDISK_WINDOWS:
type = WINstr;
break;
case FDISK_EXT_WIN:
type = EWINstr;
break;
case FDISK_FAT95:
type = FAT95str;
break;
case FDISK_EXTLBA:
type = EXTLstr;
break;
case FDISK_LINUX:
type = LINUXstr;
break;
case FDISK_CPM:
type = CPMstr;
break;
case FDISK_NOVELL2:
type = NOV2str;
break;
case FDISK_NOVELL3:
type = NOVstr;
break;
case FDISK_QNX4:
type = QNXstr;
break;
case FDISK_QNX42:
type = QNX2str;
break;
case FDISK_QNX43:
type = QNX3str;
break;
case FDISK_LINUXNAT:
type = LINNATstr;
break;
case FDISK_NTFSVOL1:
type = NTFSVOL1str;
break;
case FDISK_NTFSVOL2:
type = NTFSVOL2str;
break;
case FDISK_BSD:
type = BSDstr;
break;
case FDISK_NEXTSTEP:
type = NEXTSTEPstr;
break;
case FDISK_BSDIFS:
type = BSDIFSstr;
break;
case FDISK_BSDISWAP:
type = BSDISWAPstr;
break;
case EFI_PMBR:
type = EFIstr;
if (LE_32(Table[i].numsect) == DK_MAX_2TB)
is_pmbr = 1;
break;
default:
type = Ostr;
break;
}
startcyl = LE_32(Table[i].relsect) /
(unsigned long)(heads * sectors);
if (LE_32(Table[i].numsect) == DK_MAX_2TB) {
endcyl = Numcyl - 1;
length = endcyl - startcyl + 1;
} else {
length = LE_32(Table[i].numsect) /
(unsigned long)(heads * sectors);
if (LE_32(Table[i].numsect) %
(unsigned long)(heads * sectors))
length++;
endcyl = startcyl + length - 1;
}
percent = length * 100 / Numcyl_usable;
if ((remainder = (length * 100 % Numcyl_usable)) != 0) {
if ((remainder * 100 / Numcyl_usable) > 50) {
percent++;
}
}
if (percent > 100)
percent = 100;
(void) printf(
"\n %d %s %-12.12s %4d %4d %4d"
" %3d",
i + 1, stat, type, startcyl, endcyl, length, percent);
}
if (nopartdefined()) {
(void) printf(W_LINE);
(void) printf("WARNING: no partitions are defined!");
} else {
(void) printf(W_LINE);
if (!is_pmbr && (dev_capacity > DK_MAX_2TB))
(void) printf("WARNING: Disk is larger than 2 TB. "
"Upper limit is 2 TB for non-EFI partition ID\n");
}
} |
1. Field of the Invention
The present invention relates to a semiconductor device configured by mounting a wiring board on a semiconductor chip, and a method for manufacturing the semiconductor device.
2. Description of the Related Art
Japanese Patent Laid-Open No. 9-260536 discloses a semiconductor device with a configuration in which a flexible wiring board is disposed on a principal surface of a semiconductor chip using an intervening elastomer placed between the flexible wiring board and the semiconductor chip, and an electrode pad of the semiconductor chip, and a lead part of wiring disposed in an aperture part of the wiring board are electrically connected. An external terminal is provided in the other surface of the wiring board. Sealing material made of insulating resin covers an electrode pad of the semiconductor chip, which is disposed in the aperture part of the wiring board, and covers the lead part.
Such a semiconductor device is configured so that the electrode pad of the semiconductor chip and the lead part of the wiring board are electrically connected in the aperture part which is provided in the wiring board. Thus, the semiconductor device is configured so that the external terminal can not be disposed around just below the electrode pad of the semiconductor chip.
Year by year, an operation rate of the semiconductor device has been increased. In the semiconductor device, since the distance from the electrode pad of the semiconductor chip, for example, a wiring distance becomes longer, the operation speed may be lowered. Thus, for the semiconductor devices, there is a requirement shorten substantially the wiring distance to prevent the operation speed from being lowered, and to obtain favorable electrical characteristics.
As described above, since it is difficult to dispose the external terminal around just below the electrode pad of the semiconductor chip, the number of the external terminals may be also decreased which are disposed in an area of the wiring board on which a semiconductor chip is mounted. In the semiconductor device, there is such a trend that the number of the external terminals is increased, and it becomes necessary to dispose the external terminals outside of the area of the wiring board on which the semiconductor chip is mounted, so that an area of the wiring board may become larger. If the area of the wiring board becomes larger, a package size of the semiconductor device may become larger. This is a problem. In addition, if the area of the wiring board becomes larger, the number of the wiring boards that can be manufactured in one process is decreased during the wiring board manufacturing process, and the manufacturing cost of the wiring board may be increased. This is also a problem.
The above semiconductor device related to the present invention is configured so that the semiconductor chip is mounted on the wiring board using an intervening elastomer (elastic material) placed between the flexible wiring board and the semiconductor chip to improve the reliability when the semiconductor device is mounted on a printed wiring board such as a motherboard, so-called, in the case of the secondary mounting. By mounting the semiconductor chip on the wiring board using an intervening elastomer placed between the flexible wiring board and the semiconductor chip, it is possible to reduce stress because of a difference between the thermal expansion coefficients, and to improve the reliability in the case of the secondary mounting. However, since elastomer is relatively expensive material, the manufacturing cost of the semiconductor device may be increased.
In the semiconductor device related to the present invention, the semiconductor chip is mounted on the flexible wiring board by using the TAB (Tape Automated Bonding) method. Thus, in this semiconductor device, because of the influence caused by the size tolerance or the roll of sheet material configured in the wiring board, there exists such a problem in which the required mounting accuracy can not be obtained or a problem in which expensive mounting equipment may become necessary. Since the pitch of the electrode pad, the wiring and the like of the semiconductor device trends to be narrower, it becomes also necessary to improve mounting accuracy. |
//use this to get the matrix for stuff
ModelViewMatrix TransformComponent::CreateTransformMatrix() {
ModelViewMatrix m_modelViewTransform;
m_modelViewTransform.SetTranslation3D(m_position);
m_modelViewTransform.SetScale(m_scale);
m_modelViewTransform.SetRotationDegrees3D(m_orientation);
return m_modelViewTransform;
} |
Some aspects of biology and fishery of walleye pollock Theragra chalcogramma in the southwestern Chukchi Sea relative to the size and age structure Catch distribution and size-age structure of walleye pollock in the Chukchi Sea are considered on the data obtained in surveys conducted by TINRO in 20182020. The age of pollock was determined by otoliths. Two age groups were presented in the catches: the first group of juveniles and 1-year old fish and the second group of 722-year old fish, mostly 815 years old (90 %). The fish of 36 year old were absent in the catches. This age structure suggests that the stock is formed by the fish migrated from the northern Bering Sea. However, the backward migration is doubtful; the pollock, once migrated to the Chukchi Sea, remain in this new habitat, as could be seen from the age-length dependence for a part of the stock distinguished by lower growth rate because of dwelling in severe conditions of this area. Aggregations of the fast-growing (just migrated from the Bering Sea) and slow-growing (local residents) pollock had different distribution patterns in the surveyed area in the southwestern Chukchi Sea. The fast-growing allochthonous pollock distributed widely, including the seaward waters, whereas the resident pollock preferred the coastal waters. The walleye pollock fishery has started in the southern coastal area of the Chukchi Sea in 2021, so the resident stock is exploited mainly. |
1. Field of the Invention
The present invention relates to a semiconductor integrated circuit device and, more particularly, to a semiconductor integrated circuit device suitably used for diagnosing its internal logic circuit.
2. Description of the Related Art
With the increasing needs for high performance and high integration density of semiconductor integrated circuit devices, a great difficulty has been found in formation of test data required for determination of functions of internal logic circuits in manufactured semiconductor devices and for analysis of defective parts thereof. A scanning technique for internal logic circuit diagnosis of semiconductor integrated circuit devices is known as a promising technique for performing logic diagnostic tests with a small number of input/output terminal pins used in devices. According to this test technique, when a semiconductor device under test is failed and a logically abnormal operation is caused, in order to analyze its cause, the device is normally operated after the state of its internal logic circuit is externally and directly set, and then the state of the internal logic circuit after the operation is detected, thereby performing a logic diagnostic test.
According to such a conventional internal logic circuit diagnostic test technique, however, conflicting problems are posed, i.e., it is very difficult to effectively perform an internal logic diagnosis while minimizing the number of required input/output pins of a device. Especially, when an internal logic circuit arrangement of a semiconductor device under test is divided into several circuit units and only a desired circuit unit or units selected from these units are subjected to internal circuit diagnostic tests, input/output pins must be arranged, basically, in each circuit unit in order to meet this requirement. Otherwise, test efficiency or test speed is degraded. If all the circuit units are series-connected between the respective input and output pins, the number of pins in the device can be reliably minimized. However, a test process for designating a desired unit among all the circuit units becomes complicated and takes considerable time. On the contrary, if input/output pins are arranged in every circuit unit, a process of selecting or designating a desired circuit unit is simplified. In this case, however, the total number of input/output pins of the device is undesirably increased. |
This application claims priority from Korean Patent Application No. 2003-84961, filed on Nov. 27, 2003, in the Korean Intellectual Property Office, the disclosure of which is incorporated herein in its entirety by reference.
1. Field of the Invention
The present invention relates to a semiconductor memory device and a method of manufacturing the same, more particularly, to a semiconductor memory device with storage electrodes and a method of manufacturing the same.
2. Description of the Related Art
As the integration density of semiconductor devices has increased, the design rule of the semiconductor devices has reduced. More specially, pitches between electrodes in a capacitor of a memory device such as dynamic random access memory (DRAM), have gradually been reduced for rapid advancement of high integration and scaling of the memory device. Unfortunately, reducing the pitches to meet design rules is undesirable because it also reduces capacitance and semiconductor memory devices require a high capacitance in order to operate smoothly without problems like soft errors.
There are options to increase capacitance. Enlarging the surface area of a storage electrode (a capacitor lower electrode), decreasing the thickness of a dielectric layer, and using a dielectric layer with a high dielectric constant are methods of increasing the capacitance of the capacitor. Among these methods, enlarging the surface area of the storage electrode is most commonly used, including maximizing the height of a cylindrical capacitor.
A storage electrode with a cylindrical shape has been manufactured with the following method. First, a mold oxide layer with the same height as a predetermined height of a storage electrode may be formed on the upper surface of a semiconductor substrate whereon a semiconductor circuit, for example, a MOS transistor, is formed. A photoresist pattern is formed on the upper surface of the mold oxide layer using a conventional photolithography process so that the predetermined region of the storage electrode is exposed. After the storage electrode region is defined by etching the mold oxide layer using the photoresist pattern, the photoresist pattern is removed. Then an electrode material is adhered on the patterned mold oxide layer and planarized, thereby exposing the surface of the mold oxide layer forming the storage electrode with a cylindrical shape.
The desire for highly-integrated semiconductor memory device has required capacitor height to increase significantly in order to secure the large capacitance. Therefore, the mold oxide layer defining the height of the storage electrode has been formed with a thickness of 1.5 to 2 μm. As will be explained, this increased thickness has created new challenges.
Parts of the photoresist pattern are eliminated by an etching gas used for etching the mold oxide layer because the photoresist pattern has a low etch selectivity with respect to the mold oxide layer. However, when the thickness of the mold oxide layer is increased, the photoresist pattern can become deformed. Therefore, the shape of the photoresist pattern is changed, and if the mold oxide layer is etched using the photoresist pattern, as described above, the shape of the storage electrode region is also changed. Such a phenomenon is referred to as striation. Therefore, a desirable form of the storage electrode region has been difficult to secure.
To prevent defects like the striation, a hard mask layer has been conventionally used instead of the photoresist pattern. Referring to FIGS. 1 and 2, a method of forming the storage electrode using the hard mask layer will now be described.
Referring to FIG. 1, a mold oxide layer 20 is formed on the upper surface of a semiconductor substrate 10 where a circuit device (not shown) is formed. A polysilicon layer 30, to be used as a mask layer, is adhered on the upper surface of the mold oxide layer 20, and a silicon nitride layer 40, to be used as an anti-reflection layer, is adhered on the upper surface of the polysilicon layer 30. A photoresist pattern (not shown) defining a storage electrode, is formed on the upper surface of the silicon nitride layer 40. The silicon nitride layer 40 and the polysilicon layer 30 are then etched using the photoresist pattern as an etch mask, and a hard mask pattern 50 is formed. Next, the photoresist pattern is removed.
Referring to FIG. 2, the mold oxide layer 20 is then dry etched using the hard mask pattern 50 as an etch mask, thereby forming a storage electrode region 60. Then, a conductive layer is adhered in the storage electrode region 60 and on the surface of the mold oxide layer 20. Next, the conductive layer is planarized to form a storage electrode 70 in the storage electrode region 60.
However, when the storage electrode region is formed using the hard mask pattern including the polysilicon layer 30 and the silicon nitride layer 40, a curved surface A of the sidewalls of the mold oxide defining the storage electrode region 60 may occur.
The following describes the cause of the curved surface A.
Generally, when the photoresist pattern is used as the mask, the etching gas for etching the mold oxide layer 20, which is a fluorocarbon compound, reacts with elements of the photoresist pattern, generating etching residual products, or polymers, on sidewalls of the storage electrode region 60. Etching residual products remaining on the sidewalls of the storage electrode region 60 may protect the sidewalls of the storage electrode region 60, even though the etching gas is ion scattered an angle to the sidewalls.
However, the hard mask pattern 50 including the polysilicon layer 30 and the silicon nitride layer 40 hardly react with the etching gas that is a fluorocarbon compound, thereby etching residual products on the sidewalls of the storage electrode region 60 are hardly generated. Therefore, when the etching gas is ion scattered an angle to the sidewalls, portions of the sidewalls of the storage electrode region 60 are etched (removed), the curved surfaces A occur as shown in FIGS. 2 and 3.
If the storage electrode 70 is formed with the curved surface A in the storage electrode region 60, and the mold oxide layer 20 is removed by wet cleaning, the resultant storage electrode 70 collapses and contacts an adjacent storage electrode 70 because of the surface tension of the storage electrode 70. Thus, leaning and bit fails of the storage electrode 70 can occur, causing the resulting device to function improperly.
Embodiments of the invention address these and other limitations in the prior art. |
Performance of An Multicast-enabled Optical Packet Switch Using a Prioritized Packet Scheduling Scheme This paper evaluates and analyzes the traffic performance of our recently proposed multicast-enabled optical packet switch under a hybrid traffic model. A prioritized packet scheduling algorithm is proposed for the output contention resolution of the switch. The simulation results show that the multicast packet loss probability can be greatly improved by slightly increasing the number of multicast modules in conjunction with the proposed packet scheduling. For a given effective traffic load, the improvement on the total packet loss probability by increasing the number of multicast modules is related to the multicast traffic proportion. It is also shown that the average packet delay for the switch is little affected by increasing the number of multicast modules since the multicast packets are given higher priority than the unicast packets. |
<filename>app/src/main/java/com/example/jmf/timetest/utils/SizeUtils.java
package com.example.jmf.timetest.utils;
import android.content.Context;
/**
* Created by 贾梦飞 on 2018/7/11 10:40.
* QQ:821176301
* 微信：j821176301
* desc：
*/
public class SizeUtils {
public static float Dp2Px(Context context, float value) {
float scale = context.getResources().getDisplayMetrics().density;
return value * scale ;
}
public static float Sp2Px(Context context , float value){
float scale = context.getResources().getDisplayMetrics().density;
return value * scale;
}
}
|
'Shiloh' Star Blake Heron Dead at 35
'Shiloh' Star Blake Heron Dead at 35
EXCLUSIVE
9:07 PM P.T. -- Cops say Heron died of an apparent illicit substance overdose...First responders attempted to revive the actor with Narcan, but life saving measures were ineffective.
Blake Heron, the actor who played Marty Preston in the 1996 movie, "Shiloh," is dead ... TMZ has learned.
Law enforcement tells TMZ, Heron's girlfriend went to his L.A. area home Friday morning and found him dead. Paramedics worked on Heron for 40 minutes trying to revive him, to no avail. He was pronounced dead at the scene.
We're told Heron had been sick the last few days.
Blake had battled heroin and had just gotten out of rehab ... literally days ago.
We're told EMTs who responded did not find any illegal drugs. There were several prescriptions, but they were for the flu. Our sources also say there was no evidence he had consumed alcohol.
Along with starring in "Shiloh," Heron had supporting roles in films "We Were Soldiers" and "11:14." He was recently in a documentary called "A Thousand Junkies" which premiered at Tribeca Film Festival.
Heron was 35.
RIP |
Gliosarcoma of the posterior fossa with features of a malignant fibrous histiocytoma A rare case of gliosarcoma occurring in the posterior fossa of a 62yearold man is reported. Histologically, the tumor closely resembled that of a typical case of malignant fibrous histiocytoma (MFH). Such features have not been reported previously in gliosarcoma. The importance of using an immunoperoxidase preparation against the glial fibrillary acidic protein (GFAP) in diagnosing gliosarcoma is emphasized. Our case also lends support to the contention that MFHlike histologic features may occur in poorly differentiated neoplasms of diverse origins. |
<reponame>mronte/metaplex<filename>js/packages/web/src/contexts/meta/isMetadataPartOfStore.ts<gh_stars>1-10
import { Metadata, ParsedAccount } from '@oyster/common';
import { Store, WhitelistedCreator } from '../../models/metaplex';
export const isMetadataPartOfStore = (
m: ParsedAccount<Metadata>,
store: ParsedAccount<Store> | null,
whitelistedCreatorsByCreator: Record<
string,
ParsedAccount<WhitelistedCreator>
>,
useAll: boolean,
) => {
if (useAll) {
return true;
}
if (!m?.info?.data?.creators || !store?.info) {
return false;
}
return m.info.data.creators.some(
c =>
c.verified &&
(store.info.public ||
whitelistedCreatorsByCreator[c.address]?.info?.activated),
);
};
|
import { EntityRepository } from '@mikro-orm/core';
import { InjectRepository } from '@mikro-orm/nestjs';
import { HttpException, HttpStatus, Injectable, Logger } from '@nestjs/common';
import { ConfigService } from '@nestjs/config';
import { isString } from 'lodash';
import mkdirp from 'mkdirp';
import path from 'path';
import sharp from 'sharp';
import { Chapter } from 'src/entities/Chapter';
import { Page } from 'src/entities/Page';
import { Story } from 'src/entities/Story';
import { LongstripService } from '../longstrip/longstrip.service';
import { CreatePageDto } from './dto/create-page.dto';
import { ImageQueryDto, SharpFitType } from './dto/image-query.dto';
import { UpdatePageDto } from './dto/update-page.dto';
const createPath = (...parts: string[]) => path.join(...parts.filter((part) => isString(part)));
const createDirectoryPath = (...parts: string[]) =>
parts.filter((part) => isString(part)).join('/');
const createFilename = (filename: string, extension: string) => [filename, extension].join('.');
const createFullPath = (directoryPath: string, filename: string) =>
[directoryPath, filename].join('/');
@Injectable()
export class PagesService {
private readonly logger = new Logger(PagesService.name);
constructor(
private configService: ConfigService,
private readonly longstripService: LongstripService,
@InjectRepository(Page)
private readonly pageRepository: EntityRepository<Page>,
@InjectRepository(Chapter)
private readonly chapterRepository: EntityRepository<Chapter>,
@InjectRepository(Story)
private readonly storyRepository: EntityRepository<Story>,
) {}
async create(createPageDto: CreatePageDto, file: Express.Multer.File) {
const story = await this.storyRepository.findOneOrFail(createPageDto.storyUuid, ['mediaType']);
const chapter = await this.chapterRepository.findOne(createPageDto.chapterUuid);
// Create Folder if it does not exist
const filesRoot = this.configService.get<string>('filesRoot');
await mkdirp(createPath(filesRoot, story.title, chapter.title));
// Process longstrip for trimming filler
const imagesCoordinates = await this.longstripService.process(file);
// Create page
const pages = [];
if (imagesCoordinates.length === 1) {
const page = new Page(createPageDto.number);
const fullpath = createPath(
filesRoot,
story.title,
chapter.title,
createFilename(page.number, 'png'),
);
page.fullpath = fullpath;
page.filename = fullpath.split('/').slice(-1)[0];
page.story = story;
page.chapter = chapter;
try {
await sharp(file.buffer).toFile(page.fullpath);
pages.push(page);
} catch (err) {
this.logger.error(err);
}
} else {
const promises = imagesCoordinates.map(async (coordinate, index) => {
const page = new Page(`${createPageDto.number}_${index}`);
const fullpath = path.join(
filesRoot,
story.title,
chapter.title,
createFilename(`${page.number}_${index}`, 'png'),
);
page.fullpath = fullpath;
page.filename = fullpath.split('/').slice(-1)[0];
page.story = story;
page.chapter = chapter;
return sharp(file.buffer)
.extract(coordinate)
.toFile(page.fullpath)
.then(() => pages.push(page))
.catch((err) => this.logger.error(err));
});
await Promise.all(promises);
}
this.pageRepository.persistAndFlush(pages);
}
async findAll() {
return await this.pageRepository.findAll();
}
async findOne(uuid: string) {
const page = await this.pageRepository.findOne(uuid);
if (!page) {
throw new HttpException('Page not found', HttpStatus.NOT_FOUND);
}
return page;
}
async update(uuid: string, updatePageDto: UpdatePageDto) {
const page = await this.pageRepository.findOne(uuid);
if (!page) {
throw new HttpException('Page not found', HttpStatus.NOT_FOUND);
}
if (updatePageDto.number) {
page.number = updatePageDto.number;
}
if (updatePageDto.storyUuid) {
const story = await this.storyRepository.findOneOrFail(updatePageDto.storyUuid);
page.story = story;
}
if (updatePageDto.chapterUuid) {
const chapter = await this.chapterRepository.findOne(updatePageDto.chapterUuid);
page.chapter = chapter;
}
this.pageRepository.persistAndFlush(page);
return page;
}
async remove(uuid: string) {
return `This action removes a #${uuid} page`;
}
async getImage(uuid: string, imageQuery: ImageQueryDto) {
const page = await this.pageRepository.findOneOrFail(uuid);
const promise = sharp(page.fullpath);
if (imageQuery.width || imageQuery.height) {
promise.resize({
width: imageQuery.width,
height: imageQuery.height,
fit: imageQuery.fit || SharpFitType.CONTAIN,
});
}
const imageBuffer = await promise.toBuffer();
return imageBuffer;
}
}
|
Nutritional Deficiency After Sleeve Gastrectomy: A Comprehensive Literature Review Sleeve gastrectomy (SG) has been recognised as an effective procedure for the treatment of morbid obesity and associated comorbidities; however, the shortcomings of SG, such as staple line leak, haemorrhage, vomiting, and weight regain, have also been well-reported. An underestimated adverse effect of SG is nutritional deficiency (ND). While ND is a well-known complication of malabsorptive bariatric procedures, it can still occur after restrictive operations, including SG, yet its incidence and mechanism are still unclear. In an attempt to learn about the incidence and type of ND after SG we performed an organised literature search of electronic databases searching for articles that assessed the incidence and type of ND after SG. The median incidence of iron and zinc deficiency after SG was 8.8% and 18.8%, respectively. The majority of patients already had vitamin D deficiency preoperatively, with a median of 35.5% of patients still demonstrating vitamin D deficiency postoperatively. Comparing ND before and after SG, the incidence of iron and vitamin D deficiency declined postoperatively; in contrast, there was a tangible increase in the incidence of vitamin B1, B6, B12, and calcium deficiency. Vitamin B1 and B12 deficiencies were recorded in a median of 10.0% and 11.7% of patients, respectively, and were associated with neurologic manifestations in <1% of patients. Prevention of ND after SG requires proper recognition and correction of preoperative ND with immediate supplementation of trace elements and vitamins postoperatively, in addition to long follow-up. |
Sarah Tew/CNET
There are few things that come in as wide a variety of prices as cables and interconnects. HDMI cables, for instance, can run from $1 to over $1,000 for the same length. USB cables can be similarly cheap or high-end. Speaker cable is even more extreme, from pennies per foot, to hundreds of dollars for the same 12 inches.
We've written about cables a lot, and -- for the most part -- we recommend spending as little as possible.
But there are rare times where spending a bit more is actually a good idea. Here are when those occasional exceptions to the rule occur -- along with the 99 percent of the time they don't.
HDMI
For the most part, all HDMI cables work the same way. If you get an image, it is the exact image sent by the source (Blu-ray player, media streamer, cable box, or what have you). If the image doesn't flicker or have sparkles, it's perfect.
If you're sending 1080p (i.e. from a Blu-ray player) or UltraHD "4K" video, make sure you have an HDMI cable labeled "High Speed." There's no such thing as " 4K HDMI cables" or " HDMI 2.0" cables. High Speed cables cover all of that.
Despite millions of dollars in marketing money devoted to convincing people otherwise, it's not possible for different HDMI cables to deliver different video and audio quality. Expensive High Speed HDMI cables don't provide better resolution, better framerates, better color, or anything else. A High Speed HDMI cable is just a dumb tube. Get the cheapest dumb tube you can.
Sarah Tew/CNET
However, there are some cases where spending a bit more makes sense. Active cables, such as those that use Redmere technology, have chips built into them that help boost the signal. (They siphon a bit of power from the connected devices to power the chip.) As a result, they make it far more likely that you'll get a signal over long-distance runs. We're talking 20 feet (6 meters) or more. Many times, depending on the display (TV or projector) and/or the source, a cheap passive cable will work fine. Other times, it won't. There's no way to tell until you try it. Thicker gauge HDMI cables may also do the trick, or you may need an active cable.
Occasionally you might want thinner cables, and again, active cables allow that, too. Plugs at angles can place less stress on the connection if you use a thinner cable. And if you're doing an in-wall installation be sure to use cables rated for in-wall use.
But, to repeat: no expensive HDMI cable will make your TV's image look better, unless your previous HDMI cable was faulty or otherwise massively messed-up. If that's the case, replace it with a cheap one.
Sarah Tew/CNET
USB (and Lightning)
It seems the cable manufacturers, finding that you, dear readers, are too smart to buy their mumbo-jumbo about HDMI cables, have moved on to fleecing audiophiles on USB cables. Yep, USB cables. There are even reviews about how, after upgrading to a $1,000-plus USB cable, the sound on their USB Digital Audio Converter (DAC) "came alive" or something. Ahhh, expectation bias.
I'm also including Lightning because they're effectively just USB cables, with a fancy proprietary Apple nubbin at the end.
As far as the data going across it, USB is also a dumb tube. It won't improve video or audio quality.
The exception is with USB cables used to charge devices. Not all USB cables can charge devices at the same rate. I've actually found this, anecdotally, and Wirecutter did some extensive testing and found the same thing.
Among different USB cables, some will allow more current to make it from the charger to the device. Better-made cables can pass more amps (a measure of electric current) than poorly made cables. So if you want to charge your devices as fast as your charger and device allow, make sure you get a decent USB cable. What's decent? That Wirecutter test liked a $1.23 Monoprice cable best.
Over time, power throughput can wane. If you crumple up your cables, the minuscule wires inside can get damaged, reducing current flow. I've had some cheap one that lasted, and I've had some expensive ones that didn't. Keep in mind, I'm a digital nomad, so my cables probably get more abuse than most.
If there's something wrong with your USB cable, or you're trying to pass more data than that cable can handle, you can get dropouts or pops in the audio when using a USB DAC. A different, working, cheap cable is all you need.
But, to repeat: an expensive USB cable isn't going to make your audio sound better, your pictures look better, or your printouts look sharper.
The Cable Company
Speaker cables
Some audiophiles will swear up and down that expensive speaker cables radically change the sound of audio systems, really "opening up" the music, offering "improved clarity," letting them "see God," blah blah blah. For hundreds of dollars a foot, I'd expect it to also make a solid cup of coffee and clean my house when I'm away.
In the case of speaker cable, however, there's actually science and objective testing to back up a little of the notion that cable quality affects sound quality. The speaker, receiver/amplifier, and cable all create an electrical circuit. Changing the resistance and capacitance of the cable can slightly change how the amplifier and speakers interact. I've done blind A/B testing that proves this, and audio guru Brent Butterworth has done objective tests of a wide range of speaker cables that reveal subtle audible differences.
CNET audio reviewer Steve Guttenberg says speaker cables are important. "I use Analysis Plus, AudioQuest, XLO, and Zu Audio cables in my home system," he writes.
Does this mean you should spend more on speaker cables? Not really. Which cables offer the "best" sound for your system (and to your ears) is impossible to predict and has nothing to do with price. An expensive cable might sound worse on your system than cheap cable. Or it might sound better.
The important thing to remember is that even if it does sound better, it's such a minuscule improvement that pretty much anything else you can do will have a greater effect on the sound. Moving the speakers, for example, or getting a different DAC, or a different receiver. Heck, even getting a bookcase and some curtains will do more to affect the sound than new speaker cable.
This is a different scenario from USB and HDMI. Speaker cables are analog, USB and HDMI (and most of the other cables you use today) are digital, and do not work the same way as analog cables. In essence, digital cables only use electricity as a way to transmit 1s and 0s, while analog cables use it to create a circuit that can affect audio and video quality (very slightly).
Optical cables
Most of what you'll be transmitting over optical cables is digital, namely audio in PCM (Pulse Code Modulation) or Dolby Digital format. All Dolby Digital decoders are designed to cut out completely if they don't get a perfect signal. If bits are missing or wrong, the decoder transmits silence before it risks sending something that might damage your speakers. So if you're getting a Dolby Digital signal, and it's not cutting out, your optical cable is fine.
If you're transmitting PCM, the audiophile answer is that different optical cables can cause different amounts of jitter. The reality is, the digital-to-analog converter in your gear has vastly more effect on the sound. Could a "better" optical cable result in audibly better PCM sound? Doubtful.
Ethernet
Category 6/6a cables have a more robust specification than Category 5/5e. There probably won't be much of a speed difference on your home network (Cat5 is still really fast), but the extra shielding can't hurt. Since Cat6 cables are only fractionally more expensive, there's no reason not to go with them.
As far as different Ethernet cables looking or sounding better with A/V gear... nope. If it works, it works.
James Martin/CNET
DVI and DisplayPort
The digital video portion of DVI is effectively the same as that of HDMI, so if you're running digital, and it works, then you're good to go. The same goes for DVI's replacement, DisplayPort.
Some DVI cables have an analog component, though I doubt many of you are using it. If you are, see VGA below.
VGA (RGB-15)
Not sure if anyone still uses these ancient cables, and even if you do, I'm not sure you can even find "good" ones. But since they're analog, in theory better-made cables might allow you to run higher-resolution images without problems.
But again, if you're using these you probably still have a CRT monitor, and if so, good on you. Party like it's 1999.
Power Cables
High-end power cables are seriously a thing. I'm not kidding. If you believe changing the power cable in your gear will improve the audio or video...I have an island I want to sell you.
In short (so to speak), power cables have no effect on audio, video or any other kind of fidelity.
Lifespan
There also isn't much sense to the idea of buying more expensive cables because they last longer. There's no proof of this, for one, and it doesn't make economic sense either. If a $2 cable lasts two years, you can replace it 10 times (20 years!) before a $20 cable makes sense. And chances are that $2 cable will last just as long, if not longer, than the $20 cable anyway.
Everything else
Obviously I've left out a few other types of cables, but this article has already turned into quite a tome so I'll just stop already. In the failed efforts of pith, I'll try to cover everything else with these overriding, if simplistic, pieces of advice:
If the cable transmits digital information, then with few exceptions, if it works, it works. Go cheap.
If the cable transmits analog information, then it's possible it might have some impact on the sound or video. However, such impact is likely exceptionally slight. Enough so that it you shouldn't spend much money on them.
Lastly, every cable article I've written has attracted its fair share of unbelievers: Anonymous posters claiming they've seen/heard differences and therefore expensive cables are awesome. Without links to blind A/B testing (as I've posted) or objective measurements (that I've also posted), take these assertions of magic with the skepticism they deserve.
Got a question for Geoff? First, check out all the other articles he's written on topics such as why all HDMI cables are the same, LED LCD vs. OLED vs. Plasma, why 4K TVs aren't worth it and more. Still have a question? Send him an email! He won't tell you what TV to buy, but he might use your letter in a future article. You can also send him a message on Twitter @TechWriterGeoff or Google+. |
/**
* Sequence of xy-value pairs that is iterable ascending in x. Once created, the
* x-values of a sequence are immutable. This class provides static operations
* to create instances of sequences that have both mutable and immutable
* y-values. All data supplied to these operations is defensively copied unless
* it is not necessary to do so. For instance, {@code *copyOf()} variants should
* be used where possible as x-values will never be replicated in memory.
*
* <p>Although this class is not final, it can not be subclassed. Mutable
* instances of this class are not thread-safe for operations that alter
* y-values.
*
* @author Peter Powers
*/
public abstract class XySequence implements Iterable<XyPoint> {
/**
* Create a new sequence with mutable y-values from the supplied value arrays.
* If the supplied y-value array is null, all y-values are initialized to 0.
*
* @param xs x-values to initialize sequence with
* @param ys y-values to initialize sequence with; may be null
* @return a mutable, {@code double[]}-backed sequence
* @throws NullPointerException if {@code xs} are null
* @throws IllegalArgumentException if {@code xs} and {@code ys} are not the
* same size
* @throws IllegalArgumentException if {@code xs} does not increase
* monotonically or contains repeated values
*/
public static XySequence create(double[] xs, double[] ys) {
return create(xs, ys, true);
}
/**
* Create a new, immutable sequence from the supplied value arrays. Unlike
* {@link #create(double[], double[])}, the supplied y-value array may not be
* null.
*
* @param xs x-values to initialize sequence with
* @param ys y-values to initialize sequence with
* @return an immutable, {@code double[]}-backed sequence
* @throws NullPointerException if {@code xs} or {@code ys} are null
* @throws IllegalArgumentException if {@code xs} and {@code ys} are not the
* same size
* @throws IllegalArgumentException if {@code xs} does not increase
* monotonically or contains repeated values
*/
public static XySequence createImmutable(double[] xs, double[] ys) {
return create(xs, checkNotNull(ys), false);
}
private static XySequence create(double[] xs, double[] ys, boolean mutable) {
return construct(
Arrays.copyOf(xs, xs.length),
(ys == null) ? new double[xs.length] : Arrays.copyOf(ys, ys.length),
mutable);
}
/**
* Create a new sequence with mutable y-values from the supplied value
* collections. If the y-value collection is null, all y-values are
* initialized to 0.
*
* @param xs x-values to initialize sequence with
* @param ys y-values to initialize sequence with; may be null
* @return a mutable, {@code double[]}-backed sequence
* @throws NullPointerException if {@code xs} are null
* @throws IllegalArgumentException if {@code xs} and {@code ys} are not the
* same size
* @throws IllegalArgumentException if {@code xs} does not increase
* monotonically or contains repeated values
*/
public static XySequence create(
Collection<? extends Number> xs,
Collection<? extends Number> ys) {
return create(xs, ys, true);
}
/**
* Create a new, immutable sequence from the supplied value collections.
* Unlike {@link #create(Collection, Collection)} , the supplied y-value
* collection may not be null.
*
* @param xs x-values to initialize sequence with
* @param ys y-values to initialize sequence with
* @return an immutable, {@code double[]}-backed sequence
* @throws NullPointerException if {@code xs} or {@code ys} are null
* @throws IllegalArgumentException if {@code xs} and {@code ys} are not the
* same size
* @throws IllegalArgumentException if {@code xs} does not increase
* monotonically or contains repeated values
*/
public static XySequence createImmutable(
Collection<? extends Number> xs,
Collection<? extends Number> ys) {
return create(xs, checkNotNull(ys), false);
}
private static XySequence create(
Collection<? extends Number> xs,
Collection<? extends Number> ys,
boolean mutable) {
return construct(
Doubles.toArray(xs),
(ys == null) ? new double[xs.size()] : Doubles.toArray(ys),
mutable);
}
private static XySequence construct(double[] xs, double[] ys, boolean mutable) {
checkArgument(xs.length > 0, "x-values may not be empty");
checkArgument(xs.length == ys.length, "x- and y-values are different sizes");
if (xs.length > 1) {
checkArgument(areMonotonic(true, true, xs), "x-values do not increase monotonically");
}
return mutable ? new MutableXySequence(xs, ys) : new ImmutableXySequence(xs, ys);
}
/**
* Create a mutable copy of the supplied {@code sequence}.
*
* @param sequence to copy
* @return a mutable copy of the supplied {@code sequence}
* @throws NullPointerException if the supplied {@code sequence} is null
*/
public static XySequence copyOf(XySequence sequence) {
return new MutableXySequence(checkNotNull(sequence), false);
}
/**
* Create a mutable copy of the supplied {@code sequence} with all y-values
* reset to zero.
*
* @param sequence to copy
* @return a mutable copy of the supplied {@code sequence}
* @throws NullPointerException if the supplied {@code sequence} is null
*/
public static XySequence emptyCopyOf(XySequence sequence) {
return new MutableXySequence(checkNotNull(sequence), true);
}
/**
* Create an immutable copy of the supplied {@code sequence}.
*
* @param sequence to copy
* @return an immutable copy of the supplied {@code sequence}
* @throws NullPointerException if the supplied {@code sequence} is null
*/
public static XySequence immutableCopyOf(XySequence sequence) {
return (sequence.getClass().equals(ImmutableXySequence.class)) ? sequence
: new ImmutableXySequence(sequence, false);
}
/**
* Create a resampled version of the supplied {@code sequence}. Method
* resamples via linear interpolation and does not extrapolate beyond the
* domain of the source {@code sequence}; y-values with x-values outside the
* domain of the source sequence are set to 0.
*
* @param sequence to resample
* @param xs resample values
* @return a resampled sequence
*/
@Deprecated
public static XySequence resampleTo(XySequence sequence, double[] xs) {
// NOTE TODO this will support mfd combining
checkNotNull(sequence);
checkArgument(checkNotNull(xs).length > 0);
double[] yResample = Interpolate.findY(sequence.xValues(), sequence.yValues(), xs);
// TODO disable extrapolation
if (true) {
throw new UnsupportedOperationException();
}
return XySequence.create(xs, yResample);
}
XySequence() {}
/**
* Returns the x-value at {@code index}.
* @param index to retrieve
* @return the x-value at {@code index}
* @throws IndexOutOfBoundsException if the index is out of range (
* {@code index < 0 || index >= size()})
*/
public abstract double x(int index);
abstract double xUnchecked(int index);
/**
* Returns the y-value at {@code index}.
* @param index to retrieve
* @return the y-value at {@code index}
* @throws IndexOutOfBoundsException if the index is out of range (
* {@code index < 0 || index >= size()})
*/
public abstract double y(int index);
abstract double yUnchecked(int index);
/**
* Sets the y-{@code value} at {@code index}.
* @param index of y-{@code value} to set.
* @param value to set
* @throws IndexOutOfBoundsException if the index is out of range (
* {@code index < 0 || index >= size()})
*/
@SuppressWarnings("unused")
public void set(int index, double value) {
throw new UnsupportedOperationException();
}
/**
* Returns the number or points in this sequence.
* @return the sequence size
*/
public abstract int size();
/**
* Returns an immutable {@code List} of the sequence x-values.
* @return the {@code List} of x-values
*/
public List<Double> xValues() {
return new X_List();
}
private final class X_List extends AbstractList<Double> implements RandomAccess {
@Override
public Double get(int index) {
return x(index);
}
@Override
public int size() {
return XySequence.this.size();
}
@Override
public Iterator<Double> iterator() {
return new Iterator<Double>() {
private final int size = size();
private int caret = 0;
@Override
public boolean hasNext() {
return caret < size;
}
@Override
public Double next() {
return xUnchecked(caret++);
}
@Override
public void remove() {
throw new UnsupportedOperationException();
}
};
}
}
/**
* Returns an immutable {@code List} of the sequence y-values.
* @return the {@code List} of y-values
*/
public List<Double> yValues() {
return new Y_List();
}
private final class Y_List extends AbstractList<Double> implements RandomAccess {
@Override
public Double get(int index) {
return y(index);
}
@Override
public int size() {
return XySequence.this.size();
}
@Override
public Iterator<Double> iterator() {
return new Iterator<Double>() {
private int caret = 0;
private final int size = size();
@Override
public boolean hasNext() {
return caret < size;
}
@Override
public Double next() {
return yUnchecked(caret++);
}
@Override
public void remove() {
throw new UnsupportedOperationException();
}
};
}
}
/**
* Returns an iterator over the {@link XyPoint}s in this sequence. For
* immutable implementations, the {@link XyPoint#set(double)} method of a
* returned point throws an {@code UnsupportedOperationException}.
*/
@Override
public Iterator<XyPoint> iterator() {
return new XyIterator(false);
}
class XyIterator implements Iterator<XyPoint> {
private final boolean mutable;
private final int size = size();
private int caret = 0;
XyIterator(boolean mutable) {
this.mutable = mutable;
}
@Override
public boolean hasNext() {
return caret < size;
}
@Override
public XyPoint next() {
return new Point(caret++, mutable);
}
@Override
public void remove() {
throw new UnsupportedOperationException();
}
}
/**
* The first {@link XyPoint} in this sequence.
*/
public XyPoint min() {
return new Point(0, false);
}
/**
* The last {@link XyPoint} in this sequence.
*/
public XyPoint max() {
return new Point(size() - 1, false);
}
class Point implements XyPoint {
final int index;
final boolean mutable;
Point(int index, boolean mutable) {
this.index = index;
this.mutable = mutable;
}
@Override
public double x() {
return XySequence.this.xUnchecked(index);
}
@Override
public double y() {
return XySequence.this.yUnchecked(index);
}
@Override
public void set(double y) {
if (mutable) {
XySequence.this.set(index, y);
return;
}
throw new UnsupportedOperationException();
}
@Override
public String toString() {
return "XyPoint: [" + x() + ", " + y() + "]";
}
}
/**
* Returns a readable string representation of this sequence.
*/
@Override
public String toString() {
return new StringBuilder(getClass().getSimpleName())
.append(":")
.append(NEWLINE)
.append(Joiner.on(NEWLINE).join(this))
.toString();
}
/**
* Add a {@code term} to the y-values of this sequence in place.
*
* @param term to add
* @return {@code this} sequence, for use inline
*/
@SuppressWarnings("unused")
public XySequence add(double term) {
throw new UnsupportedOperationException();
}
/**
* Add the supplied y-values to the y-values of this sequence in place.
*
* @param ys y-values to add
* @return {@code this} sequence, for use inline
*/
@SuppressWarnings("unused")
public XySequence add(double[] ys) {
throw new UnsupportedOperationException();
}
/**
* Add the y-values of a sequence to the y-values of this sequence in place.
*
* @param sequence to add
* @return {@code this} sequence, for use inline
* @throws IllegalArgumentException if
* {@code sequence.xValues() != this.xValues()}
*/
@SuppressWarnings("unused")
public XySequence add(XySequence sequence) {
throw new UnsupportedOperationException();
}
/**
* Multiply ({@code scale}) the y-values of this sequence in place.
*
* @param scale factor
* @return {@code this} sequence, for use inline
*/
@SuppressWarnings("unused")
public XySequence multiply(double scale) {
throw new UnsupportedOperationException();
}
/**
* Multiply the y-values of this sequence by the y-values of another sequence
* in place.
*
* @param sequence to multiply {@code this} sequence by
* @return {@code this} sequence, for use inline
* @throws IllegalArgumentException if
* {@code sequence.xValues() != this.xValues()}
*/
@SuppressWarnings("unused")
public XySequence multiply(XySequence sequence) {
throw new UnsupportedOperationException();
}
/**
* Sets the y-values of this sequence to their complement in place [
* {@code 1 - y}]. Assumes this is a probability function limited to the
* domain [0 1].
*
* @return {@code this} sequence, for use inline
*/
public XySequence complement() {
throw new UnsupportedOperationException();
}
/**
* Sets all y-values to 0.
*
* @return {@code this} sequence, for use inline
*/
public XySequence clear() {
throw new UnsupportedOperationException();
}
/**
* Returns {@code true} if all y-values are 0.0; {@code false} otherwise. a
*/
public abstract boolean isClear();
/**
* Returns a new, immutable sequence that has had all leading and trailing
* zero-valued points ({@code y = 0}) removed. Any zero-valued points in the
* middle of this sequence are ignored.
*
* @throws IllegalStateException if {@link #isClear() this.isClear()} as empty
* sequences are not permitted
*/
public abstract XySequence trim();
/**
* Transforms all y-values in place using the supplied {@link Function}.
*
* @param function for transform
* @return {@code this} sequence, for use inline
*/
@SuppressWarnings("unused")
public XySequence transform(Function<Double, Double> function) {
throw new UnsupportedOperationException();
}
/**
* Adds {@code this} sequence to any exisiting sequence for {@code key} in the
* supplied {@code map}. If {@code key} does not exist in the {@code map},
* method puts a mutable copy of {@code this} in the map.
*
* @param key for sequence to add
* @param map of sequences to add to
* @throws IllegalArgumentException if the x-values of added sequences to not
* match those of existing sequences
*/
public final <E extends Enum<E>> void addToMap(E key, Map<E, XySequence> map) {
if (map.containsKey(key)) {
map.get(key).add(this);
} else {
map.put(key, XySequence.copyOf(this));
}
}
} |
<gh_stars>0
/**
* Copyright (C) 2010-2015 Morgner UG (haftungsbeschränkt)
*
* This file is part of Structr <http://structr.org>.
*
* Structr is free software: you can redistribute it and/or modify
* it under the terms of the GNU General Public License as
* published by the Free Software Foundation, either version 3 of the
* License, or (at your option) any later version.
*
* Structr is distributed in the hope that it will be useful,
* but WITHOUT ANY WARRANTY; without even the implied warranty of
* MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the
* GNU General Public License for more details.
*
* You should have received a copy of the GNU General Public License
* along with Structr. If not, see <http://www.gnu.org/licenses/>.
*/
package org.structr.core;
import java.util.ArrayList;
import java.util.Collections;
import java.util.List;
/**
* Encapsulates the result of a query operation.
*
* @author <NAME>
* @author <NAME>
*/
public class Result<T extends GraphObject> {
public static final Result EMPTY_RESULT = new Result(Collections.EMPTY_LIST, 0, false, false);
private boolean isCollection = false;
private boolean isPrimitiveArray = false;
private boolean hasPartialContent = false;
private String propertyView = null;
private List<T> results = null;
private String searchString = null;
private String queryTime = null;
private String sortOrder = null;
private String sortKey = null;
private Integer resultCount = null;
private Integer pageCount = null;
private Integer pageSize = null;
private Integer page = null;
private GraphObject metaData = null;
public Result(final List<T> listResult, final Integer rawResultCount, final boolean isCollection, final boolean isPrimitiveArray) {
this.isCollection = isCollection;
this.isPrimitiveArray = isPrimitiveArray;
this.results = listResult;
this.resultCount = (rawResultCount != null ? rawResultCount : (results != null ? results.size() : 0));
}
public Result(T singleResult, final boolean isPrimitiveArray) {
this.isCollection = false;
this.isPrimitiveArray = isPrimitiveArray;
this.results = new ArrayList<>();
this.resultCount = singleResult != null ? 1 : 0;
if (singleResult != null) {
// add result
results.add(singleResult);
}
}
public T get(final int i) {
return results.get(i);
}
public boolean isEmpty() {
return results == null || results.isEmpty();
}
public List<T> getResults() {
return results;
}
public void setQueryTime(final String queryTime) {
this.queryTime = queryTime;
}
public String getQueryTime() {
return queryTime;
}
public String getSearchString() {
return searchString;
}
public void setSearchString(final String searchString) {
this.searchString = searchString;
}
public String getSortKey() {
return sortKey;
}
public void setSortKey(final String sortKey) {
this.sortKey = sortKey;
}
public Integer getRawResultCount() {
if (resultCount != null) {
return resultCount;
}
return size();
}
public void setRawResultCount(final Integer resultCount) {
this.resultCount = resultCount;
}
public Integer getPageCount() {
return pageCount;
}
public void setPageCount(final Integer pageCount) {
this.pageCount = pageCount;
}
public Integer getPage() {
return page;
}
public void setPage(final Integer page) {
this.page = page;
}
public String getSortOrder() {
return sortOrder;
}
public void setSortOrder(final String sortOrder) {
this.sortOrder = sortOrder;
}
public Integer getPageSize() {
return pageSize;
}
public void setPageSize(final Integer pageSize) {
this.pageSize = pageSize;
}
public String getPropertyView() {
return propertyView;
}
public void setPropertyView(final String propertyView) {
this.propertyView = propertyView;
}
public boolean isCollection() {
return isCollection;
}
public boolean isPrimitiveArray() {
return isPrimitiveArray;
}
public void setIsPrimitiveArray(final boolean isPrimitiveArray) {
this.isPrimitiveArray = isPrimitiveArray;
}
public void setIsCollection(final boolean isCollection) {
this.isCollection = isCollection;
}
public int size() {
return !isEmpty() ? results.size() : 0;
}
public void setHasPartialContent(boolean hasPartialContent) {
this.hasPartialContent = hasPartialContent;
}
public boolean hasPartialContent() {
return hasPartialContent;
}
public GraphObject getMetaData() {
return metaData;
}
public void setMetaData(GraphObject metaData) {
this.metaData = metaData;
}
}
|
Although Nathan Drake's story was wrapped up in Uncharted 4, Naughty Dog revealed at last year's PSX that it wasn't entirely done with the series' universe. Chloe Frazer, a fan-favorite treasure hunter that we last saw in Uncharted 3: Drake's Deception, now takes center stage with mercenary Nadine Ross by her side. Taking place six months to a year after the previous Uncharted, Chloe and Nadine team up in search of an ancient treasure in India. Much is different this time around, with a grittier and more grounded narrative, but many elements you've come to love in Uncharted will still be present.
Here are several ways Uncharted: The Lost Legacy changes things up with a new setting, more grounded storyline, bigger environments, and more.
A New Duo of Thieves
The series moves away from Nathan Drake for the first time, and the team saw room to explore this universe further with a pair of familiar faces: Chloe Frazer and Nadine Ross. Chloe is the playable protagonist, and the two must overcome their differences in order to achieve their goal. Chloe leads the way, and has moved up in the treasure hunting business, coming into her own and returning to India in search of a treasure called the Tusk of Ganesh. She enlists mercenary Nadine, who we met in Uncharted 4, because of her particular skill set. The conflict between the two, and how that relationship unfolds, is a big part of what The Lost Legacy is about.
A Personal Setting
Chloe is half Australian and half Indian, and we learn about her Indian roots in this stand-alone entry. "The setting of the game has a personal connection with [Chloe]'s background, and it adds like a certain depth to everything you’re doing in that environment. It has more meaning for her," Uncharted writer Josh Scherr says. In a short demo we saw during our trip to Naughty Dog, Chloe and Nadine approach a large waterfall sided with two grandiose elephant statues. It's clear that these monuments hold meaning to Chloe as Nadine makes a quip about how Chloe should take a photo for her father. The treasure the two search for is also significant to Chloe, and their journey ties into mystical stories relating to Hindu gods that were told to her as bedtime stories when she was young.
Bigger Environments
Uncharted 4's Madagascar was one of the larger locales in Uncharted 4, giving players more freedom. The Lost Legacy further expands these open environments, all the while telling a linear story. In The Lost Legacy, Chloe and Nadine travel to the Western Ghats, a rural mountain range in India they traverse by jeep. It's reminiscent of Madagascar in the way that there are different terrains of mud, water, and rocks, along with a stunning vista. A key difference is the Western Ghats is geographically larger than Madagascar, and the biggest environment the series has seen yet. "We have this really great location of these rural Western Ghats, that allows us to get a real, true sense of exploration kind of unlike anything we’ve done before where the level design isn’t directing you exactly where to go, and you’re free to explore, find things, and discover things," game director Kurt Margenau says.
Meet Antagonist Asav
A new Uncharted entry also means a new central enemy. In The Lost Legacy you'll meet Asav, a barrel-chested insurgent rebel leader who formerly worked for the government. He's unearthing treasures, artifacts, and murals that are culturally significant to the region, and has several reasons behind his actions. "He has history with the government, he feels left out in solving the conflicts the government solved at one point and he’s now a lone rebel trying to create war and profit from it," creative director Shaun Escayg says. Asav believes in his cause, but Naughty Dog reminds us that this is a world of thieves; everyone is looking out for themselves, and this can make for morally grey characters despite their motivations. It's also a small world of thieves – just like how Nadine and Sully happened to know each other, Nadine has a similar connection to Asav, who she has worked with in the past.
A Condensed Story
Because it is a stand-alone game, The Lost Legacy will be more condensed. It's longer than The Last of Us DLC Left Behind but shorter than Uncharted 4. While The Lost Legacy will still have those enormous set pieces and grandiose moments Uncharted is known for, it's still a smaller scale Uncharted experience. Naughty made it clear that this is a new game, and not an expansion of Uncharted 4. It was a way for the team to look at the series' universe from a new perspective. "This is something we can do completely independently while still in the same universe with the same characters, and exploring new relationships with them," Scherr says.
Gameplay Tweaks
The Lost Legacy will feature all the pillars of Uncharted, from rope swinging to puzzle-solving, but there are smaller changes worth noting. Stealth has been an option in several Uncharted entries, but Uncharted 4 built on this idea further with sections of tall grass and awareness meters for enemies. This comes back in The Lost Legacy, with even more stealth capabilities. For the first time, you can equip a silent pistol to kill foes from afar. As for combat, Chloe has a more martial arts vibe to her fighting moves, whereas Nathan was more of a brawler.
When working as a team, Chloe and Nadine are similar to Nathan and Sam. Nadine can mark enemies for you so you can spot them quicker, and she'll help you out in combat. If you don't want to fight, sometimes that's also an option. During the Western Ghats demo we saw, it was possible to evade conflict completely while in the jeep, by driving by and ignoring hostile areas. Furthermore, a lockpicking mini-game is introduced, which we briefly saw in action during the PSX demo where Chloe lockpicks a door. Several crates lying around will only open following this short minigame, where you rotate the lock and wait for your controller to vibrate.
To find out more about Uncharted: The Lost Legacy, check out our cover reveal here or click the banner below to peruse our growing hub of exclusive content. |
From the northwest corner to its southeast one, Daffin Park was celebrated Friday for its past and cheered for its newness with two additions intended to assure its ongoing success.
As afternoon commuters watched from passing cars, Alderwoman Mary Osborne, Alderman John Hall and other city officials tossed dirt with golden shovels to plant the last of 50 palmetto trees in the median on Victory Drive near Waters Avenue, the park's northwest corner.
The family of F. Reed Dulany donated the trees to honor their wife and mother, Susan Dulany, an environmentalist who championed tree preservation. She passed away in 2011.
Victory Drive's historic avenue of palms dates to 1919, when the first ones were planted to create a military memorial boulevard. Years later, as azaleas matured and bloomed, the 19-mile boulevard became an iconic image for the city. As transportation demands increased, Victory lost its luster. City officials, including Osborne, are determined to see that change and are working on a redevelopment plan.
Minutes later, the group swept around to the opposite corner, where dozens of dogs, their owners and other supporters helped Alderwoman Mary Ellen Sprague with a ribbon cutting for the Herty Pines Dog Park, the city's first canine play area.
She thanked residents who put more than 2,000 signatures to a petition started by TailsSpin co-owners Jusak Yang Bernard and Jeff Manley, telling the crowd, "City Hall does listen and this is an example."
"With it being close to Grayson stadium, I have to say this park is a home run," Manley said. "The dogs are playing, the people are talking. It's a great place to come and socialize."
True as that is for the dog park, it's also become increasingly true for all of Daffin.
After a 10-year effort, several million in budget allocations and some donations and advocacy from groups such as area Rotary Clubs and the Savannah Tree Foundation, Daffin is enjoying a revival, city officials and residents agree. The first step was repairing crumbled sidewalks around the perimeter. Then, along the southern edge, the city removed outdoor lighting and the baseball fields that had dominated the green space, said Joe Shearouse, the city's director of Public Facilities, Events and Services.
"It gave it that lawn effect, like Forsyth Park has," he said. "It made it easier for folks to come and do what they wanted."
It also gave the city more flexibility in how it could lay out playing fields. On any given weekend, the lawn area hosts rugby, flag football, soccer and other organized play. Shearouse hopes to complete a padded jogging path, add more lighting and develop a playground area for special needs children.
Keisha Barton grew up in Savannah and has noticed the improvements. She brings her 5-year-old, Naya, to run off some energy while she relaxes on a nearby bench.
"It has evolved," she said of the park. "It's a lot cleaner, greener and they allow you to have a lot more functions here."
Rebecca Halliman drives in from Wilmington Island to use the playgrounds.
"Even though Forsyth is supposed to be nicer, the toys here are funner," she said, mentioning the merry-go-round in particular.
Youthful pursuits aside, Halliman also believes parks are an important community service.
"Parks are one of the things that are still free," she said. "It's something families can do together. And in this economy, we need that." |
After its 7-5 loss to Kent State tonight, Texas must now win three consecutive games to come out alive in the Austin Regional. The Longhorns will play Texas State Saturday at 1 p.m. and if they win, will face Kent State a few hours later, at 6:30 p.m. If they come out on top in both of those games, they’d play Kent State on Monday for the regional championship.
“It’s an uphill battle. Texas State probably doesn’t have the pitching to get by in the morning game against Texas. For the Longhorns it’ll be interesting to see whether they can build off what they did in the final inning tonight (three runs in the ninth)."
"David Starn, their number three pitcher is probably as good as a one or two guy. The big key for the Longhorns is to get off to a hot start offensively because they can’t let Starn get into a groove."
"They’re a pretty solid club. It doesn’t surprise me that they’re doing well. People expected them to do well in this regional."
"On the surface, it’s probably the second or third weakest regional. Texas State was a weak two, obviously not a good four-seed here (Princeton), but Kent State is proving that there’s at least one worthy team in this thing." |
import java.time.LocalDate;
import java.time.format.DateTimeFormatter;
import java.util.Scanner;
public class ThousandDaysAfterBirth {
public static void main(String[] args) {
Scanner console = new Scanner(System.in);
DateTimeFormatter formatter = DateTimeFormatter.ofPattern("dd-MM-yyyy");
String text = console.nextLine();
LocalDate parsedDate = LocalDate.parse(text, formatter);
LocalDate after1K = parsedDate.plusDays(999);
System.out.println(after1K.format(formatter));
}
}
|
Global value chain, industrial agglomeration and innovation performance in developing countries: insights from Chinas manufacturing industries ABSTRACT Extant research about global value chains (GVCs) has focused on its economic effects, while the innovation effects of GVCs remain understudied, especially for developing countries. This study explores the effect of GVC involvement along two dimensions GVC participation and GVC position on innovation performance in Chinas manufacturing industries. We also investigate the interaction effects of GVC involvement and industrial agglomeration on innovation performance. With a sample of 15 manufacturing industries in China from 20052015, we find that Chinas manufacturing industries have substantial participation in GVCs, but they are located mainly at low positions in GVCs. In addition, the study shows strong evidence that GVC participation has an inverted U-shaped effect on innovation performance, whereas the effect of GVC position on innovation performance is positive. Finally, we find that the interaction effect of GVC position and industrial agglomeration positively influence innovation performance, while the interaction effect of GVC participation and industrial agglomeration is negative. These empirical findings have important theoretical and policy implications. |
Virool, a programmatic video platform, raised a Series A round of $12 million from Menlo Ventures, Yahoo! Japan, Flint Capital and 500 Startups.
Building on a $7 million seed round from VC firms and investors including FundersClub, Troy Carter and Farzad (Zod) Nazem, this new round will go toward developing Virool's technology.
It will also be used to build its executive team and sales and marketing departments.
The company will broaden its North America, Latin America and Europe plans and expand into APAC (Asia-Pacific region), beginning with Japan.
Virool CEO Alex Debelov said the company started small, with just two co-founders, Debelov and Vladimir Gurgov, in an apartment. In 2012, the company launched out of Y Combinator, a seed accelerator, and now it has 72 people and offices in San Francisco, L.A., London, New York and others.
"The company has been growing really, really fast," Debelov said, adding that March was the best month in Virool's history. The new round allows Virool to bring its mission to life much more rapidly at a larger scale, he added.
In March 2015, the company announced the launch of a new in-feed video ad unit for desktop and mobile, Real-Time Daily reported. Virool works with publishers including Mashable, Adweek, The Daily Dot, The Onion and Political Insider, and brands including WestJet, Bank of America, Under Armour, Turkish Airlines and Quaker. |
/**
* Returns one {@link Place} by ID. The class is annotated with {@code @GeoJson(type = GeoJsonType.FEATURE)}.
*
* @param id the ID
* @return the {@link ResponseEntity} with place, or HTTP status 404 if not found
*/
@GetMapping("/api/places/{id}")
public ResponseEntity<Place> findById(@PathVariable("id") Long id) {
return placeRepository.findById(id)
.map(ResponseEntity::ok)
.orElse(notFound().build());
} |
// WithTMSID filters by TMS identifier
func WithTMSID(id token.TMSID) TxOption {
return func(o *txOptions) error {
o.network = id.Network
o.channel = id.Channel
o.namespace = id.Namespace
return nil
}
} |
package module3;
import java.util.Map;
import de.fhpotsdam.unfolding.UnfoldingMap;
import de.fhpotsdam.unfolding.providers.Google;
import de.fhpotsdam.unfolding.utils.MapUtils;
import processing.core.PApplet;
public class LifeExpectancy extends PApplet {
//Stop eclipse from generating a warning
private static final long serialVersionLongUID = 1L;
private UnfoldingMap map;
Map<String, Float> lifeExpByCountry;
public void setup(){
size(800,600);
map = new UnfoldingMap(this, 50, 50, 700, 500, new
Google.GoogleMapProvider());
MapUtils.createDefaultEventDispatcher(this, map);
lifeExpByCountry = loadLifeExpectancyFromCVS("data/LifeExpectancyWorldBank.cvs");
}
public void draw() {
background(10);
map.draw();
}
}
|
Missed colorectal cancers in a fecal immunochemical test-based screening program: Molecular profiling of interval carcinomas BACKGROUND For optimizing fecal immunochemical test (FIT)-based screening programs, reducing the rate of missed colorectal cancers (CRCs) by FIT (FIT-interval CRCs) is an important aspect. Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all (precursor) lesions. AIM To compare the molecular make-up of FIT-interval CRCs to lesions that are detected by FIT . METHODS FIT-interval CRCs observed in a Dutch pilot-program of FIT-based screening were compared to a control group of SD-CRCs in a 1:2 ratio, resulting in 27 FIT-interval CRC and 54 SD-CRCs. Molecular analyses included microsatellite instability (MSI), CpG island methylator phenotype (CIMP), DNA sequence mutations and copy number alterations (CNAs). RESULTS Although no significant differences were reached, FIT-interval CRCs were more often CIMP positive and MSI positive (33% CIMP in FIT-interval CRCs vs 21% in SD-CRCs (P = 0.274); 19% MSI in FIT-interval CRCs vs 12% in SD-CRCs (P = 0.469)), and showed more often serrated pathway associated features such as BRAF (30% vs 12%, P = 0.090) and PTEN (15% vs 2.4%, P = 0.063) mutations. APC mutations, a classic feature of the adenoma-carcinoma-sequence, were more abundant in SD-CRCs (68% vs 40% in FIT-interval CRCs P = 0.035). Regarding CNAs differences between the two groups; FIT-interval CRCs less often showed gains at the regions 8p11.22-q24.3 (P = 0.009), and more often gains at 20p13-p12.1 (P = 0.039). CONCLUSION Serrated pathway associated molecular features seem to be more common in FIT-interval CRCs, while classic adenoma carcinoma pathway associated molecular features seem to be more common in SD-CRCs. This indicates that proximal serrated lesions may be overrepresented among FIT-interval CRCs. INTRODUCTION Fecal immunochemical test (FIT)-based screening worldwide has had a major impact on reducing colorectal cancer (CRC)-related mortality. Despite this success, the issue of false negative tests giving rise to FIT interval CRCs (e.g., CRCs diagnosed after a negative FIT but before the next FIT invitation) leaves room for improvement. Monitoring the incidence of FIT-interval CRCs is a key quality indicator of a FIT-based screening program, and any CRC that occurs in spite of recent screening can be regarded as an unwanted program outcome. The sensitivity of FIT for CRC is approximately 75%-85%, which indicates that still 1 in 4-5 CRCs will be missed in any single screening round. Possible reasons for FIT-interval CRCs are the limited sensitivity of FIT for specific molecular types of CRCs that were already present at the time of FIT-screening, or rapid progression of premalignant lesions during the interval between two screening rounds. Both of these causes may be the consequence of differences in tumor biology between FIT-interval CRCs and screen-detected CRCs (SD-CRCs). Such biological differences may translate e.g., into a lower bleeding tendency of colorectal lesions or an increased progression rate. CRC has several precursor lesions reflecting different tumor-biology. Adenomas are well-known precursors of CRC. Adenomas may follow the canonical adenoma-carcinoma sequence with APC and KRAS mutations and subsequent typical patterns of chromosomal copy number alterations (CNAs) as classic features to develop into CRC. More recently, also sessile serrated lesions (SSLs) have been identified as precursors of CRC. SSLs may follow the serrated neoplasia pathway resulting in CRCs that are more often microsatellite instable (MSI), CpG island methylator phenotype (CIMP) high and harbor BRAF mutations. As a consequence of a different tumor biology, colorectal lesions can have Population and study design From 2006 onwards, two cohort studies of biennial FIT-based CRC screening have been conducted in the southwest and northwest regions of the Netherlands. After three screening rounds, these two cohorts were combined in 2014 to conduct a fourth round of FIT screening. A threshold of 10 g hemoglobin (Hb) per gram feces was used. Screenees with a fecal Hb concentration above this threshold were referred for colonoscopy. Colonoscopies were performed according to international quality guidelines. Details about the design of this study have been reported previously. After finishing the fourth screening round in 2015, the total cohort was linked to the Netherlands Cancer Registry, managed by the Netherlands Comprehensive Cancer Organization (Utrecht, The Netherlands), in order to identify CRC missed by FIT testing during the three completed screening rounds including 2 years of follow up. Definitions All CRCs detected during colonoscopy after a positive FIT (threshold ≥ 10 g Hb/g feces) were recorded and labeled as SD-CRC. FIT-interval CRCs were defined as a CRC diagnosed after a negative FIT (threshold < 10 g Hb/g feces) and before the date of the next invitation for FIT-screening. If a participant had a negative FIT and was not invited for a consecutive round (for having passed the upper age limit or after moving out of the target area) but developed CRC within the 2.37 years interval (median time between invitations), this CRC was also defined as a FIT-interval CRC. Persons who had been inconsistent in participating in FIT screening and developed CRC outside the screening interval (median 2.37 years) were not defined as an interval CRC and not included in this study. Data on tumor stage and location (at time of resection) were collected for both FIT-interval CRC and SD-CRCs. With regard to tumor location, the colon was divided into proximal (cecum, ascending, hepatic flexure, and transverse colon) and distal colon (splenic flexure, descending colon, sigmoid colon, and rectum). All cancers were staged according to the 7 th edition of the American Joint Committee on Cancer. In the three intervals between four screening rounds, including the 2.37 years follow up for individuals that had reached the upper age limit after any of the first three rounds, in total 27 FITinterval CRCs were identified. Besides, a total of 116 SD-CRCs was detected in the four screening rounds. All 27 FIT-interval CRCs were included in the study, and a random sample of SD-CRCs in a 1:2 ratio to SD-CRCs, yielding a control group of 54 SD-CRCs. Sample collection and DNA isolation All tissue samples of FIT-interval CRCs and SD-CRCs were collected from 11 departments of pathology through the Dutch National Pathology Registry. DNA from formalin-fixed, paraffin-embedded material was isolated as previously described. Good quality DNA could be obtained from 25 of 27 FIT-interval CRCs and 46 of 54 SD-CRCs (see Supplementary Figure 1). CIMP status analysis CIMP status was analyzed in the Pathology Department at the University of Maastricht. The CIMP panel (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1) was determined by nested methylationspecific polymerase chain reaction (PCR) using sodium bisulfite modified genomic DNA (EZ DNA methylation kit (ZYMO research Co., Orange, CA, United States) as described before, and CIMP positive was defined when ≥ 3 of the 5 CIMP markers were methylated. In some samples DNA was no longer available, in other samples the analysis was performed but failed, leaving CIMP-analysis results available for 21 of 27 FIT-interval CRCs and 39 of 54 SD-CRCs (see Supplementary Figure 1). MSI status analysis MSI status analysis was performed using the multiplex marker PCR panel from Promega (MSI Multiplex System Version 1.2, Promega, Madison, WI, United States). When two or more markers were unstable, the sample was interpreted as MSI. All other samples were classified as microsatellite stable. In some samples insufficient DNA was left, while in others the results obtained did not meet the quality criteria, leaving results for MSI analysis available for 21 of 27 FIT-interval CRCs and 41 of 54 SD-CRCs (see Supplementary Figure 1). Mutation analysis For mutation analysis, targeted sequencing was performed. DNA libraries were prepared using the KAPA HyperPrep Kit (KAPA Biosystems, Wilmington, MA, United States) as described in the KAPA HyperPrep Kit protocol (KR0961-v5.16). Target enrichment was performed using a custom 48 gene xGen® Predesigned Gene Capture Pools (Integrated DNA Technologies, San Diego, CA, United States), as previously described. In some samples, DNA was no longer available, and one sample was analyzed but sequencing was not sufficiently deep to draw conclusions for almost all genes, leaving mutation analysis results available for 20 of 27 FIT-interval CRCs and 42 of 54 SD-CRCs (see Supplementary Figure 1). Genes and/or samples with ≥ 50% of low-quality reads, were excluded from analysis, as the results were not reliable. Mutation calling was done as previously described. Raw mutation data have been deposited in the European Genome-Phenome Archive (EGA), with the study ID: EGAS00001004683. DNA copy number analysis DNA CNAs were analyzed with low-coverage whole genome sequencing as described previously. Briefly, DNA was fragmented by sonication (Covaris S2, Woburn, MA, United States) and run on the HiSeq 2500 (Illumina, San Diego, CA, United States) on a 65 basepairs single-read modus using the KAPA HyperPrepKit (KAPA Biosystems, KK8504, Wilmington, MA, United States). This yielded a coverage of 0.13x (IQR 0.12-0.14) genome coverage. To compare the frequencies of alterations in the two groups, the R-package CGHtest was used. Good quality DNA copy number profiles were obtained for 19 of 27 FIT-interval CRCs and for 44 of 54 SD-CRCs (see Supplementary Figure 1). Raw DNA copy number data has been deposited in the EGA, with the study ID: EGAS00001004683. Statistical analysis Differences between groups were evaluated for statistical significance using the Chi square-test statistic, Fisher's exact test statistic, linear-by-linear test or Mann-Whitney-U test where appropriate. Two-sided P values < 0.05 were considered to indicate statistically significant differences. Differences between proportions were reported as mean with 95%CI. Ethics approval and tissue handling Ethics approval for performing FIT-based screening including linkage to the Netherlands Cancer Registry was provided by the Dutch National Health Council (WBO 2642467, 2832758, 3049078 and 161536-112008, The Hague, The Netherlands). No separate ethics approval was necessary for the additional molecular analysis, as judged by the scientific ethics board of the AMC University Hospital. Collection and use of tissue and patient data were performed in compliance with the 'Code for Proper Secondary Use of Human Tissue in the Netherlands' (www.federa.org). All authors had access to the study data and reviewed and approved the final manuscript. Patient and public involvement It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research. Clinicopathological characteristics Demographic and clinicopathological characteristics of the patients with FIT-interval CRCs and SD-CRCs are shown in Table 1. No significant differences were found between both groups. Almost 60% of all patients were men. Among the FIT-interval CRCs, 21 patients (77.8%) were estimated to have a "normal/average" socioeconomic status, compared to 33 patients (61.1%) in the SD-CRC group. In the group of FIT-interval CRCs, fecal Hb concentrations were undetectable (n = 12, 44%) or below the threshold (n = 12, 44%). For three screenees (11%), the precise level of Hb/g feces was not available. Supplementary Table 1 shows per patient and per CRC type (SD-CRC or FIT-interval CRC) how many rounds of FIT participation had been completed prior to the diagnosis of CRC. Mutation analysis Results of the mutation analysis in FIT-interval CRCs and SD-CRCs are shown in Figure 1. Of the 48 genes tested, 37 genes were mutated in at least one sample (see Figure 1). -3.78, 28.9); P = 0.063] mutations were more abundant in FIT-interval CRCs compared to SD-CRC but this difference did not reach statistical significance (see Figure 1). November DISCUSSION Of all interventions currently available, screening is one of the most powerful approaches for reducing CRC-related mortality. Nevertheless, like all screening programs, CRC screening is facing the challenges of overdiagnosis and underdiagnosis. The latter mainly manifests as interval cancers. In the Dutch CRC screening program with a target population of 2.2M screenees, per screening round 544 interval cancers are observed, consistent with a FIT sensitivity of approximately 85%. Theoretically, these FIT interval cancers consist of cancers that were present at the time the FIT was performed, but were missed, as well as cancer precursors missed at the time FIT was performed and that showed a rapid progression to a symptomatic cancer. On one hand sensitivity and specificity are simply determined by the cut off chosen, given the characteristics of the test. On the other hand, specific tumor characteristics driven by the underlying biology may differ between screened detected and interval cancers, a subject that so far has received little attention. To address that question, the aim of the present study was to investigate the molecular characteristics between both categories. While we had access to a large well documented cohort of individuals followed over multiple screening rounds, the absolute number of interval cancers still was limited, which we consider to be the main reason why for most variables, differences were not statistically significant. Moreover, due to inherent formalin-fixed, paraffin-embedded associated artifacts, like DNA cross-links, the quality reads of some of the downstream analyses was poor and therefore some of the selected cases were further excluded from the final analysis (Supplementary Figure 1). Inherently these findings are exploratory in nature, yet they provide important indications on a major healthcare issue. Indeed, the results of this exploratory study indicate that FIT-interval CRCs seem to more frequently carry the molecular features of the serrated neoplasia pathway and NP-CRNs than SD-CRCs do. FIT interval CRCs present more often CIMP high, MSI high and carry mutations like ALK, BRAF, CSF1R, EGFR, FGR2, PTEN, KDR, MET and MPL compared to SD-CRC. PTEN and KDR were previously described mutations detected in SSLs with high-grade dysplasia. Furthermore, APC and KRAS mutations, which classically are part of the canonical adenoma-carcinoma sequence 27], were less frequently found in FIT-interval CRCs. Regarding DNA CNAs, FIT-interval CRCs showed very similar profiles to SD-CRCs, with only differences observed in the frequency of two genomic regions, namely, less often gains at 8p11.22-q24.3, and more often gains in FIT-interval CRCs at 20p13-p12.1. So, these results suggest that FIT-interval cancers are a mixed group of classical pathway and serrated pathway cancers, although with more commonly serrated pathway features and less commonly classical pathway features (both mutations and CNAs) in comparison with SD-CRCs. The overall pattern is striking, even if the individual variables do not reach statistical significance. Levin et al also evaluated whether FIT-interval CRCs differed from FIT-positive patients with CRC by analyzing 7 KRAS mutations and 10 aberrantly methylated DNA biomarkers. They did not find any differences in their DNA profiles. In our study, however we investigated other genomic features and additional genes and did find differences as described above. FIT is a good test to detect cancers. However, it does not perform so well in the detection of precursor lesions, in particular sessile serrated polyps. In a study that compared sensitivities of several FITs in a screening population, FIT sensitivity for SSLs of > 1 cm was only 5.1%. One possible explanation might be the result of less bleeding tendency due to the low vessel density in serrated lesions in combination with their flat morphology and proximal location. Another explanation could be that serrated pathway lesions may show faster progression to cancer than classic adenomas. This indicates that in FIT-screening, a substantial number of serrated polyps will be missed, and therefore cancers derived from these precursor lesions might be overrepresented in FIT-interval CRCs. NP-CRNs also show distinct molecular features compared to classical polypoid adenomas, are frequently located in the right colon and might bleed less. In previous studies, NP-CRNs have been described as being less often APC and KRAS-mutated. In a study comparing PC-CRCs and prevalent CRCs, KRAS mutation was inversely associated with PC-CRCs. Comparably, FIT-interval CRCs were less often APC mutated in the present study (40% in FIT-interval CRCs vs 68% in SD-CRCs, P = 0.035). However, although KRAS was less often mutated in FIT-interval CRCs, the difference was not significant (30% in FIT-interval CRCs vs 37% in SD-CRCs, P = 0.705). In the previously mentioned study on PC-CRCs, BRAF-mutation was present in 28% of PC-CRCs vs 19% of prevalent CRCs (not significant). These percentages are comparable to our findings on FIT-interval CRCs (BRAF mutated in 30% of FIT-interval CRCs vs 12% of SD-CRCs, not significant). Previously, it has been shown that PC-CRCs were more likely CIMP positive and MSI than sporadic CRCs. A separate study in a large PC-CRC cohort in the Netherlands also shows PC-CRCs to be more likely CIMP positive, MSI and BRAF mutated than prevalent CRCs. This suggests that the molecular patterns observed in the interval cancers suggest that these cancers arose via non-polypoid precursors and/or serrated precursors. This may reflect that interval cancers, both FIT interval CRCs and PC-CRCs, indeed have a different biology compared to prevalent CRCs but at the same time pose technical challenges because of their morphology (difficult to be detected during colonoscopy) as well their lack of bleeding (difficult to be detected by FIT). Some CNAs are associated to progression of adenoma to carcinoma chromosomal instability canonical pathway, and these are labeled as cancer associated events. As of yet, no CNAs have been well characterized in the CRCs originating from SSLs. A study of serrated polyps, with data on a set of 38 serrated polyps (12 traditional serrated adenomas and 26 SSLs) found gains at chromosome 7, 13 and 15q. The present study did not show any differences at these specific regions. However, FIT-interval CRCs had less frequent gains at chromosome 8q, and more frequent gains at chromosome 20p then SD-CRCs. As 8q is one of the genomic regions associated with the canonical adenoma-to-carcinoma progression, this finding could mean that to a certain extent, FIT-interval CRCs follow a different progression pathway. As stated above, FIT-interval CRCs identified in multiple screening rounds represent a case-mix of cancers originated from, not only the difficult to detect NP-CRNs and sessile serrated polyps, but also classic adenomas. Precursor lesions could simply be missed by FIT just because of the low sensitivity of this test to detect advanced adenomas and not representing a different biology as reason for missing the lesion. Yet, while molecular differences were observed between FIT-interval CRCs and SD-CRCs, not all of these were statistically significant. Still these findings provide an indication that FIT-interval CRCs are a heterogeneous mixture of phenotypes and underlying molecular biology, including CRCs from flat serrated lesions, from flat adenomas, and others, that for whatever reason shed blood in a way that levels are, at least intermittently, below the limit of detection of the FIT test. In view of this, there is a clinical need to improve in screening tests for CRC early detection. Multi-target molecular stool DNA (mt-sDNA) testing has recently been recognized as a valid CRC screening option by the American Cancer Society, and its test characteristics seem especially favorable for the detection of serrated lesions. In a large trial, mt-sDNA testing showed a higher detection rate of larger serrated sessile polyps than FIT (sensitivity of 42.4% for mt-sDNA-test and 5.1% for FIT, for serrated polyps > 1 cm). The combined sensitivity for advanced precancerous lesions was also higher for mt-sDNA testing than for FIT (42.4% vs 23.8%). However, although the sensitivities are better compared to FIT, the mt-sDNA test shows lower specificity, compared to FIT, which is very important in programmatic screening. Recently, a panel of protein markers detected in stool showed also a higher sensitivity for advanced adenomas without losing in specificity, in comparison to FIT. This protein-based approach would have the potential to improve effectivity of FIT screening without major impact for program logistics or cost effectivity. Implementation of a more accurate test could have the potential to detect a substantial number of CRCs or precursor lesions that would otherwise result in FIT-interval CRCs. Strengths of our study include that FIT-interval CRCs were identified over multiple rounds in a biennial FIT-based screening cohort, and tissue specimens of each tumor could be obtained. We were able to compare FIT-interval CRCs to a control group of SD-CRCs within the same screening population, region and time-span. However, an important limitation is the sample size. A total of 27 FIT-interval CRCs is still a limited number, reflecting the rarity of this entity, with inherent consequences for the statistical power of the study. To address this issue, a larger control group was composed through random selection in a 1:2 ratio. Due to budgetary and logistical constraints, we were not able to enlarge the control group. Also, we were not informed about the family history for cancer among the persons included in the study. Although rare, some of the FIT-interval CRCs might be related to familial CRC. So, although the findings of our study are suggestive for a difference in molecular make-up, further studies are needed to support our findings. We did not report tumor size and morphology of all CRCs, as this is not easy to determine in cancers (as compared to adenomas or SSLs). We were, therefore, not able to correlate size or morphology to the molecular analysis. CONCLUSION In conclusion, the present study provides evidence that SD-CRCs and FIT interval CRCs differ in the distribution of molecular tumor profiles. These findings can provide guidance on strategies for further improving stool-based CRC screening strategies. Future research should focus on the role of incorporating biomarkers in screening for identifying more CRCs during screening, thereby reducing the number of screening interval CRCs. |
/* *INDENT-OFF* */
/*INDENT OFF*/
/* Description: snn_multiple - snmultiple
*/
/******************************************************************************
* This software is covered by the zlib/libpng license.
* The zlib/libpng license is a recognized open source license by
* the Open Source Initiative: http://opensource.org/licenses/Zlib
* The zlib/libpng license is a recognized "free" software license by
* the Free Software Foundation: https://directory.fsf.org/wiki/License:Zlib
*******************************************************************************
******************* Copyright notice (part of the license) ********************
* $Id: ~|^` @(#) snn_multiple.c copyright 2011 - 2016 <NAME>. \ snn_multiple.c $
* This software is provided 'as-is', without any express or implied warranty.
* In no event will the authors be held liable for any damages arising from the
* use of this software.
*
* Permission is granted to anyone to use this software for any purpose,
* including commercial applications, and to alter it and redistribute it freely,
* subject to the following restrictions:
*
* 1. The origin of this software must not be misrepresented; you must not claim
* that you wrote the original software. If you use this software in a
* product, an acknowledgment in the product documentation would be
* appreciated but is not required.
*
* 2. Altered source versions must be plainly marked as such, and must not be
* misrepresented as being the original software.
*
* 3. This notice may not be removed or altered from any source distribution.
****************************** (end of license) ******************************/
/* $Id: ~|^` @(#) This is snn_multiple.c version 2.6 dated 2016-04-04T05:29:37Z. \ $ */
/* You may send bug reports to <EMAIL> with subject "snn" */
/*****************************************************************************/
/* maintenance note: master file /src/relaymail/lib/libsnn/src/s.snn_multiple.c */
#error OBSOLETE: code is now in snn.h
/********************** Long description and rationale: ***********************
* snmultiple returns the nearest multiple of a specified increment to a
* specified floating-point number. If the increment is 1.0, this is equivalent
* to snround. However, it can also be used to provide the nearest multiple
* of 10.0, of 0.1, of 25.4, etc.:
*
* double snmultiple(double d, double incr)
******************************************************************************/
/* ID_STRING_PREFIX file name and COPYRIGHT_DATE are constant,
other components are version control fields
*/
#undef ID_STRING_PREFIX
#undef SOURCE_MODULE
#undef MODULE_VERSION
#undef MODULE_DATE
#undef COPYRIGHT_HOLDER
#undef COPYRIGHT_DATE
#define ID_STRING_PREFIX "$Id: snn_multiple.c ~|^` @(#)"
#define SOURCE_MODULE "snn_multiple.c"
#define MODULE_VERSION "2.6"
#define MODULE_DATE "2016-04-04T05:29:37Z"
#define COPYRIGHT_HOLDER "<NAME>"
#define COPYRIGHT_DATE "2011 - 2016"
#ifndef _XOPEN_SOURCE
# define _XOPEN_SOURCE 500
#endif
#ifndef __EXTENSIONS__
# define __EXTENSIONS__ 1
#endif
/*INDENT ON*/
/* *INDENT-ON* */
/* local header files */
#include "snn.h" /* header file for public definitions and declarations */
#include "zz_build_str.h" /* build_id build_strings_registered copyright_id register_build_strings */
/* system header files needed for code which are not included with declaration header */
#include <ctype.h> /* isalnum */
#ifndef NULL
# include <stdlib.h> /* NULL */
#endif
#include <string.h> /* strrchr */
#include <syslog.h> /* LOG_* */
/* static data and function definitions */
static char snn_multiple_initialized= (char)0;
static const char *filenamebuf = __FILE__ ;
static const char *source_file = NULL;
/* initialize snn_almost_one, etc. at run-time */
static void initialize_snn_multiple(void)
{
const char *s;
s = strrchr(filenamebuf, '/');
if (NULL == s)
s = filenamebuf;
snn_multiple_initialized = register_build_strings(NULL, &source_file, s);
}
/* return d expressed as the nearest integral multiple of incr */
/* calls: initialize_snn_multiple, snround */
/* called by: no other snn functions */
double snmultiple(double d, double incr,
void (*f)(int, void *, const char *, ...), void *log_arg)
{
#ifndef PP__FUNCTION__
static const char __func__[] = "snmultiple";
#endif
if ((unsigned char)0U == snn_multiple_initialized)
initialize_snn_multiple();
if (NULL != f) {
f(LOG_DEBUG, log_arg,
"%s: %s line %d: %s(%.24g, %.24g)",
__func__, source_file, __LINE__,
__func__, d, incr
);
}
if (0.0 > incr) incr = 0.0 - incr;
if (0.0 == incr) return d;
return incr * snround(d / incr, f, log_arg);
}
|
/* ************************************************************************** */
/* */
/* ::: :::::::: */
/* linear_interpolation.c :+: :+: :+: */
/* +:+ +:+ +:+ */
/* By: npineau <<EMAIL>> +#+ +:+ +#+ */
/* +#+#+#+#+#+ +#+ */
/* Created: 2015/01/22 14:11:09 by npineau #+# #+# */
/* Updated: 2015/05/24 15:38:41 by npineau ### ########.fr */
/* */
/* ************************************************************************** */
#include "libumlx.h"
t_color linear_interpolation(
t_color const src,
t_color const end,
double const factor)
{
return (new_color(
interpolate(src.rgb[0], end.rgb[0], factor),
interpolate(src.rgb[1], end.rgb[1], factor),
interpolate(src.rgb[2], end.rgb[2], factor),
interpolate(src.rgb[3], end.rgb[3], factor)));
}
|
import requests
from allauth.socialaccount.providers.oauth2.views import (
OAuth2Adapter, OAuth2LoginView, OAuth2CallbackView
)
from .provider import HelsinkiOIDCProvider
class HelsinkiOIDCOAuth2Adapter(OAuth2Adapter):
provider_id = HelsinkiOIDCProvider.id
access_token_url = 'https://api.hel.fi/sso/openid/token/'
authorize_url = 'https://api.hel.fi/sso/openid/authorize/'
profile_url = 'https://api.hel.fi/sso/openid/userinfo/'
def complete_login(self, request, app, token, **kwargs):
headers = {'Authorization': 'Bearer {0}'.format(token.token)}
resp = requests.get(self.profile_url, headers=headers)
assert resp.status_code == 200
extra_data = resp.json()
return self.get_provider().sociallogin_from_response(request,
extra_data)
oauth2_login = OAuth2LoginView.adapter_view(HelsinkiOIDCOAuth2Adapter)
oauth2_callback = OAuth2CallbackView.adapter_view(HelsinkiOIDCOAuth2Adapter)
|
<gh_stars>1000+
# Copyright (c) 2016 Ansible, Inc.
# All Rights Reserved.
# Python
from collections import OrderedDict
import logging
# Django
from django.core.exceptions import ImproperlyConfigured
from django.utils.text import slugify
from django.utils.translation import ugettext_lazy as _
from awx.conf.license import get_license
logger = logging.getLogger('awx.conf.registry')
__all__ = ['settings_registry']
class SettingsRegistry(object):
"""Registry of all API-configurable settings and categories."""
def __init__(self, settings=None):
"""
:param settings: a ``django.conf.LazySettings`` object used to lookup
file-based field values (e.g., ``local_settings.py``
and ``/etc/tower/conf.d/example.py``). If unspecified,
defaults to ``django.conf.settings``.
"""
if settings is None:
from django.conf import settings
self._registry = OrderedDict()
self._validate_registry = {}
self._dependent_settings = {}
self.settings = settings
def register(self, setting, **kwargs):
if setting in self._registry:
raise ImproperlyConfigured('Setting "{}" is already registered.'.format(setting))
category = kwargs.setdefault('category', None)
category_slug = kwargs.setdefault('category_slug', slugify(category or '') or None)
if category_slug in {'all', 'changed', 'user-defaults'}:
raise ImproperlyConfigured('"{}" is a reserved category slug.'.format(category_slug))
if 'field_class' not in kwargs:
raise ImproperlyConfigured('Setting must provide a field_class keyword argument.')
self._registry[setting] = kwargs
# Normally for read-only/dynamic settings, depends_on will specify other
# settings whose changes may affect the value of this setting. Store
# this setting as a dependent for the other settings, so we can know
# which extra cache keys to clear when a setting changes.
depends_on = kwargs.setdefault('depends_on', None) or set()
for depends_on_setting in depends_on:
dependent_settings = self._dependent_settings.setdefault(depends_on_setting, set())
dependent_settings.add(setting)
def unregister(self, setting):
self._registry.pop(setting, None)
for dependent_settings in self._dependent_settings.values():
dependent_settings.discard(setting)
def register_validate(self, category_slug, func):
self._validate_registry[category_slug] = func
def unregister_validate(self, category_slug):
self._validate_registry.pop(category_slug, None)
def get_dependent_settings(self, setting):
return self._dependent_settings.get(setting, set())
def get_registered_categories(self):
categories = {'all': _('All'), 'changed': _('Changed')}
for setting, kwargs in self._registry.items():
category_slug = kwargs.get('category_slug', None)
if category_slug is None or category_slug in categories:
continue
if category_slug == 'user':
categories['user'] = _('User')
categories['user-defaults'] = _('User-Defaults')
else:
categories[category_slug] = kwargs.get('category', None) or category_slug
return categories
def get_registered_settings(self, category_slug=None, read_only=None, slugs_to_ignore=set()):
setting_names = []
if category_slug == 'user-defaults':
category_slug = 'user'
if category_slug == 'changed':
category_slug = 'all'
for setting, kwargs in self._registry.items():
if category_slug not in {None, 'all', kwargs.get('category_slug', None)}:
continue
if kwargs.get('category_slug', None) in slugs_to_ignore:
continue
if read_only in {True, False} and kwargs.get('read_only', False) != read_only and setting != 'INSTALL_UUID':
# Note: Doesn't catch fields that set read_only via __init__;
# read-only field kwargs should always include read_only=True.
continue
setting_names.append(setting)
return setting_names
def get_registered_validate_func(self, category_slug):
return self._validate_registry.get(category_slug, None)
def is_setting_encrypted(self, setting):
return bool(self._registry.get(setting, {}).get('encrypted', False))
def is_setting_read_only(self, setting):
return bool(self._registry.get(setting, {}).get('read_only', False))
def get_setting_category(self, setting):
return self._registry.get(setting, {}).get('category_slug', None)
def get_setting_field(self, setting, mixin_class=None, for_user=False, **kwargs):
from rest_framework.fields import empty
field_kwargs = {}
field_kwargs.update(self._registry[setting])
field_kwargs.update(kwargs)
field_class = original_field_class = field_kwargs.pop('field_class')
if mixin_class:
field_class = type(field_class.__name__, (mixin_class, field_class), {})
category_slug = field_kwargs.pop('category_slug', None)
category = field_kwargs.pop('category', None)
depends_on = frozenset(field_kwargs.pop('depends_on', None) or [])
placeholder = field_kwargs.pop('placeholder', empty)
encrypted = bool(field_kwargs.pop('encrypted', False))
defined_in_file = bool(field_kwargs.pop('defined_in_file', False))
unit = field_kwargs.pop('unit', None)
if getattr(field_kwargs.get('child', None), 'source', None) is not None:
field_kwargs['child'].source = None
field_instance = field_class(**field_kwargs)
field_instance.category_slug = category_slug
field_instance.category = category
field_instance.depends_on = depends_on
field_instance.unit = unit
if placeholder is not empty:
field_instance.placeholder = placeholder
field_instance.defined_in_file = defined_in_file
if field_instance.defined_in_file:
field_instance.help_text = str(_('This value has been set manually in a settings file.')) + '\n\n' + str(field_instance.help_text)
field_instance.encrypted = encrypted
original_field_instance = field_instance
if field_class != original_field_class:
original_field_instance = original_field_class(**field_kwargs)
if category_slug == 'user' and for_user:
try:
field_instance.default = original_field_instance.to_representation(getattr(self.settings, setting))
except Exception:
logger.warning('Unable to retrieve default value for user setting "%s".', setting, exc_info=True)
elif not field_instance.read_only or field_instance.default is empty or field_instance.defined_in_file:
try:
field_instance.default = original_field_instance.to_representation(self.settings._awx_conf_settings._get_default(setting))
except AttributeError:
pass
except Exception:
logger.warning('Unable to retrieve default value for setting "%s".', setting, exc_info=True)
# `PENDO_TRACKING_STATE` is disabled for the open source awx license
if setting == 'PENDO_TRACKING_STATE' and get_license().get('license_type') == 'open':
field_instance.read_only = True
return field_instance
settings_registry = SettingsRegistry()
|
Synthesis and characterization of cocoa pods waste carbon for Radar Absorber Material Synthesis and characterization of Radar Absorber Material (RAM) has been done. The raw material of the carbon is waste cocoa pods as dielectric material. An activated carbon of waste cocoa pods has porous and large inner surface that has high absorbency and can be implemented as alternative RAM. The carbon was prepared using carbonization and activated using chemicals activator KOH and HCL. The active carbon is characterized using a Vector Network Analyzer (VNA) to investigate the return loss for variation of the thickness of the material in the frequency range 4 to 8GHz (C-band). Morphology characterization is performed using Scanning Electron Microscopy (SEM). The experiment result obtain the maximum absorption of the developed carbon is −14.0dB at 8mm thickness with 1M KOH activation substances. The result shows the reflectivity response of the carbon is satisfied in the frequency range of studied. The SEM measurement present the activated carbon has more porous compare to a non activated carbon. Based on this study, a carbon active of waste cocoa pods can be used as a RAM. |
Human protein S cleavage and inactivation by coagulation factor Xa. Human factor Xa specifically cleaves the anticoagulant protein S within the thrombin-sensitive domain. Amino-terminal amino acid sequencing of the heavy chain cleavage product indicates cleavage of protein S by factor Xa at Arg60, a site that is distinct from those utilized by alpha-thrombin. Cleavage by factor Xa is unaffected by the presence of hirudin and is completely blocked by tick-anticoagulant-peptide and D-Glu-Gly-Arg-chloromethyl ketone, the latter two being specific inhibitors of factor Xa. The cleavage requires the presence of phospholipid and Ca2+, and is markedly inhibited by the presence of factor Va. Factor Xa-cleaved protein S no longer possesses its activated protein C-dependent or -independent anticoagulant activity, as measured in a factor VIII-based activated partial thromboplastin time clot assay. The apparent binding constant for protein S binding to phospholipid (Kd approximately 4 nM +/- 1.0) is unaffected by factor Xa or thrombin cleavage, suggesting that the loss of anticoagulant activity resulting from cleavage is not primarily due to the loss of membrane binding ability. Cleavage and inactivation of protein S by factor Xa may be an additional way in which factor Xa exerts its procoagulant effect, after the initial stages of clot formation. Protein S is a vitamin K-dependent, 635-amino acid, nonenzymatic glycoprotein (M r 78,000; Ref. 1) that acts as an anticoagulant in blood. The domain organization of protein S is similar to other plasma vitamin K-dependent proteins in that it contains an amino-terminal ␥-carboxyglutamate-rich domain and several (four) epidermal growth factor-like domains. Unique to protein S, however, is a 29-amino acid thrombin-sensitive domain, located between the ␥-carboxyglutamate and first epidermal growth factor-like domains. The thrombin-sensitive domain corresponds to exon IV of the protein S gene. Protein S also contains a sex steroid binding protein-like domain at the carboxyl-terminal end of the protein, in place of the serine protease domain found in the vitamin K-dependent plasma proteases. The sex steroid bind-ing protein-like domain has been identified as being composed of two tandem repeat units homologous to the Cys-poor laminin A globular (G) domain found in a number of extracellular ligand binding basement membrane proteins involved in cellular growth and differentiation. Schneider and co-workers have described a cultured cell growth arrest-specific protein (Gas6) from NIH 3T3 mouse cells and human IMR90 fibroblasts, which, except for the absence of a thrombinsensitive domain, is homologous throughout to protein S. Thrombin cleavage converts protein S into a two-chain, disulfide-linked protein that no longer possesses anticoagulant activity. The thrombin cleavage sites were first established for bovine protein S (at Arg 52 and Arg 70 ) by Dahlback et al. and recently at the corresponding residues (Arg 49 and Arg 70 ) for human protein S. The defined mechanism(s) by which protein S exhibits its anticoagulant activity is presently unknown. Walker and coworkers were the first to show an acceleration by protein S of the APC 1 -mediated inactivation of factor Va and factor VIIIa. It is well established that factor Va inactivation by APC can be prevented by factor Xa in the bovine system and that protein S functions by abrogating this protection. Initially, Kalafatis and Mann in the bovine system and, subsequently, Rosing et al. and Egan et al. in the human system have reported that protein S stimulates APCmediated factor Va inactivation by selectively promoting the cleavage of factor Va at Arg 306. A kinetic study of factor Va inactivation by APC revealed that protein S increases the K cat of inactivation by 2-fold without changing the apparent K m for factor Va. Shen and Dahlback in a purified component system were the first to observe a synergistic effect of protein S and factor V on APC inactivation of factor VIIIa. This synergistic effect of protein S has been recently confirmed using human factor VIII. Besides APC cofactor activity, protein S has also recently been reported by several groups to exhibit APC-independent anticoagulant activity. The first report of APC-independent protein S anticoagulant activity was that of Mitchell et al., in which protein S appeared to act as a competitive inhibitor in prothrombin activation. Heeb et al. have also reported the inhibition of the prothrombinase complex by protein S. They also observed direct, reversible binding of protein S to factor Va, which was competitive with prothrombin binding. In a follow-up study, Heeb et al. also observed the direct, phospholipid-independent reversible binding and slow inhibition of factor Xa by protein S. Bouma's laboratory has also reported the inhibition by protein S of prothrombinase activity on the surface of cultured human umbilical vein endothelial cells or unstimulated platelets. They have also observed inhibition by protein S of factor Xa generation by the "tenase" complex (purified factors X, IXa, and VIIIa; Ca 2 ; and synthetic phospholipid or endothelial cells or platelets). A correlation between protein S binding to synthetic phospholipid vesicles and inhibition of both the purified component prothrombinase and tenase complexes suggests that the APC-independent anticoagulant effect of protein S is at least in part due to its competition for phospholipid surface sites. Despite the lack of a clear understanding of the mechanism by which protein S acts as an anticoagulant and its modest cofactor activity, the importance of in vivo protein S anticoagulant activity has been inferred from the correlation of inherited familial protein S deficiency and predisposition to recurrent venous thrombosis (29 -31). The common clinical manifestations of early age, recurrent superficial thrombophlebitis, deep vein thrombosis, and pulmonary embolism are similar to those associated with familial protein C deficiency, consistent with, but not proving, the believed cofactor role of protein S in the protein C anticoagulation pathway. The incidence of heterozygous protein S deficiency in patients with thrombotic disease has been estimated to be between 5% and 8%, roughly comparable with those for protein C and antithrombin-III deficiency. In many cases, it is likely that other factors contribute to disease. For example, APC resistance resulting from Arg 506 3 Gln mutation in factor V greatly increases the risk of thrombosis in protein S-deficient individuals. The procoagulant factor Xa, another member of the vitamin K-dependent family of plasma proteins, plays a crucial role in the amplification phase of the blood clotting cascade by enzymatically converting its target, prothrombin, to its active form, thrombin (for reviews, see Refs.. Factor Xa also plays a pivotal role in blood clotting as a result of its generation by both the intrinsic (factors IXa and VIIIa) and the extrinsic (factor VIIa and tissue factor) pathways. We report here the specific cleavage and inactivation of human protein S by factor Xa. This cleavage and inactivation of protein S may represent a second important mechanism by which factor Xa exerts its procoagulant effect. Materials Plasma-derived HPS (pHPS) was purified as described elsewhere or purchased from Enzyme Research Laboratories Inc. (South Bend, IN) and was judged by SDS-PAGE to be 15-20% cleaved. Purified human APC and factor Xa and dansylated Glu-Gly-Arg-chloromethyl ketone (DEGR) were generous gifts from Dr. Paul Haley, Hematologic Technologies, Inc. (Essex Junction, VT). Synthetic phospholipid vesicles composed of 75% L-palmitoyl-2-oleoyl phosphatidylcholine and 25% Lpalmitoyl 2-oleoyl phosphatidylserine (PCPS) and ␣-thrombin were prepared as described previously. Human factor V was purified and converted to the active form of the cofactor (Va) as described by Katzmann et al.. Human recombinant protein S (rHPS) was produced in human kidney 293 cells, purified, and chemically characterized as described elsewhere. Hirudin was obtained from Genentech (South San Francisco, CA). Tick anticoagulant peptide was a gift from Dr. Sriran Krishnaswamy (Emory University, Atlanta, GA). D-Glu-Gly-Arg-chloromethyl ketone and D-Phe-Pro-Arg-chloromethyl ketone (PPACK) were purchased from Calbiochem. Benzamidine was purchased from Aldrich. Human plasma-derived factor VIII (outdated Hemofil M, Baxter Healthcare Corp.) was a gift from Dr. Katherine High, Children's Hospital (Philadelphia, PA). Time-dependent Protein S Cleavage by Factor Xa Recombinant HPS (300 nM) was digested with factor Xa (6 nM) in the presence of 20 M PCPS in 20 mM HEPES (pH 7.4), 150 mM NaCl, 5 mM CaCl 2, 20 nM hirudin for various times (0 -120 min) at 37°C. The samples were then mixed with 2% SDS, 2% -mercaptoethanol and heated for 5 min at 90°C prior to electrophoresis on a 10% SDS-PAGE gel and visualized by silver staining. For amino-terminal sequencing, the contents of the gel were electroblotted onto a polyvinylidene difluoride membrane and stained with Coomassie Brilliant Blue as previously detailed. The transferred protein S heavy chain 2-h digestion product (see Fig. 1) was submitted to conventional Edman degradation and product resolution on an Applied Biosystems 475A sequencer in the laboratory of Dr. Alex Kurosky (University of Texas, Medical Branch of Galveston). To test the effect of factor Va, rHPS was also digested in the context of the "prothrombinase" complex (20 M PCPS, 6 nM factor Xa, and 20 nM factor Va). The possibility of cleavage caused by any contaminating thrombin was excluded by the presence of 20 nM hirudin. Protein S Functional Assay A modified three-stage assay was developed to measure functional protein S activity, in which the end point is a factor VIII(a)-dependent activated partial thromboplastin time clot time. Stage 1-HPS (300 nM) was incubated with 30 nM factor Xa in the presence of 100 M PCPS in 20 mM HEPES, 150 mM NaCl, 5 mM CaCl 2 (pH 7.4) (HBS/Ca 2 buffer), for 2 h at 37°C. Following incubation, DEGR was added to all samples (100 nM final concentration), and they were kept at room temperature for 30 min. The samples were then dialyzed twice in Slide-A-Lyzer cassettes (Pierce) versus HBS-Ca 2 buffer at room temperature for 3 h to remove unreacted DEGR and tested in a factor Xa chromogenic assay for remaining active factor Xa and DEGR. Portions of the dialyzed samples were run on reduced SDS-PAGE gels to confirm complete cleavage (see Fig. 3B). Factor Xa was determined to be completely and irreversibly inhibited by DEGR, and unreacted DEGR was effectively removed by dialysis, (based upon amidolytic assays with synthetic substrate Spectrozyme® factor Xa according to the manufacturer (American Diagnostica Inc., Greenwich, CT) (data not shown). Stage 2-Human plasma-derived factor VIII (outdated Hemofil M, Baxter Healthcare Corp.) at 30 nM concentration (1 unit 0.07 pmol) was incubated for various times (0 -120 min) at 37°C in HBS/Ca 2, 50 M PCPS, in the absence or presence of 5 nM APC, or in 5 nM APC plus 100 nM factor Xa-cleaved HPS or undigested HPS from stage 1. Stage 3-Equal volumes (100 l) of HBS buffer, activated partial thromboplastin time reagent (Organon Teknika Corp., Durham, NC), and factor VIII-deficient human plasma (George King Bio-Medical Inc., Overland Park, KS) were combined and preincubated for 1 min at 37°C. One-l volumes (10 fmols of initial factor VIII) of samples from stage 2 were then added, followed immediately by initiation of clot formation at 37°C by the addition of 100 l of 25 mM CaCl 2. In control experiments, the cleavage and inactivation of protein S by human ␣-thrombin was also measured. The procedure was the same as that described above except 15 nM ␣-thrombin, no PCPS or Ca 2, and a 1-h incubation was used in stage 1. The ␣-thrombin was completely and irreversibly inhibited by incubation with 50 nM PPACK, and dialysis removed all active PPACK, as determined with amidolytic assays employing synthetic substrate Spectrozyme® TH (American Diagnostica Inc.) (data not shown). Stages 2 and 3 were identical to those described above. Protein S Binding to Phospholipid The effect of digestion by factor Xa on protein S binding to phospholipid was determined with a solid phase microtiter plate procedure described by van Wijnen et al.. Protein S was first digested with factor Xa in the presence of PCPS vesicles as described for stage 1 of the functional assay, above. EDTA was then added to 10 mM, and the digested protein S was loaded onto a Fast-Q-Flow column (0.2-ml bed volume) and washed with 10 column volumes of 20 mM Tris, pH 7.4, 150 mM NaCl, 5 mM benzamidine, 10 mM EDTA (to disrupt the calcium-dependent interaction of protein S with phospholipid and to remove the phospholipid by elution. The column was then washed with 10 volumes of the above wash solution lacking EDTA, followed by elution of the purified protein S with 400 l of 20 mM Tris, pH 7.4, 150 mM NaCl, 20 mM CaCl, as described previously. Digestion of protein S was confirmed by SDS-PAGE of the eluted protein as described above, and protein concentration was determined by the micro-BCA protein assay (Pierce) following the supplier's instructions and using purified, untreated human rHPS as a standard. Protein S was also digested with ␣-thrombin as described for stage 1 of the functional assay (above), followed by inhibition of thrombin by the addition of 40 mM PPACK, and directly added to the phospholipid-coated wells without column purification. Increasing concentrations of digested protein S and undigested protein S (submitted to identical treatment without the addition of factor Xa or ␣-thrombin) were used in the solid phase lipid binding assay, as described in detail elsewhere. Briefly, PCPS (2.5 M, 100 l) was used to coat microtiter wells overnight at 4°C in 50 mM NaHCO 3, pH 9.6, followed by blocking with 1% bovine serum albumin in 50 mM Tris, pH 7.4, 150 mM NaCl, 3 mM CaCl 2 for 1 h at room temperature. Different amounts of protein S (in 100 l) were then added in the above buffer containing 0.3% bovine serum albumin (binding buffer) and incubated for 2 h at room temperature, followed by three 10-min washes with 150 l of binding buffer. Bound protein S was then released by the addition of 100 l of 50 mM Tris, pH 7.4, 150 mM NaCl, 10 mM EDTA (elution buffer), and 2-h incubation at room temperature. The eluted protein S was then measured in an enzyme-linked immunosorbent assay. Microtiter wells were coated with rabbit anti-human protein S IgG (P4555 Sigma), 100 l at 5 g/ml in the above binding buffer overnight at 4°C, followed by three 10-min washes with binding buffer. Eluted protein S from the phospholipid titer wells (100 l of elution buffer) was then added to the antibody-coated wells and incubated for 3 h at room temperature, followed by three 10-min washes with binding buffer. Mouse anti-human protein S monoclonal antibody 2a was then added (100 l, 2 g/ml) and incubated overnight at 4°C. After washing, 100 l of a 1:4000 dilution of horse anti-mouse IgG monoclonal antibody-peroxidase conjugate (PI-2000, Vector Laboratories, Burlingame CA) was applied and incubated for 1 h at room temperature. The plates were then washed six times with binding buffer, followed by the addition of enzyme substrates (100 l of 50 mM citrate buffer, pH 5.0, containing 0.1 mg of o-phenylenediamine and 0.04 l of 30% H 2 O 2 ) and a 5-min incubation at room temperature. The reactions were quenched by the addition of 50 l of 4 M H 2 SO 4, and the absorbance at 490 nm was measured on a V max spectrophotometer (Molecular Devices, Menlo Park, CA). Absorbance at 490 nM versus initial protein S concentration was plotted, and apparent K d values were calculated with the computer software PRIZM (GraphPad, San Diego, CA), assuming that protein S has one global binding site for phospholipid. Fig. 1A shows the time-dependent cleavage of rHPS by factor Xa. The results indicate that a heavy chain cleavage product is generated, which is indistinguishable from that resulting from ␣-thrombin cleavage (lane 10). The digestion of protein S, shown in Fig. 1, was performed in the presence of 20 nM hirudin, demonstrating that the cleavage is not due to contaminating ␣-thrombin in the purified plasma-derived factor Xa. The addition of tick anticoagulant peptide (90 nM) or D-Glu-Gly-Arg-chloromethyl ketone (150 M), both specific factor Xa inhibitors, completely blocked the digestion of rHPS by factor Xa under identical conditions as that described in Fig. 1 (2-h incubation), indicating that the cleavage is indeed factor Xaspecific (data not shown). Also, no cleavage by factor Xa is observed in the presence of 5 mM EDTA or in the absence of CaCl 2 or phospholipid (data not shown), indicating that the cleavage is both phospholipid-and Ca 2 -dependent. RESULTS As shown in Fig. 1B, we also observed that factor Va nearly abolishes this cleavage under conditions where all the factor Xa is in the prothrombinase complex. These results suggest that factor Va inhibits the cleavage by interacting directly with factor Xa and preventing factor Xa accessibility to protein S. The results of NH 2 -terminal amino acid sequencing are shown in Table I. Comparison of the observed Edman degradation amino acid products with the published sequence of human protein S reveals that cleavage occurs on the carboxylterminal side of Arg 60 and is distinct from the two ␣-thrombin cleavage sites (shown schematically in Fig. 4). The effect of protein S cleavage by factor Xa on functional activity was measured in a factor VIII-dependent clotting assay. As a control, the effect of protein S cleavage by factor Xa was compared with that by ␣-thrombin. The functional consequences of rHPS digestion by factor Xa are presented in Fig. 2A. Under the conditions employed and as previously demonstrated, APC alone has impaired capabilities in inactivating factor VIII (filled squares). The effect of APC alone is equal to the effect of HPS alone (filled triangles). Thus, as described previously, HPS has an APC-independent effect on the intrinsic tenase. In the presence of both APC and HPS, there is a significant increase in factor VIII inactivation (filled circles). This increase in inactivation rates may be the result of increased rate of cleavages at Arg 336 and Arg 562. It is also possible that the increase in the inactivation rate seen in the pres- a The number in parenthesis indicates pmol of amino acid at the given cycle. b No predominant amino acid was observed, which is consistent with Cys at this point based on the sequence shown in Fig. 4. ence of HPS is the result of the two effects together (i.e. APCdependent and -independent) for intrinsic tenase formation. Following cleavage by factor Xa, there is loss of the APCindependent effect of HPS on factor VIII. Further, no effect on factor VIII inactivation by APC could be observed when factor Xa-treated HPS was added to the mixture. Thus, most likely, HPS acts synergistically with APC for the inactivation of intrinsic tenase assembly. APC acts by slow cleavage at Arg 336 and Arg 562 of factor VIII, whereas HPS acts by displaying factor VIII from the surface as described. Essentially identical time-dependent curves for factor VIII(a) inactivation were obtained for thrombin-digested rHPS and pHPS digested with factor Xa or thrombin. Fig. 2B depicts the results obtained following a 60-min incubation of factor VIII with APC with the various forms of HPS (plasma or recombinant) shown in Fig. 3C. A loss in the APC-dependent and -independent activity of both HPS and rHPS was observed under the conditions employed following treatment with either factor Xa or thrombin. These data are apparently in contradiction with previously published observations. The apparent discrepancy between our study and the study of Koppelman et al. can, however, be explained by the low concentration of HPS and the high lipid concentration used in our experiments. In order to determine whether the loss of protein S anticoagulant activity following cleavage by factor Xa or ␣-thrombin is due to a loss of its ability to bind to the lipid membrane surface, direct binding of protein S to PCPS was measured. As shown in Fig. 3, the binding curves for uncleaved and cleaved protein S, either by factor Xa or thrombin, are indistinguishable within the error of this assay. In all cases, an apparent K d of approximately 4 nM was derived. This low value, relative to other vitamin K-dependent plasma proteins, is in good agreement with those reported by others (7-70 nM) for human protein S from different sources and using various purification procedures and initially observed semiquantitatively by Nelsestuen et al.. Our results suggest that cleav-FIG. 2. Effect of rHPS with or without APC on factor VIII clotting activity. A, time course of factor VIII inactivation. Plasma-derived human factor VIII was incubated with dialyzed undigested or digested (factor Xa or thrombin) rHPS (with or without APC) for varying lengths of time, and the percentage of functional activity was measured in a clot-based assay as described under "Experimental Procedures." Percentage of activity is based upon a standard curve using different amounts of untreated factor VIII. Zero time incubation factor VIII alone clot time in the assay was 67 2 s, and no added factor VIII gave a clot time of 124 1 s., factor VIII alone; f, factor VIII plus APC; OE, factor VIII plus rHPS; q, factor VIII plus APC and rHPS;, factor VIII plus factor Xa-digested rHPS; E, factor VIII plus factor Xa-digested rHPS and APC. A decrease in percentage of factor VIII activity reflects functional HPS and APC anticoagulant activity. B, comparison of functional activity for different forms of protein S. 60-min incubation time points from panel A (rHPS (r) factor Xa digestion, with or without APC) are plotted on a bar graph. Also presented are 60-min time points from similar plots of remaining factor VIII activity after incubation with undigested or factor Xa (Xa)digested plasma-derived HPS (p) and with thrombin (Th)-digested HPS, in the presence or absence of APC. age of protein S by either factor Xa or thrombin has no apparent effect on its ability to bind to phospholipid and suggest that the loss of anticoagulant activity is not due to the protein's inability to bind to the lipid bilayer. DISCUSSION In this paper, we report the specific cleavage of protein S by the procoagulant factor Xa. This cleavage is both phospholipidand Ca 2 -dependent and is blocked by tick anticoagulant peptide and D-Glu-Gly-Arg-chloromethyl ketone, both specific inhibitors of factor Xa. As measured by a factor VIII-based clotting assay, factor Xa destroys both the APC-dependent and -independent anticoagulant activity of protein S under the conditions used. These results suggest a second or alternative proteolytic mechanism by which the anticoagulant activity of protein S may be physiologically regulated, involving factor Xa. Cleavage of protein S by factor Xa results in a heavy chain cleavage product that is indistinguishable by SDS-PAGE analysis from that generated by thrombin, suggesting that factor Xa cleavage is also in the thrombin-sensitive disulfide loop of protein S. This conclusion was confirmed by direct NH 2 -terminal sequencing of the heavy chain product, which indicates cleavage by factor Xa at Arg 60. It is notable that this site (shown in Fig. 4) is different from that for ␣-thrombin (Arg 49 and Arg 70 ). Furthermore, it does not resemble the canonical substrate cleavage site in the primary target for factor Xa on prothrombin, -Ile-Glu/Asp-Gly-Arg-X-, and therefore represents a novel cleavage site for factor Xa Our data demonstrate that cleavage of protein S by factor Xa at Arg 60 inhibits both its APC-dependent and -independent inhibitory activity with respect to the intrinsic tenase. Our data are in apparent contradiction with the data published by Koppelman et al.. However, the latter study used very high amounts of protein S in a system where limited membrane surface is available. In contrast, our study uses low amounts of protein S and saturating amounts of phospholipids. Thus, the APC-independent effect of factor Xa-cleaved or thrombincleaved protein S on the intrinsic tenase activity can be only visible under conditions where limited membrane surface is available. It is also possible that the discrepancy between our results and the results of Koppelman et al. is due to the use of two different assays (activated partial thromboplastin time assay in the present work as compared with an Xa generation assay in the study of Koppelman et al.). Within experimental error, digestion by factor Xa or ␣-thrombin had no effect on the affinity of protein S for surface phospholipid (K d app 4 nM). The capacity for PCPS binding to thrombin-cleaved protein S appeared to be slightly reduced but not statistically significant. Failure of either factor Xa or ␣-thrombin cleavage of protein S to significantly alter the binding of protein S to phospholipid suggests that the loss of protein S anticoagulant activity by proteolysis is not the result of reduced membrane surface binding but is more likely due to the direct interactions of protein S with target protein components or with APC. van Wijnen et al. observed no difference between thrombin-cleaved and uncleaved human protein S binding to phospholipid. Contradictory results have been reported for thrombin-cleaved protein S by others using different forms of protein S and different assay systems. Walker observed a marked reduction in binding capacity (6-fold) for thrombin-cleaved bovine protein S but no difference in apparent K d, as measured by light scattering. Hackeng et al. also observed a reduced capacity of thrombin-cleaved human protein S to bind to cultured human umbilical vein endothelial cells. In contrast, Dahlback et al. observed no difference in binding of throm- FIG. 3. Effect of factor Xa or ␣-thrombin digestion on protein S binding to phospholipid. Absorbance at 490 nm due to enzyme-linked immunosorbent assay substrate conversion is plotted versus the concentration of rHPS present in the initial phospholipid binding assay (see "Experimental Procedures" for detail of the assay). Inset, apparent K d values were determined from the curves with the computer program PRISM. f, recombinant protein S undigested and not submitted to Fast Q-Flow Sepharose chromatography to remove PCPS prior to phospholipid binding (control); OE, undigested rHPS submitted to chromatography after the addition of PCPS;, factor Xa-digested rHPS submitted to chromatography;, thrombin-cleaved rHPS not submitted to chromatography. bin-cleaved versus uncleaved human protein S to platelet microparticles. The basis of these discrepancies is unclear and is not commented upon by the above authors, and it may involve the type of protein S utilized, the extent of proteolysis, purified component versus cellular substrates, and/or the nature of the binding assay. It is possible that endothelial cells have a protein receptor for protein S; thus, binding to synthetic phospholipid may be different in nature from binding to endothelial cells and cannot be compared. One very interesting finding presented here is that factor Va markedly inhibits cleavage of protein S by factor Xa. It is well established that factor Xa alone and factor Xa associated with factor Va (within prothrombinase) behave as two different enzymes. The most striking example of this is the activation of prothrombin to thrombin. Factor Xa alone activates prothrombin to thrombin with a first cleavage at Arg 284 followed by a second cleavage at Arg 322. In contrast, the order of cleavage is inverted when using prothrombinase, and prothrombin activation proceeds through the active intermediate meizothrombin. The inability of factor Xa to readily cleave protein S when it is associated with factor Va in the prothrombinase complex is consistent with a change in the catalytic properties of the enzyme. Under the initiation stages of whole blood clotting, the limiting component in prothrombinase formation (and thereby active thrombin generation) is factor Xa. Also, under these initial conditions factor Va is maintained in excess of prothrombinase. Our data suggest that an additional way in which factor Va acts to promote an initial procoagulant state is by sequestering factor Xa and/or altering its specificity, thereby increasing its ability to generate thrombin and reducing its ability to cleave protein S, which would also be expected to be present. An added benefit of this inhibition is that during the initial and propagation phases of clotting, protein S is spared from cleavage so that it can function at a later time as an anticoagulant and at distal locations from the site of desired clot formation. It has been known for many years that thrombin cleaves and abolishes the APC-dependent and -independent anticoagulant activity of protein S. However, this inactivation by thrombin may not be of physiological significance, as evidenced by the complete inhibition of protein S cleavage by thrombin at physiological concentrations of Ca 2 (2.5 mM). Furthermore, the endothelial surface protein, thrombomodulin, whose major role is to potentiate the activation of protein C via thrombin cleavage, also inhibits the cleavage of protein S by thrombin. Finally, at least in the context of protein S APC-cofactor function, cleavage and inactivation of protein S by thrombin would be inconsistent with thrombin's role as an anticoagulant via the protein C pathway. Cleavage and inactivation of protein S by a second protease, factor Xa, supports the idea that the thrombin-sensitive disulfide loop is conformationally poised for cleavage. Our results suggest that the cleavage of protein S by factor Xa may be an important component in physiological regulation of anticoagulant activity and hemostasis. |
package io.khasang.freefly.model;
/*
*
*
*
* */
public interface Call {
String getInfo();
}
|
def longestPrefix(left: str, right: str):
endMatch = 0
for i in range(0, min(len(left), len(right))):
if(left[i] == right[i]):
endMatch = endMatch + 1
else:
break
return left[0:endMatch]
class Node:
def __init__(self, key, keyNode):
self.keyNode = keyNode
self.key = key
# The children dict uses the first char,
# this makes efficient matching without looping
# possible.
self.children = {}
def matchOnChildren(self, key: str) -> tuple:
"""
Find a child that matches with this key. The key
returned shares the prefix returned. But might
be larger then the prefix.
If prefix == key -> it was an exact match.
If prefix != key -> only partial match len(key) > len(prefix)
returns: tuple(prefix, key)
"""
if key[0] in self.children:
k = self.children[key[0]].key
lp = longestPrefix(k, key)
if lp is not None:
return (lp, k)
return ("", "")
class RadixTrie:
def __init__(self):
self.root = Node(key=None, keyNode=False)
def search(self, key: str):
currentPosition = 0
node = self.root
while currentPosition < len(key):
remainingKey = key[currentPosition:]
(prefix, childKey) = node.matchOnChildren(remainingKey)
if prefix == "" or len(prefix) != len(childKey):
return None
if prefix == childKey:
node = node.children[childKey[0]]
currentPosition = currentPosition + len(prefix)
return node
def remove(self, key: str):
# same code as search, but keep track of the visited nodes
currentPosition = 0
node = self.root
visited = [node]
while currentPosition < len(key):
remainingKey = key[currentPosition:]
(prefix, childKey) = node.matchOnChildren(remainingKey)
if prefix == "" or len(prefix) != len(childKey):
return False
if prefix == childKey:
node = node.children[childKey[0]]
currentPosition = currentPosition + len(prefix)
visited.append(node)
# visited contains all the nodes up to the one that needs removal.
# Pop off the back and remove the nodes while they have no other
# children, and are not a keyvalue.
current = visited.pop()
current.keyNode = False
while(len(visited) > 0):
previous = visited.pop()
if not current.keyNode and len(current.children) == 0:
assert current.key[0] in previous.children
del previous.children[current.key[0]]
current = previous
def contains(self, key: str):
n = self.search(key)
return (n is not None) and (n.keyNode)
def insert(self, key: str):
currentPosition = 0
node = self.root
while currentPosition < len(key):
remainingKey = key[currentPosition:]
(prefix, childKey) = node.matchOnChildren(remainingKey)
if prefix == "":
# no match found -> add new edge
assert remainingKey[0] not in node.children
node.children[remainingKey[0]] = \
Node(key=remainingKey, keyNode=True)
return
elif prefix == childKey:
# either partial match or full match
node = node.children[childKey[0]]
if prefix == remainingKey:
node.keyNode = True
return
elif prefix != childKey:
# requires split!
interNode = Node(key=prefix, keyNode=False)
oldNode = Node(key=childKey[len(prefix):], keyNode=True)
interNode.children[oldNode.key[0]] = oldNode
newNode = Node(key=remainingKey[len(prefix):], keyNode=True)
if interNode.key != newNode.key:
interNode.children[newNode.key[0]] = newNode
del node.children[childKey[0]]
node.children[interNode.key[0]] = interNode
else:
assert False
currentPosition = currentPosition + len(prefix)
t = RadixTrie()
t.insert("hello")
t.insert("helloworld")
t.insert("china")
t.insert("chinese")
assert t.contains("china")
t.remove("china")
assert not t.contains("china")
|
The Kano Model Use to Evaluate the Perception of Intelligent and Active Packaging of Slovak Customers Abstract Intelligent innovation represents any autonomic change with positive impact to the customer. They increase the comfort of the customer and concurrently they represent more effective, more economical, healthier and safer solution. This term is not so usual in Slovakia, however intelligent innovation are present on the market. For that in the article intelligent innovation assessment, we focused on intelligent and active packaging, the occurrence of which we have mostly noticed on the Slovak market. The paper deals with the evaluation of the perception of packaging innovations by using the Kano model. According to research results, intelligent and active packaging influence customers and therefore constitutes a tool of competitiveness in Slovakia. However, considering the specification of their requirements, the degree of impact is very variable and specific to customers of different gender and age. |
Virtual reference amid COVID-19 campus closure: a case study and assessment Purpose This case study was conducted to assess and make changes to the consortial virtual reference service for the remainder of the period of fully virtual reference (campus closure);a second objective was to consider implications for service design and delivery upon the eventual return to the physical campus. Design/methodology/approach This paper begins by introducing the institution, reference practices prior to the pandemic and the changes to reference service necessitated by the campus closure. After a literature review of material related to reference and the pandemic, several years of virtual reference service data are analyzed. Findings The use of consortial virtual reference service has significantly increased in the pandemic, as demonstrated by questions asked by users and questions answered by librarians. Changes to work practices based on these data have been made. Originality/value This work is original in that it relates to the physical closure of the campus due to the pandemic, about which, to date, little has been published specifically concerning the design and delivery of reference services. |
<reponame>IanFinlayson/moonpatrol-gba
/* audio.c
* functions to handle audio playback */
#include "gba.h"
extern const signed char music_16K_mono [];
/* global variables to keep track of how much longer the sounds are to play */
unsigned int channel_a_vblanks_remaining = 0;
unsigned int channel_a_total_vblanks = 0;
unsigned int channel_b_vblanks_remaining = 0;
/* play a sound with a number of samples, and sample rate on one channel 'A' or 'B' */
void play_sound(const signed char* sound, int total_samples, int sample_rate, char channel) {
/* start by disabling the timer and dma controller (to reset a previous sound) */
TIMER0_CONTROL = 0;
if (channel == 'A') {
REG_DMA1_CONTROL = 0;
} else if (channel == 'B') {
REG_DMA2_CONTROL = 0;
}
/* output to both sides and reset the FIFO */
if (channel == 'A') {
SOUND_CONTROL |= SOUND_A_RIGHT_CHANNEL | SOUND_A_LEFT_CHANNEL | SOUND_A_FIFO_RESET;
} else if (channel == 'B') {
SOUND_CONTROL |= SOUND_B_RIGHT_CHANNEL | SOUND_B_LEFT_CHANNEL | SOUND_B_FIFO_RESET;
}
/* enable all sound */
MASTER_SOUND = SOUND_MASTER_ENABLE;
/* set the dma channel to transfer from the sound array to the sound buffer */
if (channel == 'A') {
REG_DMA1_SOURCE = (unsigned int) sound;
REG_DMA1_DESTINATION = (unsigned int) FIFO_BUFFER_A;
REG_DMA1_CONTROL = DMA_DEST_FIXED | DMA_REPEAT | DMA_32 | DMA_SYNC_TO_TIMER | DMA_ENABLE;
} else if (channel == 'B') {
REG_DMA2_SOURCE = (unsigned int) sound;
REG_DMA2_DESTINATION = (unsigned int) FIFO_BUFFER_B;
REG_DMA2_CONTROL = DMA_DEST_FIXED | DMA_REPEAT | DMA_32 | DMA_SYNC_TO_TIMER | DMA_ENABLE;
}
/* set the timer so that it increments once each time a sample is due
* we divide the clock (ticks/second) by the sample rate (samples/second)
* to get the number of ticks/samples */
unsigned short ticks_per_sample = CLOCK / sample_rate;
/* the timers all count up to 65536 and overflow at that point, so we count up to that
* now the timer will trigger each time we need a sample, and cause DMA to give it one! */
TIMER0_DATA = 65536 - ticks_per_sample;
/* determine length of playback in vblanks
* this is the total number of samples, times the number of clock ticks per sample,
* divided by the number of machine cycles per vblank (a constant) */
if (channel == 'A') {
channel_a_vblanks_remaining = total_samples * ticks_per_sample * (1.0 / CYCLES_PER_BLANK);
channel_a_total_vblanks = channel_a_vblanks_remaining;
} else if (channel == 'B') {
channel_b_vblanks_remaining = total_samples * ticks_per_sample * (1.0 / CYCLES_PER_BLANK);
}
/* enable the timer */
TIMER0_CONTROL = TIMER_ENABLE | TIMER_FREQ_1;
}
/* this function is called each vblank to get the timing of sounds right */
void on_vblank() {
/* disable interrupts for now and save current state of interrupt */
INTERRUPT_ENABLE = 0;
unsigned short temp = INTERRUPT_STATE;
/* look for vertical refresh */
if ((INTERRUPT_STATE & INTERRUPT_VBLANK) == INTERRUPT_VBLANK) {
/* update channel A */
if (channel_a_vblanks_remaining == 0) {
/* restart the sound again when it runs out */
channel_a_vblanks_remaining = channel_a_total_vblanks;
REG_DMA1_CONTROL = 0;
REG_DMA1_SOURCE = (unsigned int) music_16K_mono;
REG_DMA1_CONTROL = DMA_DEST_FIXED | DMA_REPEAT | DMA_32 |
DMA_SYNC_TO_TIMER | DMA_ENABLE;
} else {
channel_a_vblanks_remaining--;
}
/* update channel B */
if (channel_b_vblanks_remaining == 0) {
/* disable the sound and DMA transfer on channel B */
SOUND_CONTROL &= ~(SOUND_B_RIGHT_CHANNEL | SOUND_B_LEFT_CHANNEL | SOUND_B_FIFO_RESET);
REG_DMA2_CONTROL = 0;
}
else {
channel_b_vblanks_remaining--;
}
}
/* restore/enable interrupts */
INTERRUPT_STATE = temp;
INTERRUPT_ENABLE = 1;
}
|
Influence of Gain Saturation Effect on Transverse Mode Instability Considering Four-Wave Mixing Transverse mode instability (TMI) has been recognized as onse of the primary limiting factors for the average power scaling of high-brightness fiber lasers. In this work, a static model of the TMI effect based on stimulated thermal Rayleigh scattering (STRS) is established while considering the four-wave mixing (FWM) effect. The focus of the model is to theoretically investigate the TMI phenomenon and threshold power dominated by FWM. The gain saturation effect and fiber laser system parameters, such as seed power, pumping direction, and core numerical aperture, which have not been considered in the previous perturbation theory model, are also investigated. This work will enrich the perturbation theory model and extend its application scope in TMI mitigation strategies, providing guidance for understanding and suppressing TMI. |
. The receptor-binding domain(RBD) protein of HCoV-NL63 is a major target in the development of diagnostic assay and vaccine, it has a pivotal role in receptor attachment, viral entry and membrane fusion. In this study, we prepared 2 purified recombinant HCoV-NL63 RBD proteins using in E. coli system and identified the proteins by Western blotting. We first optimized codon and synthesized the RL (232-684aa)coding gene, then amplified the RL or RS(476-616aa) coding gene via PCR using different primers. The RL or RS coding gene was cloned into the pM48 expression vector fused with TrxA tag. The RBD (RL and RS) of HCoV-NL63 were expressed majorly as inclusion body when expressed in E. coli BL21pLys S under different conditions. The expressed products were purified by affinity chromatography then analyzed by SDS-PAGE and Western blotting. Our results showed that the recombinant RBD proteins were maximally expressed at 37 degrees C with 0. 8mM IPTG induction for 4h. RL or RS protein with 95 % purity was obtained and reacted positively with anti-sera from mice immunized with the recombinant vaccinia virus (Tiantan strain) in which HCoV-NL63 RL or RS protein was expressed. In conclusion, the purified recombinant RBD proteins(RL and RS)derived from E. coli were first prepared in China and they might provide a basis for further exploring biological role and vaccine development of HCoV-NL63. |
Structure-to-Function Relationship of Mini-Lipoxygenase, a 60-kDa Fragment of Soybean Lipoxygenase-1 with Lower Stability but Higher Enzymatic Activity* Lipoxygenase-1 (Lox-1) is a member of the lipoxygenase family, a class of dioxygenases that take part in the metabolism of polyunsatured fatty acids in eukaryotes. Tryptic digestion of soybean Lox-1 is known to produce a 60 kDa fragment, termed mini-Lox, which shows enhanced catalytic efficiency and higher membrane-binding ability than the native enzyme (Maccarrone, M., Salucci, M. L., van Zadelhoff, G., Malatesta, F., Veldink, G. Vliegenthart, J. F. G., and Finazzi-Agr, A. Biochemistry 40, 68196827). In this study, we have investigated the stability of mini-Lox in guanidinium hydrochloride and under high pressure by fluorescence and circular dichroism spectroscopy. Only a partial unfolding could be obtained at high pressure in the range 13000 bar at variance with guanidinium hydrochloride. However, in both cases a reversible denaturation was observed. The denaturation experiments demonstrate that mini-Lox is a rather unstable molecule, which undergoes a two-step unfolding transition at moderately low guanidinium hydrochloride concentration (04.5 m). Both chemical- and physical-induced denaturation suggest that mini-Lox is more hydrated than Lox-1, an observation also confirmed by 1-anilino-8-naphthalenesulfonate (ANS) binding studies. We have also investigated the occurrence of substrate-induced changes in the protein tertiary structure by dynamic fluorescence techniques. In particular, eicosatetraynoic acid, an irreversible inhibitor of lipoxygenase, has been used to mimic the effect of substrate binding. We demonstrated that mini-Lox is indeed characterized by much larger conformational changes than those occurring in the native Lox-1 upon binding of eicosatetraynoic acid. Finally, by both activity and fluorescence measurements we have found that 1-anilino-8-naphthalenesulfonate has access to the active site of mini-Lox but not to that of intact Lox-1. These findings strongly support the hypothesis that the larger hydration of mini-Lox renders this molecule more flexible, and therefore less stable. Lipoxygenases (Loxs) 1 form a homologous family of nonheme, non-sulfur iron containing lipid-peroxidizing enzymes, which catalyze the dioxygenation of polyunsatured fatty acids to the corresponding hydroperoxy derivatives. Mammalian Loxs have been implicated in the pathogenesis of several inflammatory conditions such as arthritis, psoriasis, and bronchial asthma. They are also thought to have a role in atherosclerosis, brain aging, human immunodeficiency virus infection, kidney diseases, and terminal differentiation of keratinocytes, because they are key enzymes in the arachidonate cascade, together with cyclooxygenases. In plants, lipoxygenases are active in germination, in the synthesis of traumatin and jasmonic acid, and in the response to abiotic stress. Recently, Lox activity has been shown to be instrumental in inducing irreversible damages to organelle membranes (4 -5), a process that might be the basis for the critical role of Loxs in programmed cell death induced by various pro-apoptotic stimuli. The biological activities of Loxs have attracted a growing interest on both their functional and structural properties. Plant and mammalian Loxs are made by a single polypeptide chain folded in a two-domain structure. The N-terminal domain is a -barrel of 110 -115 (mammals) and 150 (plants) residues, whereas the larger C-terminal domain is mainly helical and contains the catalytic site. Soybean lipoxygenase-1 (Lox-1) is widely used as a prototype for studying the structural and functional properties of lipoxygenases from tissues of different species. Lox-1 has a 30-kDa N-terminal domain and a 60-kDa C-terminal domain containing the catalytically active iron and the substrate-binding pocket. The function of the N-terminal -barrel domain has been elusive for several years, for Lox-1 as well as for other Loxs. Recently, the N-terminal domain has been shown to be essential for calcium binding and activation of 5-lipoxygenase activity and for nuclear membrane translocation of this Lox isoform (9 -10). Equilibrium unfolding experiments on Lox-1 have shown that the C-terminal domain is less stable than the N-terminal domain, undergoing chemical denaturation in the early steps of the complex protein unfolding process. The smaller N-terminal domain seems to retain a large part of its -barrel structure even at high urea concentration, suggesting that this portion of the protein structure might be important for the overall protein stability. Limited proteolytic cleavage of Lox-1 into the N-and C-terminal do-mains, and their subsequent isolation, have added new important structural and functional information. In particular, the electrophoretic, chromatographic, and spectroscopic analyses of the purified 60-kDa C-terminal domain of Lox-1 (termed "mini-Lox") have shown that the trimmed enzyme is still folded. Surprisingly, mini-Lox was shown to have a greater catalytic activity than intact Lox-1, thus suggesting a built-in inhibitory role for the N-terminal domain. In addition, mini-Lox displayed a higher binding affinity than Lox-1 for artificial membranes, attributable to the enhanced surface hydrophobicity exposed after removal of the 30-kDa N-terminal fragment. Interestingly, similar results have been recently reported about the effect of the N-terminal domain removal on the activity and membrane-binding ability of the reticulocytetype 15-lipoxygenase. A three-dimensional representation of mini-Lox can be generated from the Lox-1 crystallographic data (Fig. 1). The high number of trypthophans renders this enzyme spectroscopically very complex, as demonstrated by the great heterogeneity of the mini-Lox fluorescence spectrum. A somewhat greater solvent accessibility of aromatic chromophores of mini-Lox with respect to Lox-1 is apparent probably associated to a conformational change after proteolytic cleavage. In our study we have investigated the relationship between the activity of mini-Lox (e.g. enhanced enzymatic activity) and its structural features checked by circular dichroism, 1-anilino-8-naphthalenesulfonate (ANS) binding, steady-state, and dynamic fluorescence. Because the balance between the loss of hydrophobic interactions and the enhanced solvation upon the N-terminal removal is crucial to understand the mini-Lox properties, we have also studied the stability of mini-Lox using complementary techniques, such as chemical equilibrium unfolding measurements and denaturation by hydrostatic pressure. The results demonstrate that the removal of the Nterminal domain makes the mini-Lox more sensitive to denaturation by both guanidinium hydrochloride (GdHCl) and pressure. Furthermore, dynamic fluorescence measurements and ANS binding experiments provide new evidence that the active site is more accessible in the mini-Lox than in the Lox-1 and that quite different conformational changes follow the substrate binding in the two enzymes. All together these results provide a new structural rationale that might explain the peculiar mini-Lox features. EXPERIMENTAL PROCEDURES Materials and Enzymes-Linoleic (9,12-octadecadienoic) acid and 5,8,11,14-eicosatetraynoic acid (ETYA) were purchased from Sigma. Ultrapure guanidinium hydrochloride and ANS were purchased from US Biochemical Corp. and Molecular Probes Inc., respectively. Lipoxygenase-1 (linoleate:oxygen oxidoreductase, EC 1.13.11.12; Lox-1) was purified from soybean (Glycine max Merrill, Williams) seeds as reported, and mini-Lox was prepared as previously described. Briefly, Lox-1 was digested with trypsin at a Lox-1/trypsin 10:1 (w/w) ratio, which allowed completion of the reaction within 30 min. Chromatographic separation of the tryptic fragments was performed by high performance liquid chromatography gel-filtration on a Biosep-SEC-S3000 column (600 7.8 mm, Phenomenex, Torrance, CA). Fractions corresponding to the 60-kDa fragment eluted after 10 min as a single peak, and were pooled, dialyzed against water, and concentrated on Centricon 30 ultrafiltration units (Amicon, Beverly, MA). This 60-kDa fragment, referred to as mini-Lox, was found to be electrophoretically pure on 12% SDS-polyacrylamide gels, and its N-terminal amino acid analysis showed the sequence STPIEFHSFQ, which corresponds to a unique trypsin cleavage site between lysine 277 and serine 278. Such a cleavage should indeed remove a 30-kDa N-terminal domain of Lox-1, leading to a fragment of the expected molecular mass of 63,695 Da. Protein concentration was determined according to Bradford, using bovine serum albumin as a standard. Dioxygenase activity of mini-Lox in 100 mM sodium borate buffer (pH 9.0) was assayed spectrophotometrically at 25°C by recording the formation of conjugated hydroperoxides from linoleic acid at 234 nm. Except for lifetime measurements, all the experiments were performed dissolving Lox-1 and mini-Lox in 0.1 M Tris-HCl buffer (pH 7.2) at a final protein concentration of 1.5 M. For lifetime measurements, Lox-1 and mini-Lox were used at 10 M, to obtain a good signal to noise ratio. Equilibrium Unfolding Measurements-Protein denaturation by GdHCl was obtained after a 12 h incubation at 4°C in the presence of different amounts of denaturant. Fluorescence and CD spectra were recorded at 20°C after 30 min of incubation. Unfolding and refolding pathways were independent of protein concentration. Refolding of fully unfolded mini-Lox samples was achieved by diluting the denaturant concentration with buffer. The analysis of the unfolding transition was performed as described elsewhere, according to a two step denaturation pathway according to Scheme 1, (Table I). In the inset the mini-Lox enzymatic activity is reported as a function of GdHCl (filled triangles). The activity recovered upon refolding is instead indicated by empty symbols. A non-linear least-squares fit was used to evaluate the parameters reported in Table I, according to the minimum 2 value. A single transition model was instead sufficient to fit both the CD and activity data. Circular Dichroism, Steady-State, and Dynamic Fluorescence Measurements-CD spectra were recorded on a Jasco-710 spectropolarimeter, at 20°C, using a 0.1 cm quartz cuvette. Steady-state fluorescence spectra have been recorded using an ISS-K2 spectrofluorometer (ISS), at 20°C upon excitation at 280 nm. No differences were observed in fluorescence spectra when the excitation wavelength was varied from 280 to 295 nm due to a very efficient energy transfer from tyrosines to tryptophans. High pressure measurements were performed with the same instrument, using the high pressure ISS cell equipped with an external bath circulator. The analysis of the high pressure unfolding transition was performed assuming a two-state equilibrium model between native and intermediate species as shown in Equation 2 as follows, with ⌬G RTlnK 1 and ⌬V ( lnK 1 )/P). The fluorescence emission decay of both Lox-1 and mini-Lox was extrapolated from the phase-shift and demodulation data, obtained with the cross-correlation technique upon excitation at 280 nm, using the frequency-modulated light of an arc-xenon lamp, in the range 5-200 MHz. The emission was observed through a 305 nm cutoff filter to avoid the contribution of scattered light. 1-Anilino-8-naphthalenesulfonate Binding Measurements-ANS binding was measured as follows. Fluorescence spectra in the range 420 -550 nm were recorded as a function of the amount of ANS ( exc 350 nm), at fixed protein concentration, then each spectrum was resolved according to the linear combination in Equation 3 where S exp, S F, and S B are column vectors corresponding to the experimental, ANS-free, and ANS-bound spectra. C F and C B represent the extrapolated linear correlation coefficients representing the percentage of free and bound ANS, respectively. The spectrum of the totally bound ANS (S B ) was extrapolated, in a separate experiment, by varying the protein concentration, in the presence of a fixed amount of ANS. The ANS binding data have been represented as Scatchard plots and fitted according to models for one or two independent classes of sites as follows, L where represents the moles of ANS bound per moles of protein, is the concentration of free ANS, i 1 or 2, and n i and k i are the number of binding sites and the association constant of each class of sites. The fits were performed using the SPW 1.0 version of the Sigmaplot scientific graphic software (by Jandel Scientific). RESULTS AND DISCUSSION Mini-Lox Is a Rather Unstable Molecule-The stability of mini-Lox has been studied by equilibrium unfolding measurements at increasing GdHCl concentrations (Fig. 2). The noncoincidence of the fluorescence and CD measurements demon-strates that the unfolding transition was not cooperative and that the presence of stable intermediate species had to be taken into account. The simplest denaturation model, which successfully fitted the experimental data, was a three-state process, N 7 I 7 U (see "Experimental Procedures"), whose parameters are reported in Table I. As shown by the very early and steep increase of the fluorescence signal (Fig. 2), a small free energy of unfolding (Table I) characterizes the first transition (0 -1.5 M GdHCl). No relevant change occurred in the CD signal at low GdHCl concentration, and the data could be fitted according to a two-state model ( Table I). The overall stabilization energy obtained from the spectroscopic measurements (⌬G tot ). Combined refolding and proteolysis experiments have suggested that the C-terminal domain of Lox-1 is the less stable part of the intact enzyme. This domain, which roughly corresponds to the whole mini-Lox molecule, is probably fully unfolded in the intermediate state found in the Lox-1 denaturation pathway. The transition from the native structure to this intermediate species is characterized by a quite large free energy change (⌬G 1 0 14 kcal/mol), as compared with the total stabilization energy of mini-Lox (Table I). It can be therefore concluded that the low stability of mini-Lox is due to the removal of the 30-kDa N-terminal domain. As a matter of fact this hypothesis is indirectly supported by the m i values reported in Table I. The m parameter, which describes the cooperativity of the unfolding process, is strictly correlated to the change in protein-accessible surface area upon denaturation. In particular, greater hydration has been found to correspond to larger m values and vice versa. It is also well known that m values obtained with GdHCl are about 2.2 larger than those obtained with urea. Thus, even though different unfolding agents have been used in the equilibrium unfolding measurements of Lox-1 and mini-Lox (urea and GdHCl, respectively), it is possible to compare the different results obtained for the two proteins. In particular, from the results reported by Sudharshan and Appu Rao, it can be expected that the GdHCl-induced denaturation of Lox-1 would yield m 1 4.4 kcal/mol M and m 2 3.5 kcal/mol, for the first and second step of its unfolding pathway. On the other hand, the total m value for mini-Lox (Table I) is 3 kcal/mol, i.e. 30% less than that obtained in the first transition of Lox-1. This lower value stands for a smaller change in the solvent-exposed surface area, indicating that the native mini-Lox is more hydrated than the C-terminal domain of Lox-1. Thus, the Nterminal Lox-1 domain plays a fundamental structural role, shielding the other domain from the solvent and therefore enhancing its stability. Characterization of Mini-Lox Unfolding Intermediate under Hydrostatic Pressure-Despite its low stabilization energy, the mini-Lox unfolding pathway was complex (Fig. 2), suggesting Measurements of enzymatic activity demonstrated that the protein biological activity was progressively lost between 0 and 1.5 M GdHCl (Fig. 2, inset). The corresponding free energy value (⌬G 1.0 0.2 kcal/mol), very close to that calculated for the first fluorescence phase (Table I), reflects the high instability of the enzyme, especially around the active site region. In fact, in the same range a significant loosening of the protein tertiary structure was taking place, as revealed by the change (50%) of the protein intrinsic fluorescence signal (Fig. 2). These findings suggest that the intermediate state is partially un-folded, but it retains a native-like secondary structure. Such features resemble those of the so-called molten globule state, an unfolding intermediate species described in the denaturation pathway of several globular proteins. The most relevant property of this structure is indeed a greater exposure of the protein hydrophobic moieties to the solvent. In the case of mini-Lox, the great heterogeneity of the fluorescence spectrum, due also to a high number of tryptophan residues (Fig. 1), makes it impossible to dissect the contribution of each domain to the fluorescence of the intermediate state. In the last years, several studies have demonstrated that molten globule intermediates may be also produced by hydrostatic pressure, which may force solvent into the protein core. Fig. 3 reports the fluorescence spectra of mini-Lox at 1 and 2400 bar. A shift of the emission signal toward longer wavelengths at higher pressure values is observed (Fig. 3, inset), supporting the hypothesis of a progressive hydration of the internal tryptophylic residues. It almost perfectly overlaps the steady-state spectrum in the presence of 1.5 M GdHCl (Fig. 3), demonstrating that physically induced unfolding may neatly reproduce chemical denaturation. Actually, the two-state fit reported in the inset of Fig. 3 yields the same free energy of unfolding ( 1.5 kcal/mol) characterizing the first denaturation transition in GdHCl (Table I). The corresponding volume change has also been evaluated (see "Experimental Procedures") and resulted to be quite small (69 9 ml/mol), despite the large protein size ( 63,000 Da) as usually found by compression of globular proteins (24 -25). Recent studies on the pressure-induced molten globule state of cytochrome c, ␣-lactalbumin, apomyoglobin, and the Ras domain of RalGDS reported ⌬V values from 15 to 70 ml/mol, quite similar to that found here for mini-Lox, which, however, is a much larger molecule. In this line, the results obtained with point mutants of staphylococcal nuclease have suggested that the collapse of internal cavities under pressure might be the main source of the volume changes. Because the number and size of cavities in a protein have been found to be related to its molecular weight, the low ⌬V value obtained for mini-Lox could be explained by assuming that most protein cavities are already solvated at ambient pressure. Not only this hypothesis is consistent with the chemical denaturation experiments, but it could also explain the easier resiliency of mini-Lox with respect to Lox-1. In fact, at variance with the native enzyme (11, 34 -35), both pressure and GdHCl unfoldings of mini-Lox were fully reversible, being activity, CD, and fluorescence spectra fully recovered after restoring the initial conditions. Mini-Lox Conformational Changes upon ETYA Binding-Because mini-Lox is more active but less stable than Lox-1, we have investigated which conformational changes were involved in the biological activity. To this aim, both steady-state and dynamic fluorescence measurements were performed in the presence of ETYA, an irreversible inhibitor of lipoxygenase that rapidly binds at the active site. Normalized steady-state spectra of mini-Lox and Lox-1 in the presence and absence of ETYA are reported in Figs. 4a and 5a, respectively. The decrease in the emission intensity indicated that ETYA strongly quenches the intrinsic fluorescence of both proteins, yet the overall effect was remarkably different in the two cases. First of all, as revealed by the peak position (325 nm) and the full width at half-maximum, the spectral shape of Lox-1 spectrum did not change after incubation for 30 min in the presence of the inhibitor. The difference spectrum was symmetrical and centered at the same wavelength (325 nm), indicating that quenching is affecting in the same way both exposed and buried tryptophans. Instead, the fluorescence spectrum of mini-Lox appeared to be red-shifted and narrowed in the presence of ETYA (Fig. 4a). The difference spectrum, peaking around 315 nm, was diagnostic of a preferential quenching of the less hydrated tryptophylic residues in the protein. It is worth mentioning that the drop in fluorescence intensity following ETYA addition was not sudden, but required almost 30 min to reach equilibrium for both proteins (see insets of Figs. 4a and 5a). This finding strongly suggests that the quenching mechanism must be indirect, probably due to an induced protein conformational change upon ETYA binding. As a matter of fact, spectroscopic, structural, and chemical denaturation studies have shown that some tryptophylic residues are essential for the enzymatic activity of Lox-1, located in the hydrophobic substrate-binding site. Thus, a simple diffusion of ETYA into the active site would have led to a much faster quenching process than observed for both proteins (insets of Figs. 4a and 5a). Interestingly, the time course of this process was not the same in the two proteins: the fluorescence intensity of mini-Lox decreased exponentially, whereas much slower kinetics were observed in the case of Lox-1 (insets of Figs. 4a and 5a). One possible explanation for this different behavior might be the larger degrees of freedom experienced by the mini-Lox molecule. Thus, larger conformational changes might be expected for mini-Lox upon ETYA binding. This hypothesis has been checked by dynamic fluorescence measurements, which are in fact extremely sensitive to changes in the protein tertiary structure. The fluorescence decay of large, multi-tryptophan-containing proteins is heterogeneous and generally best described by continuous distributions of lifetimes, rather than by few discrete components. Previous measurements have shown that the dynamic fluorescence of Lox-1 may be resolved into a pair of lorentzian lifetimes distributions, probably associated to two distinct classes of tryptophylic residues, depending on their relative exposure to the solvent molecules. In the present study the phase and demodulation technique has been used to characterize the fluorescence decay of mini-Lox and Lox-1 upon excitation at 280 nm. The results, shown in Figs. 4b and 5b, demonstrate that in both cases a double distribution is required to fit the experimental data. Despite the peak positions being quite similar (i.e. c 1 1.25 ns and c 2 3.5 ns), the relative fractional intensities were inverted for mini-Lox (i.e. F 1 was greater than F 2 ). This result rules out the possibility that the short-lived component was essentially due to tryptophans located in the N-terminal domain of Lox-1, as previously suggested by urea unfolding measurements. The average lifetimes, evaluated from the distribution analysis of Lox-1 and mini-Lox, were Lox-1 1.18 ns and mini-Lox 1.00 ns, respectively, indicating a 20% more efficient dynamic quenching in the case of mini-Lox. This result could be indeed expected for a more solvated structure, as suggested for mini-Lox (see above). The analysis of the dynamic fluorescence measurements performed in the presence of ETYA yielded very similar distribution profiles (Figs. 4b and 5b), characterized by an overall shift toward shorter lifetimes and a marked decrease in the fractional intensity of the first component, F 1. The last effect was more evident for mini-Lox and paralleled the asymmetrical change of the fluorescence spectrum upon ligand binding (Fig. 4a). In conclusion, kinetics, steady-state and dynamic fluorescence measurements point to the occurrence of larger conformational changes in the tertiary structure of mini-Lox than of Lox-1. ANS Binding Experiments-ANS is a well known fluorescent probe, whose quantum yield considerably increases upon binding to hydrophobic pockets of proteins. Its emission spectrum also depends on the environment, being blue-shifted the deeper and tighter its interaction with the protein matrix. Hence ANS is a very suitable probe to investigate the formation of protein-fatty acids complexes (46 -47). Previous measurements on Lox-1 have demonstrated that the native enzyme has one binding site for ANS and that the enzymatic activity is not inhibited by the fluorescent probe. It was therefore concluded that ANS does not interact with the fatty acid-binding site, but rather interacts with another hydrophobic patch present in the protein structure. The above reported unfolding measurements and spectroscopic assays of mini-Lox have pointed out that the main structural differences between the two enzymes are associated with the solvent accessibility, at the level of their tertiary structure. We have therefore analyzed the binding of ANS to the protein. Fig. 6a reports the Scatchard plot for ANS binding to mini-Lox, showing a clear biphasic behavior indicative of the presence of multiple binding sites. Because no evidence for cooperativity was obtained by other procedures (e.g. Hill plots), the data were fitted according to models taking into account one or two different classes of independent binding sites (see "Experimental Procedure"). This last fit gave the best results (Fig. 6a), with one and four binding sites for the two classes, respectively, hence confirming that the mini-Lox surface is characterized by a larger number of hydrophobic patches than Lox-1. The association constants of the two classes (Fig. 6a) were largely different (the first one being 50 times greater than the second), indicating that the single site had enhanced affinity for ANS. At variance with Lox-1, a significant reduction of the enzymatic activity was obtained in the presence of ANS (Fig. 7, inset), suggesting that some kind of interaction between the probe and the protein active site was possibly taking place. To check this possibility another approach was used, i.e. measuring the spectrum of ANS after the mini-Lox active site was occupied by the irreversible inhibitor ETYA. The results demonstrated that the occupancy of the active site by ETYA reduced the ANS fluorescence by about 22% (Fig. 7), suggesting that the two molecules compete for the mini-Lox catalytic site. This hypothesis has been further tested by performing a titration of ANS binding to the mini-Lox-ETYA complex. In this case the linearity of the Scatchard plot (Fig. 6b) is a clear indication of similar binding sites. Indeed, a fit of the data yielded four identical, low affinity binding sites (Fig. 6b). This finding allows us to identify the higher affinity ANS-binding site found in the absence of ETYA with the enzyme active site. No effect of ETYA on the ANS binding was observed in control experiments performed with Lox-1 (data not shown). Kinetic measurements of ANS binding to both mini-Lox and Lox-1 revealed another interesting difference between the two enzymes ( Fig. 8). As shown in Fig. 8, a and b, the change of ANS fluorescence signal upon binding to mini-Lox was rather slow, requiring 15-20 min to reach equilibrium. This timedependence was observed only at low ANS/protein ratios, namely between 0.6:1 (Fig. 8a) and 2:1 (Fig. 8b). In these cases the ANS fluorescence intensity changes are probably due to re-arrangements of the protein tertiary structure, and in particular to fluctuations in the polarity of the ANS-binding site. No time dependence was detected in the case of Lox-1, at any ANS concentration (Fig. 8, a, b, and c, insets). Interestingly, the time course characterizing ANS fluorescence changes was the same found for ETYA binding, indicating that similar conformational changes might be induced in the protein tertiary structure to allow their access into the active site. CONCLUSIONS The fact that mini-Lox, the 60-kDa fragment of Lox-1, is more efficient than the whole native protein in both dioxygenase activity and membrane-binding ability is rather intriguing. In this paper we attempted to figure out which possible correlation holds between biological and structural features of mini-Lox. We have shown that the removal of the 30-kDa fragment from the 90-kDa molecule generates a more hydrated protein, which displays an increased affinity for hydrophobic probes like ANS. Mini-Lox appears to undergo larger conformational changes than Lox-1 upon ETYA and ANS binding, displaying greater sensitivity but also better reversibility after pressure-and GdHCl-induced unfolding. It could be argued that a larger structural flexibility due to the partial loosening of the tertiary structure is the main reason for the enhanced activity. In particular, the possibility of binding ANS in the active site is a direct evidence that mini-Lox gives the substrates an easier access to the hydrophobic cavity, where the catalysis takes place. In this context, the hypothesis that the N-terminal domain of Lox-1 could act as a built-in inhibitor of the enzymatic activity takes ground. It seems noteworthy that trypsin-trimmed Lox-1, as well as "reconstituted" Lox-1 obtained by adding the tryptic fragments of molecular mass 60 kDa to mini-Lox, showed the same activity as isolated mini-Lox, suggesting that these 60 kDa fragments had no effect on enzyme activity. This result is at variance with a previous report. On the other hand, an inhibition of mini-Lox by these fragments could be expected, in view of the enhanced activity of the trimmed enzyme compared with the native form. It can be proposed that the lack of effect (either stimulatory or inhibitory) of the 60 kDa fragments on mini-Lox activity simply reflects a different interaction between the N-terminal and C-terminal fragments after proteolysis. In addition, the N-terminal fragment could also make the native enzyme less able to bind hydrophilic molecules, and more selective toward hydrophobic molecules like its natural lipid substrates. By the way soybean Lox-1 is a 15-lipoxygenase and interestingly its mammalian counterpart, i.e. the rabbit reticulocyte 15-lipoxygenase, has a similar site for trypsin cleavage. The C-terminal domain generated by a cleavage at this site would have almost the same size (535 versus 562 amino acid residues) and an overall structure like mini-Lox (Fig. 9). Furthermore, the C-terminal domain of rabbit 15-lipoxygenase is similar to that of human 5-lipoxygenase. Therefore, it is tempting to speculate that what was found with mini-Lox might hold true also for mammalian lipoxygenases, and that the trimmed enzymes might play a role in physio(patho)logical conditions, where enhanced lipoxygenase activity and membrane lipoperoxidation have been observed, such as kidney disease in humans and programmed cell death in animals and plants. Noteworthy, in the latter organisms, a trypsin-like protease, termed SNP1, has been shown to be expressed during infection by pathogens, a typical situation where lipoxygenase is known to be activated. |
Pannexins in Acute Kidney Injury Acute kidney injury (AKI) is highly prevalent among hospitalized patients and is associated with serious consequences with limited pharmacological treatment options. Pannexin 1 (Panx1) channel is a ubiquitously expressed nonselective membrane transport channel that efficiently effluxes ATP and plays a central role in the progression of inflammatory diseases. Animal models that target Panx1 through pharmacological inhibition or genetic deficiency have better outcomes in minimizing inflammation and associated pathology. Given the involvement of Panx1 at multiple steps of inflammatory pathology, Panx1 could be a potential therapeutic target in the treatment of AKI. Further research is needed in elaborating the mechanisms and identifying Panx1-specific inhibitor molecules to better understand the role of Panx1 in AKI pathology arising due to diverse insults. |
Feta, a briny white cheese from Greece, is usually made from a mixture of goat and sheep’s milk. The tangy flavour of the cheese lends well to both uncooked and cooked preparations and is uniquely wonderful in dessert.
Tomatoes and cucumbers are two things you're guaranteed to find every single time you head to the market. Their beauty shines bright in a light and refreshing Greek salad. Briney olives emphasise the beauty of feta's saltiness while mint permeates the entire dish with minty, floral notes. Some people can barely cut onions without crying far less for eating it. If you're one of those who find raw red onion too pungent, soak your thin slices in a bowl of ice water for at least 10 minutes. This will tame its bite and surprisingly, won't leave you with smelly breath. Ensure you add it to your salad though, it's sharp bite makes this dish all the more interesting to eat. For a more filling meal, scoop up with a whole-wheat pita, or serve with hummus.
1 Add all the dressing ingredients to a small mixing bowl and mix. Season with salt to taste and store in refrigerator until you're ready to use it.
2 Add cucumber, tomatoes, onion, olives, feta and mint to a serving plate or large bowl.
3 A few minutes before serving, drizzle the dressing over top and gently toss to evenly coat. |
Differentially expressed microRNAs in dystrophindeficient muscle. Mutations in the dystrophin gene, resulting in the production of nonfunctional protein products, are responsible for causing Duchenne muscular dystrophy. What remains less clear is the underlying mechanisms whereby dystrophin deficiency results in well recognized pathologies. MicroRNAs are a subclass of RNA that generally cause degradation of specific transcripts, resulting in reduced protein expression. To better understand downstream consequences of dystrophin deficiency, we analyzed microRNA expression in dystrophic skeletal muscle. Our hypothesis was that dystrophin deficiency would cause a change in expressed microRNAs compared to control muscle. Purified total RNA from six week old, male gastrocnemii (n=4 mdx; n=4 C57) were analyzed with miRCURY™ LNA arrays (Exiqon, Denmark). We identified 37 microRNAs that were differentially expressed (p<0.0001). Of these, 17 were downregulated and 20 were upregulated, including mir206, in mdx mice compared to controls. Evaluation of the genes these microRNAs are predicted to regulate revealed an array of processes that are potential candidates for miRNA regulation. Therefore, these results may help to identify novel pathways that contribute to disease pathology. Partially supported by CIAG. |
Auto-generation of a centerline graph from a geometrically complex roadmap of real-world traffic systems using a hierarchical quadtree for cellular automata simulations This paper proposes a method of auto-generation of a centerline graph from a geometrically complex roadmap of real-world traffic systems by using a hierarchical quadtree for cellular automata simulations. Our method is summarized as follows. First, we store the binary values of the monochrome image of target roadmap (one and zero represent the road and the other areas, respectively) in the two-dimensional square map. Second, we recursively divide the square map into sub-leafs by a quadtree until the summed-up value of pixels included inside the leaf becomes equal to or less than one. Third, we gradually remove the distal leaves that are adjacent to the leaves whose depths are shallower than the distal leaf. After that, we trace the remaining distal leaves of the tree using Morton's space-filling curve, while selecting the leaves that keep a certain distance among the previously selected leaves as the nodes of the graph. Finally, each selected node searches the neighboring nodes and stores them as the edges of the graph. We demonstrate our method by generating a centerline graph from a complex roadmap of a real-world airport and by carrying out a typical network analysis using Dijkstra's method. INTRODUCTION Cellular automaton (CA), which was established by Neumann, has attracted scientists and researchers for years. Notably, after Wolfram found the Elementary CA Rule 184, the various families of CA have been acknowledged in the field of traffic flow problems. In recent vehicular traffic simulations, cellular automata have taken advantage of fine-grained background cells to represent the complex geometries of real-world systems. As depicted in Fig.1, the system selects representative cells from the background cells as the checkpoints and constructs a graph by connecting them. Because the vehicles move on the centerlines of the routes of the graph during simulations, it is necessary to extract a centerline graph from a roadmap for pre-processing in realistic vehicular traffic simulations. This study aims to conduct a preliminary research as the first step toward the auto-generation of the network graph used in practical traffic CA simulations. Promising approaches for centerline extraction from twisted paths can be found in computed tomography, environmental and urban engineering, distance-measurement based learning algorithms, and topological thinning. Here, focusing our interest on the problems of vehicular traffic simulations restricts the geographic shape of the target graphs, which are summarized as follows: A two-dimensional graph is sufficient. The graph passes around the centerline of the original road map when it is on straight roads. The graph has multiple lanes at intersections in order to represent various movements of vehicles around corners in realistic cases. Figure 2 illustrates the characteristics of to for reference. By considering these restrictions in this study, we can develop new techniques that comprises both straightforwardness and computational efficiency compared to the aforementioned related studies. In this paper, we propose a method to generate a centerline network graph from geometrically complex roadmaps of real-world systems by dynamically changing the structure of a hierarchical tree, by taking advantage of the characteristics of solid images. Our proposed method can be summarized as follows. First, we store the binary values of the monochrome image of target roadmap (one and zero represent the road and the other areas, respectively) in the two-dimensional square map. Second, we recursively divide the square map into sub-leafs by a quadtree until the summed-up value of pixels included inside the leaf becomes equal to or less than one. Third, we gradually remove the distal leaves that are adjacent to the leaves whose depths are shallower than that of the distal leaf, during the shrinking process. After that, we trace the remaining distal leaves of the tree using Morton's space-filling curve, while selecting the leaves that keep a certain distance from among the previously selected leaves as the nodes of the graph. Finally, each selected node searches the neighboring nodes and stores them as the edges of the graph. In short, we attempt to generate a centerline graph just by releasing the distal leaves. Our method significantly improves computational efficiency compared to the existing algorithms. For example, a grid search technique associated with the distance functions requires a computational time of O(N 2 ), where N indicates the number of pixels in one direction of the square map. If a graph generation algorithm includes the traveling salesman problem (TSP), it requires a computational time of O(N!) to get the exact solutions, and O(N 2 2 N ) to get approximations using a dynamic programming algorithm in typical cases, where N indicates the number of nodes. Meanwhile, the topological thinning-based algorithm reported in, which is the closest to our approach, requires a computational time of O(N 2 ), where N indicates the number of leaves. The reason for the high computational costs is because the algorithm in carries out the reconstruction of a quadtree in every iterative step of the shrinking process. In contrast, our method requires a one-time recursive tree construction. Substantially, our algorithm requires a computational time of O(klogN) to O(kN) for a shrinking process, where k indicates a scalar constant value. In this manner, our method not only has significant straightforwardness but also shows computational efficiency equal to that of the fastest state-of-the-art algorithms such as the one in. Note that, based on these advantages, we determine the value corresponding to the parameter k experimentally, as discussed in Section 2.4. The remainder of this paper is structured as follows. Section 2, which is divided into four parts, describes our method. In Section 3, we analyze the shortest path search using Dijkstra's algorithm. Section 4 summarizes our results and concludes this paper. Figure 3 shows the target roadmap, which we abstracted from a real-world airport, namely the Tokyo International Airport in Japan. We can divide our method into four processes: the construction process of a recursive tree on the roadmap, the release of distal leaves, the selection of nodes, and the connection of nodes by tracing the distal leaves using a space-filling curve. Figure 4 shows a flowchart of our proposed method. Data structure of leaves We store each element of the monochrome image of the roadmap depicted in Fig. 3 in a corresponding cell of the two-dimensional N r N r array. Here, the value of one or zero in each cell represents the road and the other areas, respectively. The parameter N r denotes the number of cells in either of the vertical or horizontal directions in the original roadmap, whichever is larger. After that, we recursively divide the square map into 2 2 sub-leafs by a quadtree, each leaf of which has the following data structure: Here, the vectors L min and L max indicate the minimum and maximum coordinates of the leaf and correspond to and (N r, N r ) at a depth of zero, respectively. The parameter D represents the depth of the leaf. The parameter R indicates the ordering index designated by their parent leaf, which determines the geometric location of the leaf among the bundle of sub-leafs. A space-filling curve is a recursive curve that fills a space or area with a single stroke of a brush ; by making the ordering indices of sub-leafs correspond to the space-filling curve, we can trace all the distal leaves using a sequential single curve. Here, the ordering pattern R is individually determined by the type of space-filling curve. There exist several types of space-filling curves. In this paper, we use Morton's curve (Z-curve) because of its simplicity. The Morton's curve gives indices between 0 and 4 to the sub-leafs; therefore, the trajectory of traversing the sub-leafs produces a "Z" shape. Hence, the parameter R is always a number from 0 to 4. The binary parameter F end represents whether the leaf is a distal leaf or not. We determine the F end of each leaf in Algorithm 1, which is shown later. Meanwhile, we use the binary parameter F del and parameter S del to judge whether we can release the distal leaf or not in Algorithm 5. In addition, the parameter F chk indicates whether we can select the leaf as a node of the graph or not, and we obtain F chk of each leaf using Algorithm 6. Recursive quadtree construction Algorithm 1 describes the procedure of the recursive quadtree construction. Lines2-9 show the process of initialization of all the parameters of each leaf. In the process after line9, we recursively divide the N r N r map into 2 2 sub-leafs by a quadtree. The parameter B p indicates the state of a cell, which becomes one when the leaf is inside the road and zero in other cases. In line10, we define B s p as the summed up value of B p inside the leaf. We keep performing recursive division of the tree until the value of B s p in each leaf becomes equal to or less than one. As a result, each of the deepest distal leaves corresponds to a single cell on the road. Figure 5 shows a hierarchically structured mesh constructed on the roadmap of the airport depicted in Fig. 3. Here, two important observations are made. First, the distal leaves covering the cells on the inner edges of the roads always have the maximum depth of the tree. Second, each cell on the inner edges of the roads are always adjacent to the other leaves that have a shallower depth than the cell. By utilizing these characteristics, we retain only the leaves located around the centerline by releasing leaves through the processes in Algorithms 3 to 5. Figure 6 shows the process of tracing all the distal leaves by "a single stroke of a brush" using Morton's curve. Here, for easy access to the distal leaf of the tree, we introduce a conventional technique of a pointer table as shown in Algorithm 2. We can set a sequential number for all the distal leaves by incrementing the number every time Morton's curve traverses two different distal leaves. We can create one more N r N r array and fill the area paved by a distal leaf with the index of the leaf. Similarly, it is possible to store the pointer of each distal leaf in an N r N r array, as shown in line8. This pointer table not only makes it easier to access all the distal leaves but also simplifies all the algorithms. Additionally, we store a pointer of the parent leaf in line 2, which we use in the process of releasing the leaves in Algorithm 5. Figure 7 illustrates a schematic of releasing the distal leaves. Here, we consider a one-dimensional case using a binary tree for easy explanation. The parameter D mes max indicates the maximum depth of the tree measured by tracing all the distal leaves using Morton's curve. First, we find out the leaves that are adjacent to the leaves having a shallower depth by one level compared to the deepest leaf. We flag them as the candidates and change their F del from false to true. In this case, we flag the leaf d and leaf f as the candidates because leaf e has a shallower depth. We need to prevent the tree from over-releasing leaves because the tree releases them by units of a bundle of sub-leafs. We count the number of F del whose state is true in every bundle of sub-leafs and store it in the S del of their parent leaf. When the S del of a leaf is zero, the leaf has no candidate sub-leaf to be released. Hereinafter, we refer to such a leaf as "a stable leaf." Next, leaf B searches the state of neighboring leaves (A and C). Because leaf B is connected with a stable leaf A, we keep the distal leaf d as a candidate sub-leaf to be released. On the other hand, we have to exclude leaf f from the list of candidates regardless of the state of leaf D because leaf f connects with a vacant leaf g, which is located outside the roads. In the end, leaf B, a bundle comprising leaf c and leaf d, is released. Leaf.R ← R 6: Release of distal leaves Leaf.F end ← false 7: Leaf.F del ← false 8: Leaf.S del ← 0 return Leaf 23: end function Algorithm 3 shows the procedure of selecting the candidates to be released. First, we detect one of the distal leaves by the process in lines 2-6. After finding a distal leaf, we examine the depth of the four neighboring leaves existing in the vertical or horizontal direction of the distal leaf as described in lines12-26. If we find that at least one of the four neighboring leaves has a shallower depth than D mes max, we change the F del of the leaf from false to true as shown in lines27-29. After that, in Algorithm 4, we count the number of F del whose state is true in every bundle of sub-leafs and store it in the S del of their parent leaf as described in lines 9-14. As aforementioned, when the value of S del of a leaf becomes zero, the leaf has no candidate sub-leaf to be released (the leaf can be considered a "stable leaf"). Finally, we remove leaves according to the procedure in Algorithm 5. We detect one of the parents of the distal leaves through the process in lines2-7. After finding a parent of a distal leaf, we descend to each of the four child leaves of the leaf as described in line10. We then examine the value of S del of each parent of the leaves neighboring each child leaf as described in lines13-24. When the value of S del becomes zero, a bundle of the leaves including the neighboring leaf of the child leaf remains; we conclude that the child leaf is connected to "a stable leaf". In this case, we change the F nbr from false to true. On the other hand, we check the value of F del of each child leaf. If at least one of F del of child leaves is true, we change F cnd from false to true in lines27-32. As long as both F nbr and F cnd are true, we release all the child leaves as described in lines33-39. We set the parameter F stop to be false at the root of the tree. By examining the value of F stop after performing Algorithm 5, we can judge whether the release of leaves occurs at least once or not. We repeat the procedures in Algorithms 3 to 5 to shrink the area around the centerline. It should be noted that it is necessary to update the pointer table Table(i, j) and D mes max at every step after executing the processes in Algorithms 3 to 5. Let us define N rep as the number of times the shrinking process is repeated and N max rep as the number of times it is repeated until F stop changes from false to true. Practically, repeating the shrinking process N max rep times often causes over-release of the leaves. In the example shown in Fig. 8, the parameter N max rep becomes eighteen while it is adequate to set N rep to six for generating a centerline graph. Hence, it is reasonable to regard the parameter N max rep as a limit of iteration; at present, the actual number of N rep needs to be adjusted for individual cases in the range from zero to N max rep. The shrinking process by using Algorithms 2 to 5 requires less computational time compared to the case of reconstructing quadtrees in every step of the N rep iterations. Figure 9 shows a comparison of the computational time end if 14: end function consumed for the shrinking process between the repetitive reconstruction of quadtree and the proposed method, on a single core of an Intel Core i7-8650U CPU (1.90GHz). The result shows that our approach reduces the computational time by about 2.95 times compared to the repetitive tree reconstruction-based method. Selection and connection of nodes After shrinking the road areas using Algorithm 5, we trace all the remaining distal leaves of the tree by Morton's curve to choose the nodes from these distal leaves, which keep a certain distance, from among the previously selected nodes as described in Algorithm 6. To begin with, we detect one of the distal leaves by using the procedure in lines2-6. After finding a distal leaf, we check the distance between the leaf and all the already registered nodes in lines8-14. Here, the parameter N crr chk represents the number of registered nodes. If all the distances between the leaf and each node registered at that time become larger than a certain distance, we change the F chk of the leaf from false to true and add the leaf to the list of registered nodes. After that, we increment the parameter N crr chk by one as shown in line18. Algorithm 7 describes the procedure of connection of nodes, and Figure 10 shows its schematic view. First, we define a cut-off radius. Each node searches the other nodes located within the range as in lines5-6 of Algorithm 7. When the node j finds that another node i satisfies this condition, the node j checks whether the relative vector from node j to node i only traverses the cells on the roads as shown in lines7-18. If it is true, the node j adds the node i to its connectivity list as shown in lines19-21. The cut-off radius is the parameter that controls the degree of connectivity among the nodes; we experimentally determine it within a few times as large as the parameter in typical cases to strengthen the connectivity at intersections while keeping the geometry of the original roadmap. To summarize, we have two deterministic parameters and two experimental parameters: the number of cells in one direction N r, the distance among nodes, the number of times of repeating the shrinking process N rep, and the cut-off radius. Figure 11 shows a graph generated from the roadmap of Fig. 1 by using the procedures in Algorithms 1 to 7, and Figure 12 shows an enlarged view of Fig. 11. The white-colored rectangle lines indicate the hierarchically structured leaves at a depth of zero, for reference. We set the pair of (N r,, N rep, ) to be to generate the graph. It was confirmed that the paths were constructed near the centerlines for the straight roads and multiple lanes were connected around each intersection. A short path search using Dijkstra's algorithm As a case study, we carry out a shortest-path finding using Dijkstra's algorithm for a network generated from the Tokyo International Airport in Japan. In one example, we calculate the shortest paths from the entrance of the high-speed taxiway in runway B to the departure lane of runway C or that of runway D via a checkpoint in Terminal 1. end if 32: end function Figure 13 shows the calculated paths from node a to node b or node c via node d by using Dijkstra's algorithm, and Figure 14 shows an enlarged view of Figure 13. Several reasonable results are observed. First, the calculated paths show a characteristic of Euclidean distance rather than Manhattan distance because of the high-resolution image of the roadmap. We confirmed that the path connecting node a and node d crosses the runway A as diagonally as possible. This is understandable because of the "triangle inequality" relation among the three edges of a rectangle, the diagonal vertices of which are given as node a and node b. A similar explanation can be made for the fact that the path connecting node d and node c shows two straight lanes including a single corner. Discussions for future work As mentioned in the Introduction, this paper aims to conduct a preliminary study as the first step toward the autogeneration of the network graph used in practical traffic CA simulations. To discuss the applicability of our method to traffic CA simulations quantitatively, we examine the node connectivity of the generated graph in Fig.14. Figures 15(a) to (e) show the histograms of the node connections for different between 12 and 44; the horizontal axis indicates the number of connections per node, and the vertical axis shows their distributions in each case. In Fig.15(c), the nodes on the straight roads contribute to the emergence of a peak at the value of six, which indicates that the nodes on the straight lines connect each other not only between the neighboring nodes but also among three nodes away in the front end if 17: end function and back directions. It can be said that this redundant connectivity could enrich the functionality of the applications such as bypass roads or passing phenomena. Furthermore, Fig.15(f) shows the dependence of the positions of the peaks generated by the nodes of the straight roads on the parameter. Figure 15 clearly shows that the number of connections between nodes on straight roads is proportional to the parameter. Meanwhile, the nodes at the intersections contribute to the moderate distribution at the lower part of each case. The dispersion of each distribution directly correlates to that of the connections at each node; thus, the sharp distribution provides a high uniformity for the number of selections of paths at intersections. From Fig.15(a), it can be seen that most of the nodes at the intersections connect with two nodes because of the small, and therefore the second peak emerges (here, we several nodes disconnect from each other because the parameter is too small; as for the setting of the parameter, we must adjust the parameter experimentally as described in Section 2.4). In any case, the histograms in Fig.15 give an objective view of the generated graphs. Further comparisons of these histograms in different related methods must be conducted in a future work. CONCLUSIONS In this paper, we proposed an effective method for the auto-generation of a centerline graph from geometrically complex roadmaps of real-world traffic systems by using a hierarchically structured tree. Our method is summarized as follows. First, we store the binary values of a solid image of a roadmap in a two-dimensional square map. Second, we recursively divide the square map into sub-leafs by a quadtree until the summed-up value of pixels included inside the leaf becomes equal to or less than one. Third, we gradually remove the distal leaves that are adjacent to the leaves whose depths are shallower than the distal leaf during the shrinking process. After that, we trace the remaining distal leaves of the tree using Morton's curve, while selecting the leaves that keep a certain distance from among the previously selected leaves as the nodes of the graph. In the end, each selected node searches the neighboring nodes and stores them as the edges of the graph. The features of our method are as follows: a straightforward method using only a hierarchical tree without combining any other supportive algorithms such as distance function, the direct generation from a solid image, and multiple lanes at each intersection. Besides, our method significantly improves computational efficiency compared to the existing algorithms; it requires only a one-time recursive tree construction. This is a significant point compared to the previous studies. Additionally, we demonstrated the shortest-path findings of the generated graph using Dijkstra's algorithm. It is quite meaningful that we successfully established a methodology to generate a network graph that is suitable for the studies of vehicular traffic CA simulations. Two-dimensional graph from a solid image Centerline |
. In the absence of epidemiological data concerning France, indirect assessment was undertaken of the incidence and prevalence of cerebrovascular accidents (CVA) at a national level. An international comparison of mortality data concerning diseases of the circulatory system was first made. This analysis reviewed the existence of a certain number of inherent difficulties in the use of available statistics. It is probable that a notable proportion, increasing with age, of cases of CVA, are situated in undefined causes. A similar phenomenon should be noted with regard to cardiac causes (changes in diagnostic practice in the case of ischemic heart disease). Furthermore, mortality data for CVA are very sensitive to the effect of the age and sex structures of the populations considered. Between the years 50 and 80, the absolute number of annual deaths by CVA roughly rose from 60 000 to 70 000 in France. However, after adjustment taking into account changes in numbers, age and sex and undetermined causes, there is a marked decrease in comparative levels (almost 40%). This decrease is of the same order of magnitude as that for mortality of circulatory system diseases taken overall, as well as that of general mortality. CVA remains the 3rd cause of death (in terms of numbers) but it is only in 8th place, in terms of loss of life expectancy. Taking as the reference the American National Survey of Stroke, using a certain number of hypotheses, it is possible to estimate the incidence of CVA in France. This gives an annual number of cases of the order of 140 000, including approximately 100 000 cases of initial CVA. The corresponding prevalence is estimated at 470 000 (mean numbers of individuals suffering one or more CVA). |
nome = str(input('Escreva seu nome completo:')).strip()
print('Seu nome em letras maiúsculas é {}'.format(nome.upper()))
print('Seu nome em letras minúsculas é {}'.format(nome.lower()))
print('Seu nome tem ao todo {} letras'.format(len(nome)-nome.count(' ')))
print('Seu primeiro nome tem {} letras'.format(nome.find(' ')))
|
A Decision Analysis Approach to the Swine Influenza Vaccination Decision for an Individual We present a method to analyze the decision by an individual, whether to receive the swine influenza (A/New Jersey) vaccine, including an approach for health care personnel to use in informing an individual about the personal costs, benefits and probabilities, as well as indicated choices of actions, associated with such decisions. This analysis is a prototype for cases where informed consent requirements have prompted increased patient involvement in personal medical decisions. Probabilities and personally assessed values that affect the decision are: reaction to the injection, attack rates, vaccine efficacy, chances for an epidemic and concomitant probabilities of contracting influenza, and mortality. We specify a preference ordering for consequences of receiving the vaccine. The analysis yields a preference ordering for possible actions because relative values reflecting preferences are compared on a fixed consistent scale. The solution exhibited, determined in the fall of 1976, indicates conditions when selection of the action to receive the vaccine is automatic. In cases where the decision is not automatic, an individual needs additional information about the personal value of death (life), relative to other possible outcomes. We previously have developed a noneconomic approach to the determination of the value of death15 and the results, briefly described in this paper, are used to construct a decision region for the choice of receiving the vaccine that depends on both the probability of an epidemic and the value of death. Surprisingly, inclusion of information about the Guillain-Barr syndrome does not necessarily alter the decision to receive the vaccine, even though recognition of the increased incidence of the syndrome caused by the vaccine caused cancellation of the federal program. |
def drawio_executable_paths(self, platform):
if platform == 'darwin':
applications = [
os.path.expanduser('~/Applications'),
'/Applications',
]
drawio_path = os.path.join('draw.io.app', 'Contents', 'MacOS', 'draw.io')
return [os.path.join(dir, drawio_path) for dir in applications]
elif platform.startswith('linux'):
return ['/opt/draw.io/drawio']
elif platform == 'win32':
program_files = [os.environ['ProgramFiles']]
if 'ProgramFiles(x86)' in os.environ:
program_files.append('ProgramFiles(x86)')
return [os.path.join(dir, 'draw.io', 'draw.io.exe') for dir in program_files]
else:
self.log.warn('Draw.io executable paths not known for platform "{}"'.format(platform)) |
/*
Copyright 2021 The KCP Authors.
Licensed under the Apache License, Version 2.0 (the "License");
you may not use this file except in compliance with the License.
You may obtain a copy of the License at
http://www.apache.org/licenses/LICENSE-2.0
Unless required by applicable law or agreed to in writing, software
distributed under the License is distributed on an "AS IS" BASIS,
WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
See the License for the specific language governing permissions and
limitations under the License.
*/
package framework
import (
"context"
"fmt"
"testing"
"time"
)
// TestingTInterface contains the methods that are implemented by both our T and testing.T
// Notably, methods for changing control flow (like Fatal) missing, since they do not function
// in a multi-goroutine context.
type TestingTInterface interface {
Cleanup(f func())
Deadline() (deadline time.Time, ok bool)
Error(args ...interface{})
Errorf(format string, args ...interface{})
Failed() bool
Helper()
Log(args ...interface{})
Logf(format string, args ...interface{})
Name() string
Parallel()
Skip(args ...interface{})
SkipNow()
Skipf(format string, args ...interface{})
Skipped() bool
TempDir() string
}
func NewT(ctx context.Context, t *testing.T) *T {
return &T{
T: t,
ctx: ctx,
errors: make(chan error, 10),
}
}
// T allows us to provide a similar UX to the testing.T while
// doing so in a multi-threaded context. The Go unit testing
// framework only allows the top-level goroutine to call FailNow
// so it's important to provide this interface to all the routines
// that want to be able to control the test execution flow.
type T struct {
*testing.T
ctx context.Context
errors chan error
}
// the testing.T logger is not threadsafe...
func (t *T) Log(args ...interface{}) {
t.T.Helper()
t.T.Log(args...)
}
// the testing.T logger is not threadsafe...
func (t *T) Logf(format string, args ...interface{}) {
t.T.Helper()
t.T.Logf(format, args...)
}
func (t *T) Errorf(format string, args ...interface{}) {
t.errors <- fmt.Errorf(format, args...)
}
// Wait receives data from producer threads and forwards it
// to the delegate; this call is blocking.
func (t *T) Wait() {
t.T.Helper()
for {
select {
case <-t.ctx.Done():
return
case err := <-t.errors:
t.T.Helper()
t.T.Error(err)
}
}
}
var _ TestingTInterface = &testing.T{}
var _ TestingTInterface = &T{}
|
Interfacial AtomSubstitution Engineered TransitionMetal Hydroxide Nanofibers with HighValence Fe for Efficient Electrochemical Water Oxidation Abstract Developing lowcost electrocatalysts for efficient and robust oxygen evolution reaction (OER) is the key for scalable water electrolysis, for instance, NiFebased materials. Decorating NiFe catalysts with other transition metals offers a new path to boost their catalytic activities but often suffers from the low controllability of the electronic structures of the NiFe catalytic centers. Here, we report an interfacial atomsubstitution strategy to synthesize an electrocatalytic oxygenevolving NiFeV nanofiber to boost the activity of NiFe centers. The electronic structure analyses suggest that the NiFeV nanofiber exhibits abundant highvalence Fe via a charge transfer from Fe to V. The NiFeV nanofiber supported on a carbon cloth shows a low overpotential of 181mV at 10mAcm−2, along with longterm stability (>20h) at 100mAcm−2. The reported substitutional growth strategy offers an effective and new pathway for the design of efficient and durable nonnoble metalbased OER catalysts. S3 transmission electron microscope (TEM) was performed by Tecnai G2 F20 S-TWIN operated at 200 kV. X-ray diffraction (XRD) measurements were characterized by Rigaku Ultima IV with Cu K irradiation. X-ray photoelectron spectra (XPS) measurements were performed on K-Alpha™+ X-ray Photoelectron Spectrometer System (Thermo Scientific) with Hemispheric 180° dual-focus analyzer with 128-channel detector and a monochromatic Al K irradiation. X-ray absorption spectra (XAS) were collected on the beamline BL07A1 in NSRRC (National Center for Synchrotron Radiation Research). The radiation by scanning a Si double-crystal monochromator. Electrochemical Measurements: In a typical preparation of catalyst ink, 10 mg of each catalyst was blended with 1.0 mL Nafion ethanol solution (0.5 wt%) in an ultrasonic bath for 30 min. The carbon cloth (CC) and Ni foam (NF) were ultrasonically cleaned by acetone, ethyl alcohol, and ultrapure water in sequence for 20 min. Subsequently, the CC was submerged in a 2 M H 2 SO 4 solution for another 12 h, and the nickel foam was sonicated in 2 M HCl for 20 min. To remove any additional acid, the CC and NF were rinsed with ultrapure water several times and then left dry in the air. Then a fixed volume of catalyst ink (10 mg mL -1 ) was pipetted onto the NF (loading: 1 mg cm −2 ), CC (loading: 1 mg cm −2 ), and glassy carbon electrode (loading: 0.255 mg cm −2 ). All the electrochemical measurements were carried out in a conventional three-electrode cell using the Gamry reference 600 workstation (Gamry, USA) at room temperature. A commercial reversible hydrogen electrode (RHE) was used as the reference electrode, and the graphite rod was used as the counter electrode. The Ag/AgCl reference electrode calibrated with RHE in 1 M KOH was used as a reference electrode for long-time stability measurement. NF (1.0 1.0 cm 2 ) and CC The electrochemically active surface area was estimated by measuring the capacitance of the double layer at the solid-liquid interface with cyclic voltammetry. The measurement was performed S4 in a potential window of 0.82-0.92 V versus RHE, where the Faradic current on the working electrode was negligible. The series of scan rates ranging from 50 to 300 mV s −1 was applied to build a plot of the charging current density differences against the scan rate at a fixed potential of 0.87 V. The slope of the obtained linear curve was twice of the double-layer capacitance (C dl ). Electrochemical impedance spectroscopy (EIS) was carried out with a potentiostatic EIS method with a DC voltage of 1.495 V versus RHE in an Ar saturated 1.0 M KOH electrolyte from 100 kHz to 0.1 Hz with a 10 mV AC potential at 1600 rpm. The stability tests for the catalysts were conducted using chronopotentiometry at the constant working current densities of 10, 20, and 100 mA cm −2. The TOF values were calculated as the number of oxygen molecules evolved per active site per second based on the following equation: Where J is the current density (A cm -2 ) at the overpotential of 350 mV, A is the effective surface geometric area of the working electrode (0.196 cm -2 ), F is the Faraday constant, and n is the number of the active metal on the electrode. The TOFs data was calculated based on the weight content (from XPS) of the Fe in the catalysts. |
/**
* This class was generated by MyBatis Generator.
* This class corresponds to the database table weixin_message
*
* @mbg.generated Tue Sep 24 15:52:07 CST 2019
*/
protected abstract static class GeneratedCriteria {
protected List<Criterion> criteria;
protected GeneratedCriteria() {
super();
criteria = new ArrayList<Criterion>();
}
public boolean isValid() {
return criteria.size() > 0;
}
public List<Criterion> getAllCriteria() {
return criteria;
}
public List<Criterion> getCriteria() {
return criteria;
}
protected void addCriterion(String condition) {
if (condition == null) {
throw new RuntimeException("Value for condition cannot be null");
}
criteria.add(new Criterion(condition));
}
protected void addCriterion(String condition, Object value, String property) {
if (value == null) {
throw new RuntimeException("Value for " + property + " cannot be null");
}
criteria.add(new Criterion(condition, value));
}
protected void addCriterion(String condition, Object value1, Object value2, String property) {
if (value1 == null || value2 == null) {
throw new RuntimeException("Between values for " + property + " cannot be null");
}
criteria.add(new Criterion(condition, value1, value2));
}
public Criteria andMsgIdIsNull() {
addCriterion("msg_id is null");
return (Criteria) this;
}
public Criteria andMsgIdIsNotNull() {
addCriterion("msg_id is not null");
return (Criteria) this;
}
public Criteria andMsgIdEqualTo(Long value) {
addCriterion("msg_id =", value, "msgId");
return (Criteria) this;
}
public Criteria andMsgIdNotEqualTo(Long value) {
addCriterion("msg_id <>", value, "msgId");
return (Criteria) this;
}
public Criteria andMsgIdGreaterThan(Long value) {
addCriterion("msg_id >", value, "msgId");
return (Criteria) this;
}
public Criteria andMsgIdGreaterThanOrEqualTo(Long value) {
addCriterion("msg_id >=", value, "msgId");
return (Criteria) this;
}
public Criteria andMsgIdLessThan(Long value) {
addCriterion("msg_id <", value, "msgId");
return (Criteria) this;
}
public Criteria andMsgIdLessThanOrEqualTo(Long value) {
addCriterion("msg_id <=", value, "msgId");
return (Criteria) this;
}
public Criteria andMsgIdIn(List<Long> values) {
addCriterion("msg_id in", values, "msgId");
return (Criteria) this;
}
public Criteria andMsgIdNotIn(List<Long> values) {
addCriterion("msg_id not in", values, "msgId");
return (Criteria) this;
}
public Criteria andMsgIdBetween(Long value1, Long value2) {
addCriterion("msg_id between", value1, value2, "msgId");
return (Criteria) this;
}
public Criteria andMsgIdNotBetween(Long value1, Long value2) {
addCriterion("msg_id not between", value1, value2, "msgId");
return (Criteria) this;
}
public Criteria andUserIdIsNull() {
addCriterion("user_id is null");
return (Criteria) this;
}
public Criteria andUserIdIsNotNull() {
addCriterion("user_id is not null");
return (Criteria) this;
}
public Criteria andUserIdEqualTo(Integer value) {
addCriterion("user_id =", value, "userId");
return (Criteria) this;
}
public Criteria andUserIdNotEqualTo(Integer value) {
addCriterion("user_id <>", value, "userId");
return (Criteria) this;
}
public Criteria andUserIdGreaterThan(Integer value) {
addCriterion("user_id >", value, "userId");
return (Criteria) this;
}
public Criteria andUserIdGreaterThanOrEqualTo(Integer value) {
addCriterion("user_id >=", value, "userId");
return (Criteria) this;
}
public Criteria andUserIdLessThan(Integer value) {
addCriterion("user_id <", value, "userId");
return (Criteria) this;
}
public Criteria andUserIdLessThanOrEqualTo(Integer value) {
addCriterion("user_id <=", value, "userId");
return (Criteria) this;
}
public Criteria andUserIdIn(List<Integer> values) {
addCriterion("user_id in", values, "userId");
return (Criteria) this;
}
public Criteria andUserIdNotIn(List<Integer> values) {
addCriterion("user_id not in", values, "userId");
return (Criteria) this;
}
public Criteria andUserIdBetween(Integer value1, Integer value2) {
addCriterion("user_id between", value1, value2, "userId");
return (Criteria) this;
}
public Criteria andUserIdNotBetween(Integer value1, Integer value2) {
addCriterion("user_id not between", value1, value2, "userId");
return (Criteria) this;
}
public Criteria andOpenIdIsNull() {
addCriterion("open_id is null");
return (Criteria) this;
}
public Criteria andOpenIdIsNotNull() {
addCriterion("open_id is not null");
return (Criteria) this;
}
public Criteria andOpenIdEqualTo(String value) {
addCriterion("open_id =", value, "openId");
return (Criteria) this;
}
public Criteria andOpenIdNotEqualTo(String value) {
addCriterion("open_id <>", value, "openId");
return (Criteria) this;
}
public Criteria andOpenIdGreaterThan(String value) {
addCriterion("open_id >", value, "openId");
return (Criteria) this;
}
public Criteria andOpenIdGreaterThanOrEqualTo(String value) {
addCriterion("open_id >=", value, "openId");
return (Criteria) this;
}
public Criteria andOpenIdLessThan(String value) {
addCriterion("open_id <", value, "openId");
return (Criteria) this;
}
public Criteria andOpenIdLessThanOrEqualTo(String value) {
addCriterion("open_id <=", value, "openId");
return (Criteria) this;
}
public Criteria andOpenIdLike(String value) {
addCriterion("open_id like", value, "openId");
return (Criteria) this;
}
public Criteria andOpenIdNotLike(String value) {
addCriterion("open_id not like", value, "openId");
return (Criteria) this;
}
public Criteria andOpenIdIn(List<String> values) {
addCriterion("open_id in", values, "openId");
return (Criteria) this;
}
public Criteria andOpenIdNotIn(List<String> values) {
addCriterion("open_id not in", values, "openId");
return (Criteria) this;
}
public Criteria andOpenIdBetween(String value1, String value2) {
addCriterion("open_id between", value1, value2, "openId");
return (Criteria) this;
}
public Criteria andOpenIdNotBetween(String value1, String value2) {
addCriterion("open_id not between", value1, value2, "openId");
return (Criteria) this;
}
public Criteria andUserNameIsNull() {
addCriterion("user_name is null");
return (Criteria) this;
}
public Criteria andUserNameIsNotNull() {
addCriterion("user_name is not null");
return (Criteria) this;
}
public Criteria andUserNameEqualTo(String value) {
addCriterion("user_name =", value, "userName");
return (Criteria) this;
}
public Criteria andUserNameNotEqualTo(String value) {
addCriterion("user_name <>", value, "userName");
return (Criteria) this;
}
public Criteria andUserNameGreaterThan(String value) {
addCriterion("user_name >", value, "userName");
return (Criteria) this;
}
public Criteria andUserNameGreaterThanOrEqualTo(String value) {
addCriterion("user_name >=", value, "userName");
return (Criteria) this;
}
public Criteria andUserNameLessThan(String value) {
addCriterion("user_name <", value, "userName");
return (Criteria) this;
}
public Criteria andUserNameLessThanOrEqualTo(String value) {
addCriterion("user_name <=", value, "userName");
return (Criteria) this;
}
public Criteria andUserNameLike(String value) {
addCriterion("user_name like", value, "userName");
return (Criteria) this;
}
public Criteria andUserNameNotLike(String value) {
addCriterion("user_name not like", value, "userName");
return (Criteria) this;
}
public Criteria andUserNameIn(List<String> values) {
addCriterion("user_name in", values, "userName");
return (Criteria) this;
}
public Criteria andUserNameNotIn(List<String> values) {
addCriterion("user_name not in", values, "userName");
return (Criteria) this;
}
public Criteria andUserNameBetween(String value1, String value2) {
addCriterion("user_name between", value1, value2, "userName");
return (Criteria) this;
}
public Criteria andUserNameNotBetween(String value1, String value2) {
addCriterion("user_name not between", value1, value2, "userName");
return (Criteria) this;
}
public Criteria andMsgTimeIsNull() {
addCriterion("msg_time is null");
return (Criteria) this;
}
public Criteria andMsgTimeIsNotNull() {
addCriterion("msg_time is not null");
return (Criteria) this;
}
public Criteria andMsgTimeEqualTo(Date value) {
addCriterion("msg_time =", value, "msgTime");
return (Criteria) this;
}
public Criteria andMsgTimeNotEqualTo(Date value) {
addCriterion("msg_time <>", value, "msgTime");
return (Criteria) this;
}
public Criteria andMsgTimeGreaterThan(Date value) {
addCriterion("msg_time >", value, "msgTime");
return (Criteria) this;
}
public Criteria andMsgTimeGreaterThanOrEqualTo(Date value) {
addCriterion("msg_time >=", value, "msgTime");
return (Criteria) this;
}
public Criteria andMsgTimeLessThan(Date value) {
addCriterion("msg_time <", value, "msgTime");
return (Criteria) this;
}
public Criteria andMsgTimeLessThanOrEqualTo(Date value) {
addCriterion("msg_time <=", value, "msgTime");
return (Criteria) this;
}
public Criteria andMsgTimeIn(List<Date> values) {
addCriterion("msg_time in", values, "msgTime");
return (Criteria) this;
}
public Criteria andMsgTimeNotIn(List<Date> values) {
addCriterion("msg_time not in", values, "msgTime");
return (Criteria) this;
}
public Criteria andMsgTimeBetween(Date value1, Date value2) {
addCriterion("msg_time between", value1, value2, "msgTime");
return (Criteria) this;
}
public Criteria andMsgTimeNotBetween(Date value1, Date value2) {
addCriterion("msg_time not between", value1, value2, "msgTime");
return (Criteria) this;
}
public Criteria andMsgContentIsNull() {
addCriterion("msg_content is null");
return (Criteria) this;
}
public Criteria andMsgContentIsNotNull() {
addCriterion("msg_content is not null");
return (Criteria) this;
}
public Criteria andMsgContentEqualTo(String value) {
addCriterion("msg_content =", value, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentNotEqualTo(String value) {
addCriterion("msg_content <>", value, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentGreaterThan(String value) {
addCriterion("msg_content >", value, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentGreaterThanOrEqualTo(String value) {
addCriterion("msg_content >=", value, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentLessThan(String value) {
addCriterion("msg_content <", value, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentLessThanOrEqualTo(String value) {
addCriterion("msg_content <=", value, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentLike(String value) {
addCriterion("msg_content like", value, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentNotLike(String value) {
addCriterion("msg_content not like", value, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentIn(List<String> values) {
addCriterion("msg_content in", values, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentNotIn(List<String> values) {
addCriterion("msg_content not in", values, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentBetween(String value1, String value2) {
addCriterion("msg_content between", value1, value2, "msgContent");
return (Criteria) this;
}
public Criteria andMsgContentNotBetween(String value1, String value2) {
addCriterion("msg_content not between", value1, value2, "msgContent");
return (Criteria) this;
}
public Criteria andYxbzIsNull() {
addCriterion("yxbz is null");
return (Criteria) this;
}
public Criteria andYxbzIsNotNull() {
addCriterion("yxbz is not null");
return (Criteria) this;
}
public Criteria andYxbzEqualTo(String value) {
addCriterion("yxbz =", value, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzNotEqualTo(String value) {
addCriterion("yxbz <>", value, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzGreaterThan(String value) {
addCriterion("yxbz >", value, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzGreaterThanOrEqualTo(String value) {
addCriterion("yxbz >=", value, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzLessThan(String value) {
addCriterion("yxbz <", value, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzLessThanOrEqualTo(String value) {
addCriterion("yxbz <=", value, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzLike(String value) {
addCriterion("yxbz like", value, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzNotLike(String value) {
addCriterion("yxbz not like", value, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzIn(List<String> values) {
addCriterion("yxbz in", values, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzNotIn(List<String> values) {
addCriterion("yxbz not in", values, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzBetween(String value1, String value2) {
addCriterion("yxbz between", value1, value2, "yxbz");
return (Criteria) this;
}
public Criteria andYxbzNotBetween(String value1, String value2) {
addCriterion("yxbz not between", value1, value2, "yxbz");
return (Criteria) this;
}
} |
import {MethodDefinition} from '@grpc/grpc-js';
export type MethodRequest<
Definition extends MethodDefinition<any, any>
> = Definition extends MethodDefinition<infer T, any> ? T : never;
export type MethodResponse<
Definition extends MethodDefinition<any, any>
> = Definition extends MethodDefinition<any, infer T> ? T : never;
|
<gh_stars>0
package org.infinispan.container;
import static org.infinispan.commons.util.Util.toStr;
import java.util.AbstractCollection;
import java.util.AbstractSet;
import java.util.Collection;
import java.util.Collections;
import java.util.Iterator;
import java.util.Map;
import java.util.Map.Entry;
import java.util.NoSuchElementException;
import java.util.Optional;
import java.util.Set;
import java.util.Spliterator;
import java.util.Spliterators;
import java.util.concurrent.ConcurrentMap;
import java.util.function.BiConsumer;
import java.util.function.Consumer;
import org.infinispan.commons.logging.Log;
import org.infinispan.commons.logging.LogFactory;
import org.infinispan.commons.util.CloseableSpliterator;
import org.infinispan.commons.util.CollectionFactory;
import org.infinispan.commons.util.EntrySizeCalculator;
import org.infinispan.commons.util.EvictionListener;
import org.infinispan.commons.util.PeekableMap;
import org.infinispan.container.entries.CacheEntrySizeCalculator;
import org.infinispan.container.entries.ImmortalCacheEntry;
import org.infinispan.container.entries.InternalCacheEntry;
import org.infinispan.container.entries.PrimitiveEntrySizeCalculator;
import org.infinispan.eviction.ActivationManager;
import org.infinispan.eviction.EvictionManager;
import org.infinispan.eviction.EvictionType;
import org.infinispan.eviction.PassivationManager;
import org.infinispan.expiration.ExpirationManager;
import org.infinispan.factories.annotations.Inject;
import org.infinispan.filter.KeyFilter;
import org.infinispan.filter.KeyValueFilter;
import org.infinispan.marshall.core.WrappedByteArraySizeCalculator;
import org.infinispan.metadata.Metadata;
import org.infinispan.metadata.impl.L1Metadata;
import org.infinispan.notifications.cachelistener.CacheNotifier;
import org.infinispan.persistence.manager.PersistenceManager;
import org.infinispan.util.CoreImmutables;
import org.infinispan.util.TimeService;
import org.infinispan.util.concurrent.WithinThreadExecutor;
import com.github.benmanes.caffeine.cache.Cache;
import com.github.benmanes.caffeine.cache.CacheWriter;
import com.github.benmanes.caffeine.cache.Caffeine;
import com.github.benmanes.caffeine.cache.Policy;
import com.github.benmanes.caffeine.cache.RemovalCause;
import net.jcip.annotations.ThreadSafe;
/**
* DefaultDataContainer is both eviction and non-eviction based data container.
*
*
* @author <NAME>
* @author <NAME>
* @author <NAME>
* @author <a href="http://gleamynode.net/"><NAME></a>
*
* @since 4.0
*/
@ThreadSafe
public class DefaultDataContainer<K, V> implements DataContainer<K, V> {
private static final Log log = LogFactory.getLog(DefaultDataContainer.class);
private static final boolean trace = log.isTraceEnabled();
private final ConcurrentMap<K, InternalCacheEntry<K, V>> entries;
private final Cache<K, InternalCacheEntry<K, V>> evictionCache;
@Inject protected InternalEntryFactory entryFactory;
@Inject private EvictionManager evictionManager;
@Inject private PassivationManager passivator;
@Inject private ActivationManager activator;
@Inject private PersistenceManager pm;
@Inject private TimeService timeService;
@Inject private CacheNotifier cacheNotifier;
@Inject private ExpirationManager<K, V> expirationManager;
public DefaultDataContainer(int concurrencyLevel) {
// If no comparing implementations passed, could fallback on JDK CHM
entries = CollectionFactory.makeConcurrentParallelMap(128, concurrencyLevel);
evictionCache = null;
}
private static <K, V> Caffeine<K, V> caffeineBuilder() {
return (Caffeine<K, V>) Caffeine.newBuilder();
}
protected DefaultDataContainer(int concurrencyLevel, long thresholdSize, EvictionType thresholdPolicy) {
DefaultEvictionListener evictionListener = new DefaultEvictionListener();
Caffeine<K, InternalCacheEntry<K, V>> caffeine = caffeineBuilder();
switch (thresholdPolicy) {
case MEMORY:
CacheEntrySizeCalculator<K, V> calc = new CacheEntrySizeCalculator<>(new WrappedByteArraySizeCalculator<>(
new PrimitiveEntrySizeCalculator()));
caffeine.weigher((k, v) -> (int) calc.calculateSize(k, v)).maximumWeight(thresholdSize);
break;
case COUNT:
caffeine.maximumSize(thresholdSize);
break;
default:
throw new UnsupportedOperationException("Policy not supported: " + thresholdPolicy);
}
evictionCache = applyListener(caffeine, evictionListener).build();
entries = evictionCache.asMap();
}
private Caffeine<K, InternalCacheEntry<K, V>> applyListener(Caffeine<K, InternalCacheEntry<K, V>> caffeine, DefaultEvictionListener listener) {
return caffeine.executor(new WithinThreadExecutor()).removalListener((k, v, c) -> {
switch (c) {
case SIZE:
listener.onEntryEviction(Collections.singletonMap(k, v));
break;
case EXPLICIT:
listener.onEntryRemoved(new ImmortalCacheEntry(k, v));
break;
case REPLACED:
listener.onEntryActivated(k);
break;
}
}).writer(new CacheWriter<K, InternalCacheEntry<K, V>>() {
@Override
public void write(K key, InternalCacheEntry<K, V> value) {
}
@Override
public void delete(K key, InternalCacheEntry<K, V> value, RemovalCause cause) {
if (cause == RemovalCause.SIZE) {
listener.onEntryChosenForEviction(new ImmortalCacheEntry(key, value));
}
}
});
}
/**
* Method invoked when memory policy is used. This calculator only calculates the given key and value.
* @param concurrencyLevel
* @param thresholdSize
* @param sizeCalculator
*/
protected DefaultDataContainer(int concurrencyLevel, long thresholdSize,
EntrySizeCalculator<? super K, ? super V> sizeCalculator) {
this(thresholdSize, new CacheEntrySizeCalculator<>(sizeCalculator));
}
/**
* Constructor that allows user to provide a size calculator that also handles the cache entry and metadata.
* @param thresholdSize
* @param sizeCalculator
*/
protected DefaultDataContainer(long thresholdSize,
EntrySizeCalculator<? super K, ? super InternalCacheEntry<K, V>> sizeCalculator) {
DefaultEvictionListener evictionListener = new DefaultEvictionListener();
evictionCache = applyListener(Caffeine.newBuilder()
.weigher((K k, InternalCacheEntry<K, V> v) -> (int) sizeCalculator.calculateSize(k, v))
.maximumWeight(thresholdSize), evictionListener)
.build();
entries = evictionCache.asMap();
}
public static <K, V> DefaultDataContainer<K, V> boundedDataContainer(int concurrencyLevel, long maxEntries,
EvictionType thresholdPolicy) {
return new DefaultDataContainer<>(concurrencyLevel, maxEntries, thresholdPolicy);
}
public static <K, V> DefaultDataContainer<K, V> boundedDataContainer(int concurrencyLevel, long maxEntries,
EntrySizeCalculator<? super K, ? super V> sizeCalculator) {
return new DefaultDataContainer<>(concurrencyLevel, maxEntries, sizeCalculator);
}
public static <K, V> DefaultDataContainer<K, V> unBoundedDataContainer(int concurrencyLevel) {
return new DefaultDataContainer<>(concurrencyLevel);
}
@Override
public InternalCacheEntry<K, V> peek(Object key) {
if (entries instanceof PeekableMap) {
return ((PeekableMap<K, InternalCacheEntry<K, V>>)entries).peek(key);
}
return entries.get(key);
}
@Override
public InternalCacheEntry<K, V> get(Object k) {
InternalCacheEntry<K, V> e = entries.get(k);
if (e != null && e.canExpire()) {
long currentTimeMillis = timeService.wallClockTime();
if (e.isExpired(currentTimeMillis)) {
expirationManager.handleInMemoryExpiration(e, currentTimeMillis);
e = null;
} else {
e.touch(currentTimeMillis);
}
}
return e;
}
@Override
public void put(K k, V v, Metadata metadata) {
boolean l1Entry = false;
if (metadata instanceof L1Metadata) {
metadata = ((L1Metadata) metadata).metadata();
l1Entry = true;
}
InternalCacheEntry<K, V> e = entries.get(k);
if (trace) {
log.tracef("Creating new ICE for writing. Existing=%s, metadata=%s, new value=%s", e, metadata, toStr(v));
}
final InternalCacheEntry<K, V> copy;
if (l1Entry) {
copy = entryFactory.createL1(k, v, metadata);
} else if (e != null) {
copy = entryFactory.update(e, v, metadata);
} else {
// this is a brand-new entry
copy = entryFactory.create(k, v, metadata);
}
if (trace)
log.tracef("Store %s in container", copy);
entries.compute(copy.getKey(), (key, entry) -> {
activator.onUpdate(key, entry == null);
return copy;
});
}
@Override
public boolean containsKey(Object k) {
InternalCacheEntry<K, V> ice = peek(k);
if (ice != null && ice.canExpire()) {
long currentTimeMillis = timeService.wallClockTime();
if (ice.isExpired(currentTimeMillis)) {
expirationManager.handleInMemoryExpiration(ice, currentTimeMillis);
ice = null;
}
}
return ice != null;
}
@Override
public InternalCacheEntry<K, V> remove(Object k) {
final InternalCacheEntry<K,V>[] reference = new InternalCacheEntry[1];
entries.compute((K) k, (key, entry) -> {
activator.onRemove(key, entry == null);
reference[0] = entry;
return null;
});
InternalCacheEntry<K, V> e = reference[0];
if (trace) {
log.tracef("Removed %s from container", e);
}
return e == null || (e.canExpire() && e.isExpired(timeService.wallClockTime())) ? null : e;
}
private Policy.Eviction<K, InternalCacheEntry<K, V>> eviction() {
if (evictionCache != null) {
Optional<Policy.Eviction<K, InternalCacheEntry<K, V>>> eviction = evictionCache.policy().eviction();
if (eviction.isPresent()) {
return eviction.get();
}
}
throw new UnsupportedOperationException();
}
@Override
public long capacity() {
Policy.Eviction<K, InternalCacheEntry<K, V>> evict = eviction();
return evict.getMaximum();
}
@Override
public void resize(long newSize) {
Policy.Eviction<K, InternalCacheEntry<K, V>> evict = eviction();
evict.setMaximum(newSize);
}
@Override
public int size() {
int size = 0;
// We have to loop through to make sure to remove expired entries
for (Iterator<InternalCacheEntry<K, V>> iter = iterator(); iter.hasNext(); ) {
iter.next();
if (++size == Integer.MAX_VALUE) return Integer.MAX_VALUE;
}
return size;
}
@Override
public int sizeIncludingExpired() {
return entries.size();
}
@Override
public void clear() {
log.tracef("Clearing data container");
entries.clear();
}
@Override
public Set<K> keySet() {
return Collections.unmodifiableSet(entries.keySet());
}
@Override
public Collection<V> values() {
return new Values();
}
@Override
public Set<InternalCacheEntry<K, V>> entrySet() {
return new EntrySet();
}
@Override
public void evict(K key) {
entries.computeIfPresent(key, (o, entry) -> {
passivator.passivate(entry);
return null;
});
}
@Override
public InternalCacheEntry<K, V> compute(K key, ComputeAction<K, V> action) {
return entries.compute(key, (k, oldEntry) -> {
InternalCacheEntry<K, V> newEntry = action.compute(k, oldEntry, entryFactory);
if (newEntry == oldEntry) {
return oldEntry;
} else if (newEntry == null) {
activator.onRemove(k, false);
return null;
}
activator.onUpdate(k, oldEntry == null);
if (trace)
log.tracef("Store %s in container", newEntry);
return newEntry;
});
}
@Override
public Iterator<InternalCacheEntry<K, V>> iterator() {
return new EntryIterator(entries.values().iterator());
}
@Override
public Spliterator<InternalCacheEntry<K, V>> spliterator() {
return new EntrySpliterator(entries.values().spliterator());
}
@Override
public Iterator<InternalCacheEntry<K, V>> iteratorIncludingExpired() {
return entries.values().iterator();
}
@Override
public Spliterator<InternalCacheEntry<K, V>> spliteratorIncludingExpired() {
// Technically this spliterator is distinct, but it won't be set - we assume that is okay for now
return entries.values().spliterator();
}
@Override
public long evictionSize() {
Policy.Eviction<K, InternalCacheEntry<K, V>> evict = eviction();
return evict.weightedSize().orElse(entries.size());
}
private final class DefaultEvictionListener implements EvictionListener<K, InternalCacheEntry<K, V>> {
@Override
public void onEntryEviction(Map<K, InternalCacheEntry<K, V>> evicted) {
evictionManager.onEntryEviction(evicted);
}
@Override
public void onEntryChosenForEviction(Entry<K, InternalCacheEntry<K, V>> entry) {
passivator.passivate(entry.getValue());
}
@Override
public void onEntryActivated(Object key) {
activator.onUpdate(key, true);
}
@Override
public void onEntryRemoved(Entry<K, InternalCacheEntry<K, V>> entry) {
}
}
private class ImmutableEntryIterator extends EntryIterator {
ImmutableEntryIterator(Iterator<InternalCacheEntry<K, V>> it){
super(it);
}
@Override
public InternalCacheEntry<K, V> next() {
return CoreImmutables.immutableInternalCacheEntry(super.next());
}
}
public class EntryIterator implements Iterator<InternalCacheEntry<K, V>> {
private final Iterator<InternalCacheEntry<K, V>> it;
private InternalCacheEntry<K, V> next;
EntryIterator(Iterator<InternalCacheEntry<K, V>> it) {
this.it=it;
}
private InternalCacheEntry<K, V> getNext() {
boolean initializedTime = false;
long now = 0;
while (it.hasNext()) {
InternalCacheEntry<K, V> entry = it.next();
if (!entry.canExpire()) {
if (trace) {
log.tracef("Return next entry %s", entry);
}
return entry;
} else {
if (!initializedTime) {
now = timeService.wallClockTime();
initializedTime = true;
}
if (!entry.isExpired(now)) {
if (trace) {
log.tracef("Return next entry %s", entry);
}
return entry;
} else if (trace) {
log.tracef("%s is expired", entry);
}
}
}
if (trace) {
log.tracef("Return next null");
}
return null;
}
@Override
public InternalCacheEntry<K, V> next() {
if (next == null) {
next = getNext();
}
if (next == null) {
throw new NoSuchElementException();
}
InternalCacheEntry<K, V> toReturn = next;
next = null;
return toReturn;
}
@Override
public boolean hasNext() {
if (next == null) {
next = getNext();
}
return next != null;
}
@Override
public void remove() {
throw new UnsupportedOperationException();
}
}
/**
* Spliterator that wraps another to make sure to now return expired entries. This class also implements
* CloseableSpliterator to prevent additional allocations if user needs it to be closeable.
*/
private class EntrySpliterator implements CloseableSpliterator<InternalCacheEntry<K, V>> {
private final Spliterator<InternalCacheEntry<K, V>> spliterator;
// We assume that spliterator is not used concurrently - normally it is split so we can use these variables safely
private final Consumer<? super InternalCacheEntry<K, V>> consumer = ice -> current = ice;
private InternalCacheEntry<K, V> current;
private EntrySpliterator(Spliterator<InternalCacheEntry<K, V>> spliterator) {
this.spliterator = spliterator;
}
@Override
public void close() {
// Do nothing
}
@Override
public boolean tryAdvance(Consumer<? super InternalCacheEntry<K, V>> action) {
InternalCacheEntry<K, V> entryToUse = null;
boolean initializedTime = false;
long now = 0;
while (entryToUse == null && spliterator.tryAdvance(consumer)) {
entryToUse = current;
if (entryToUse.canExpire()) {
if (!initializedTime) {
now = timeService.wallClockTime();
initializedTime = true;
}
if (entryToUse.isExpired(now)) {
entryToUse = null;
}
}
}
if (entryToUse != null) {
action.accept(entryToUse);
return true;
}
return false;
}
@Override
public void forEachRemaining(Consumer<? super InternalCacheEntry<K, V>> action) {
// We don't call the forEachRemaining on the actual spliterator since, we want to keep the time between
// invocations
boolean initializedTime = false;
long now = 0;
while (spliterator.tryAdvance(consumer)) {
InternalCacheEntry<K, V> currentEntry = current;
if (currentEntry.canExpire()) {
if (!initializedTime) {
now = timeService.wallClockTime();
initializedTime = true;
}
if (currentEntry.isExpired(now)) {
continue;
}
}
action.accept(currentEntry);
}
}
@Override
public Spliterator<InternalCacheEntry<K, V>> trySplit() {
Spliterator<InternalCacheEntry<K, V>> split = spliterator.trySplit();
if (split != null) {
return new EntrySpliterator(split);
}
return null;
}
@Override
public long estimateSize() {
return spliterator.estimateSize();
}
@Override
public int characteristics() {
return spliterator.characteristics() | Spliterator.DISTINCT;
}
}
/**
* Minimal implementation needed for unmodifiable Set
*
*/
private class EntrySet extends AbstractSet<InternalCacheEntry<K, V>> {
@Override
public boolean contains(Object o) {
if (!(o instanceof Map.Entry)) {
return false;
}
@SuppressWarnings("rawtypes")
Map.Entry e = (Map.Entry) o;
InternalCacheEntry ice = entries.get(e.getKey());
if (ice == null) {
return false;
}
return ice.getValue().equals(e.getValue());
}
@Override
public Iterator<InternalCacheEntry<K, V>> iterator() {
return new ImmutableEntryIterator(entries.values().iterator());
}
@Override
public int size() {
return entries.size();
}
@Override
public String toString() {
return entries.toString();
}
@Override
public Spliterator<InternalCacheEntry<K, V>> spliterator() {
return Spliterators.spliterator(this, Spliterator.DISTINCT | Spliterator.CONCURRENT);
}
}
/**
* Minimal implementation needed for unmodifiable Collection
*
*/
private class Values extends AbstractCollection<V> {
@Override
public Iterator<V> iterator() {
return new ValueIterator(entries.values().iterator());
}
@Override
public int size() {
return entries.size();
}
@Override
public Spliterator<V> spliterator() {
return Spliterators.spliterator(this, Spliterator.CONCURRENT);
}
}
private static class ValueIterator<K, V> implements Iterator<V> {
Iterator<InternalCacheEntry<K, V>> currentIterator;
private ValueIterator(Iterator<InternalCacheEntry<K, V>> it) {
currentIterator = it;
}
@Override
public boolean hasNext() {
return currentIterator.hasNext();
}
@Override
public void remove() {
throw new UnsupportedOperationException();
}
@Override
public V next() {
return currentIterator.next().getValue();
}
}
@Override
public void executeTask(final KeyFilter<? super K> filter, final BiConsumer<? super K, InternalCacheEntry<K, V>> action)
throws InterruptedException {
if (filter == null)
throw new IllegalArgumentException("No filter specified");
if (action == null)
throw new IllegalArgumentException("No action specified");
long now = timeService.wallClockTime();
entries.forEach((K key, InternalCacheEntry<K, V> value) -> {
if (filter.accept(key) && !value.isExpired(now)) {
action.accept(key, value);
}
});
//TODO figure out the way how to do interruption better (during iteration)
if(Thread.currentThread().isInterrupted()){
throw new InterruptedException();
}
}
@Override
public void executeTask(final KeyValueFilter<? super K, ? super V> filter, final BiConsumer<? super K, InternalCacheEntry<K, V>> action)
throws InterruptedException {
if (filter == null)
throw new IllegalArgumentException("No filter specified");
if (action == null)
throw new IllegalArgumentException("No action specified");
long now = timeService.wallClockTime();
entries.forEach((K key, InternalCacheEntry<K, V> value) -> {
if (filter.accept(key, value.getValue(), value.getMetadata()) && !value.isExpired(now)) {
action.accept(key, value);
}
});
//TODO figure out the way how to do interruption better (during iteration)
if(Thread.currentThread().isInterrupted()){
throw new InterruptedException();
}
}
}
|
It's Heat-Jazz at 9 p.m. Thursday..
Second game of Heat three-game trip is against Jazz.
When/Where: 9 p.m., Vivant Smart Home Arena, Salt Lake City.
Scouting report: This is the second and final game of the two-game season series . . . The Jazz won the first meeting 102-91 Nov. 12 at AmericanAirlines Arena, behind 25 points from forward Gordon Hayward and 12 points and 12 rebounds from center Rudy Gobert, in a game the Heat were without Goran Dragic and the Jazz were without George Hill and Boris Diaw . . . The Heat have lost four of the last six meetings and four of their last five visits to Salt Lake City . . . The game is the second on a three-game trip for the Heat and concludes their third back-to-back set of the season, with an 0-2 record on the second nights of such pairings . . . The game is the second on a three-game homestand for the Jazz, who enter coming off their fourth consecutive victory, Tuesday's 120-101 decision over the visiting Rockets, when they shot 15 of 28 on 3-pointers, paced by Hayward's 31 points . . . For the Heat, Josh Richardson (ankle), Dion Waiters (groin), Justise Winslow (wrist) and Chris Bosh (blood clots) are out . . . For the Jazz, Derrick Favors (knee) is questionable, with Alec Burks (ankle) out. |
<gh_stars>0
package com.thesaihan.erms.model;
public class ChangeOfSub {
private String sub_code,start_year,end_year,sub_name;
public String getSub_code() {
return sub_code;
}
public String getStart_year() {
return start_year;
}
public String getEnd_year() {
return end_year;
}
public String getSub_name() {
return sub_name;
}
public void setSub_code(String sub_code) {
this.sub_code = sub_code;
}
public void setStart_year(String start_year) {
this.start_year = start_year;
}
public void setEnd_year(String end_year) {
this.end_year = end_year;
}
public void setSub_name(String sub_name) {
this.sub_name = sub_name;
}
@Override
public String toString() {
return "ChangeOfSub [sub_code=" + sub_code + ", start_year="
+ start_year + ", end_year=" + end_year + ", sub_name="
+ sub_name + "]";
}
}
|
del_items(0x800A2154)
SetType(0x800A2154, "void VID_OpenModule__Fv()")
del_items(0x800A2214)
SetType(0x800A2214, "void InitScreens__Fv()")
del_items(0x800A2304)
SetType(0x800A2304, "void MEM_SetupMem__Fv()")
del_items(0x800A2330)
SetType(0x800A2330, "void SetupWorkRam__Fv()")
del_items(0x800A23C0)
SetType(0x800A23C0, "void SYSI_Init__Fv()")
del_items(0x800A24CC)
SetType(0x800A24CC, "void GM_Open__Fv()")
del_items(0x800A24F0)
SetType(0x800A24F0, "void PA_Open__Fv()")
del_items(0x800A2528)
SetType(0x800A2528, "void PAD_Open__Fv()")
del_items(0x800A256C)
SetType(0x800A256C, "void OVR_Open__Fv()")
del_items(0x800A258C)
SetType(0x800A258C, "void SCR_Open__Fv()")
del_items(0x800A25BC)
SetType(0x800A25BC, "void DEC_Open__Fv()")
del_items(0x800A2830)
SetType(0x800A2830, "char *GetVersionString__FPc(char *VersionString2)")
del_items(0x800A2904)
SetType(0x800A2904, "char *GetWord__FPc(char *VStr)")
|
Dozens of people were injured in Germany after a passenger train crashed into a freight train in Duesseldorf, police said Tuesday.
The crash reportedly happened near the train station in Meerbusch, about 5 miles northwest of Duesseldorf.
The Meerbusch fire department tweeted that 155 people were on the regional commuter train. Three people suffered serious injuries, another three had slightly less serious injuries and another 41 people were mildly injured.
None of the injuries were considered life-threatening.
Emergency crews were on the scene and were helping unload people from the passenger train.
Torn-off contact wire from the overhead contact line made it difficult for emergency services to step in to aid those inside the train, according to Feuerwehr Meerbusch.
A photo tweeted by the fire department showed the passenger train partially derailed but still upright.
The cause of the crash is under investigation.
The Associated Press contributed to this report. |
package bitty
/*
Copyright 2020 IBM
Licensed under the Apache License, Version 2.0 (the "License");
you may not use this file except in compliance with the License.
You may obtain a copy of the License at
http://www.apache.org/licenses/LICENSE-2.0
Unless required by applicable law or agreed to in writing, software
distributed under the License is distributed on an "AS IS" BASIS,
WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
See the License for the specific language governing permissions and
limitations under the License.
*/
// UnitSymbol represents the measurement symbol of a binary measurement as dictated by the SI
type UnitSymbol string
// SI symbols for binary measurements including notation for former IEC measurements
const (
Bit UnitSymbol = "Bit"
Byte UnitSymbol = "Byte"
Kib UnitSymbol = "Kib"
Mib UnitSymbol = "Mib"
Gib UnitSymbol = "Gib"
Tib UnitSymbol = "Tib"
Pib UnitSymbol = "Pib"
Eib UnitSymbol = "Eib"
Zib UnitSymbol = "Zib"
Yib UnitSymbol = "Yib"
KiB UnitSymbol = "KiB"
MiB UnitSymbol = "MiB"
GiB UnitSymbol = "GiB"
TiB UnitSymbol = "TiB"
PiB UnitSymbol = "PiB"
EiB UnitSymbol = "EiB"
ZiB UnitSymbol = "ZiB"
YiB UnitSymbol = "YiB"
db UnitSymbol = "db"
hb UnitSymbol = "hb"
kb UnitSymbol = "kb"
Mb UnitSymbol = "Mb"
Gb UnitSymbol = "Gb"
Tb UnitSymbol = "Tb"
Pb UnitSymbol = "Pb"
Eb UnitSymbol = "Eb"
Zb UnitSymbol = "Zb"
Yb UnitSymbol = "Yb"
dB UnitSymbol = "dB"
hB UnitSymbol = "hB"
kB UnitSymbol = "kB"
MB UnitSymbol = "MB"
GB UnitSymbol = "GB"
TB UnitSymbol = "TB"
PB UnitSymbol = "PB"
EB UnitSymbol = "EB"
ZB UnitSymbol = "ZB"
YB UnitSymbol = "YB"
)
// UnitStandard represents a standard for unit measurement. Currently SI 9th
// edition is the supported standard, with SI notation for IEC binary and
// decimal formats
type UnitStandard int
// Unit Standard enums
const (
SI UnitStandard = iota
IEC
)
// UnitSymbolPair holds the least and greatest UnitSymbol for a given standard
// and exponent
type UnitSymbolPair interface {
Standard() UnitStandard
Exponent() int
Least() UnitSymbol
Greatest() UnitSymbol
}
var unitSymbolPairs = []UnitSymbolPair{
NewBaseUnitSymbolPair(SI),
NewBaseUnitSymbolPair(IEC),
NewIECUnitSymbolPair(Kib, KiB, 1),
NewIECUnitSymbolPair(Mib, MiB, 2),
NewIECUnitSymbolPair(Gib, GiB, 3),
NewIECUnitSymbolPair(Tib, TiB, 4),
NewIECUnitSymbolPair(Pib, PiB, 5),
NewIECUnitSymbolPair(Eib, EiB, 6),
NewIECUnitSymbolPair(Zib, ZiB, 7),
NewIECUnitSymbolPair(Yib, YiB, 8),
NewSIUnitSymbolPair(db, dB, 1),
NewSIUnitSymbolPair(hb, hB, 2),
NewSIUnitSymbolPair(kb, kB, 3),
NewSIUnitSymbolPair(Mb, MB, 6),
NewSIUnitSymbolPair(Gb, GB, 9),
NewSIUnitSymbolPair(Tb, TB, 12),
NewSIUnitSymbolPair(Pb, PB, 15),
NewSIUnitSymbolPair(Eb, EB, 18),
NewSIUnitSymbolPair(Zb, ZB, 21),
NewSIUnitSymbolPair(Yb, YB, 24),
}
|
Beneficial Effects of n3 Fatty Acids on Intestinal Lipid Transport in the Psammomys Obesus Small intestine plays an important role in the pathogenesis of dyslipidemia in insulin resistance and type 2 diabetes. The aim of the study was to examine the effect of n3 fatty acids (FA) on the various events governing intraenterocyte lipid transport in Psammomys obesus, a model of nutritionally induced metabolic syndrome. Increased dietary intake of fish oil lowered body weight and improved hyperglycemia and hyperinsulinemia. It simultaneously decreased intestinal de novo lipogenesis and lipid esterification of the major lipid classes, e.g. triglycerides (TG), phospholipids and cholesteryl esters, particularly in insulinresistant and diabetic animals. Accordingly, lessened activity of MGAT and DGAT was recorded. As assessed in cultured jejunal explants incubated with either oleic acid or methionine, fish oil feeding resulted in diminished TGrich lipoprotein assembly and apolipoprotein (apo) B48 biogenesis, respectively. The mechanisms did not involve apo B48 transcription nor alter the gene expression and activity of MTP. The suppressed production of apo B48 by n3 fatty acids was rather associated with intracellular proteasomemediated posttranslational downregulation in insulinresistant and diabetic animals. In vivo studies documented the ability of n3 FA to impede plasma TGrich lipoprotein output following orally gavage or blood circulation infusion of intralipid in animals injected Triton WR1339. Our data highlight the beneficial impact of n3 fatty acids on the adverse effects of the metabolic syndrome. |
Nigella Sativa AQUEOUS AND HYDRO-METHANOL EXTRACTS ACT AS A NOVEL BLOCKER FOR ANGIOTENSIN II RECEPTOR TYPE I IHSAN HUSAIN MOHAMMED ALI* Background: It is well known that Nigella sativa seeds have been widely used in folk medicine for the treatment of cardiovascular diseases. Little is known, however, about their effect on angiotensin II receptor type I. Studying of such impact will be valuable in producing herbal medicines with much less side effects compared to conventional drugs. Objective: The aim of the current research was to study the blocking effect of hydromethanolic (NS.HM) and aqueous (NS.Aq) extracts of Nigella sativa on angiotensin II (Ang II) receptor type I (AT1) in isolated rat's aorta. Materials and Methods: Seed's powder was soaked in 50% hydromethanol and distilled water separately for 48 hrs, then filtered through Whatman filter papers. The solvents were evaporated to yield the crude extracts (NS.HM and NS.Aq). The effect of different concentrations (1, 2, 3 & 4 mg/ml) of NS.HM and NS.Aq extracts on isolated rat's aorta contracted with various doses of Ang II (0.3, 1.0, 3.0, 10, 30 & 100 M) were evaluated. Results: NS.HM at concentrations 3 and 4 mg/ml, caused a very high significant (P< 0.001) inhibitory effect on the dose-response curves (DRCs) in aortic rings at doses 3 and 10 M of Ang II as compared to the control, and a highly significant (P< 0.01) inhibition at doses one M (for 3 mg/ml), and 1 and 30 M (for 4 mg/ml). Furthermore, NS.HM at concentrations 1 and 2 mg/ml did not produce any significant right shifting. On the other hand, NS.Aq extract at concentration 4 mg/ml caused a very high significant (P< 0.001) right shifting DRC at doses 3 and 10 M, and highly significant (P< 0.01) shifting at 30 M of Ang II. Besides, significant right shifting (P< 0.05) was observed in the DRC in the presence of the extract at dose one M as compared to the control. Nevertheless, no right shifting in the DRC of Ang II at concentrations 1, 2, and 3 mg/ml of NS.Aq was noticed. Conclusions: We conclude that Both NS.HM and NS.Aq extracts have an anti-hypertensive effect through blocking the AT1 receptors, although NS.HM extract is more potent in blocking effect on AT1R than NS.Aq. In addition, the anti-hypertensive effect of both NS.HM and NS.Aq extracts on the aorta are concentration-dependent. Duhok Med J 2020; 14 : 73-85 everal studies have shown various effects of medicinal plants on the cardiovascular system's activity, and more precisely, the blood pressure 1. Among these medicinal plants, Nigella sativa (N. Sativa) is considered a miracle plant that belongs to the family Ranunculaceae. It is widely used in folk medicine 2. The common use of N. sativa is due to the presence of several active ingredients in the N. sativa such as nigellone, thymoquinone, dithymoquinone, thymo-hydroquinone and some monoterpenes and flavonoids 3. FOR ANGIOTENSIN II RECEPTOR TYPE I Angiotensin receptors have been found in many body organs and systems like the heart, kidneys, pituitary gland, placenta, peripheral vessels, and the central nervous system 4. In the cardiovascular system, when these receptors (particularly AT1R) are activated by angiotensin II (Ang. II), they lead to vasoconstriction and thence elevation of blood pressure. Therefore, AT1R is known to have an important role in the treatment of cardiovascular disorders. It was shown that blocking of such receptors (e.g., by candesartan, irbesartan, valsartan.etc.) can greatly decrease hypertension and improve the prognosis of cardiovascular diseases such as heart failure. 5 In addition to vasoconstriction and hypertension, AT1R has many other actions like aldosterone synthesis and secretion 6, increase vasopressin secretion 7 and cardiac hypertrophy 8. It was demonstrated that N. sativa causes a pressure-lowering effect by different mechanisms such as calcium channel blockade 9, inhibition of vasomotor center in the medulla 10, activations of inositol triphosphate (IP3), ATP-sensitive K+ channel, and Ca2+ activated K+ channel 11. Furthermore, N. sativa causes a potent inhibition in the contractility and heart rate in isolated hearts of guinea pigs. The later effects may be due to Ca2+ channel blocking or opening of K+ channel of the isolated heart 12,13. Despite the aforementioned still, no data are available to date about N. sativa extract's effect on AT1R. Therefore, the current study was designed to investigate the blocking effect of hydro-methanol (NS.HM) & aqueous (NS.Aq) extracts of N. sativa on AT1R in the isolated rat's aortic rings. 14 was used as a solvent for all drugs. Angiotensin II was purchased from Santa Cruz Biotechnology, USA. n-Hexane 96% and Methanol 99.98% were procured from Scharlau (Spain). Finally, the carbogen (O2 = 95%, CO2 = 5%) was obtained from the Factory of Gas Production -Kirkuk, Iraq. Preparation of Nigella Sativa Seed Extract: Nigella sativa seeds were purchased from a local grocery store in Duhok city and were kindly authenticated by taxonomists (Forestry Department, College of Agriculture, University of Duhok). The seeds were ground into a fine powder using an electrical grinder. The powder was first defatted using pure hexane (96%) by maceration method, in which 1000 gm of N. sativa powder was soaked in three liters hexane for 48 hours at room temperature with occasional shaking. Afterward, it is filtered through Whatman filter papers (to yield a yellow filtrate). This process was repeated 10 times until a colorless filtrate was obtained. The same procedure was repeated for hydromethanol (light brown) and aqueous (light yellow) filtrates. The filtrates of each fraction were collected alone and then concentrated by evaporation under reduced pressure using a thin layer rotary evaporator (BCHI, Switzerland) at a temperature of 40 0 C (to obtain 145 g coded as NS.Hx extract, 63 g as NS.HM, and 69 g as NS.Aq respectively). 15 The extracts were transferred into plane tubes and stored at -20 0 C until use. Preparation of Isolated Aorta Rats were anesthetized after inhalation of pure diethyl ether 9. After thoracotomy, the aorta was removed out and immersed in Kreb's solution aerated with Carbogen (95% O2 and 5% CO2). After removing the excess tissue, the aorta was cut into small rings and mounted in an organ bath chamber containing 10ml Kreb's solution, which was continuously aerated with carbogen at 37 0 C and pH of 7.4. After setting, the rings were allowed to equilibrate with 2g for at least one hour. Prior to the experiment, the rings were exposed to Potassium chloride (KCl) (60mM) or phenylephrine (PE) (1M) to verify the functional integrity. Experimental Protocol To evaluate the effect of NS.HM and NS.Aq (1, 2, 3 and 4mg/ml) on angiotensin II receptors type I (AT1R) on isolated rat's aortic rings, the aortic rings were washed and equilibrated. The contraction was induced by cumulative doses (0.3, 1.0, 3.0, 10, 30 & 100 M) of angiotensin II alone as a control. After washing and reequilibration, the aortic rings were preexposed to 1, 2, 3, and 4 mg/ml NS.HM separately for 5 minutes, followed by cumulative doses of angiotensin II at 10 minutes intervals between doses. The same protocol was applied for NS.Aq extract. STATISTICAL ANALYSIS All data were translated into a computerized database structure and expressed as mean ± standard error of the mean (SEM). For multiple comparisons among the data (comparing each cell mean of one group with the cell mean of the other group in the same row), a two-way ANOVA test was used to detect the statistical significance, which was supported by Sidak's multiple comparisons test using Graph Pad Prizm program (version 6). P-value of less than 0.05 (P 0.05) was considered statistically significant. * ≤ 0.05 (Significant), ** ≤ 0.01 (high significant) and *** ≤ 0.001 (very high significant). Effect of Pre-incubation with Different Doses of NS.HM on Angiotensin II Induced Contraction on Isolated Rat's Aorta. Typical traces representing the experiments for the control and the blocking effect of NS.HM extract (3 mg/ml) on aortic rings precontracted with angiotensin II are shown in (figure 1). Cumulative dose-response curves (DRCs) of Ang. II in the absence (control) and presence of NS.HM extract (1, 2, 3, and 4 mg/ml separately) in aortic rings are shown in (figures 2 and 3). NS.HM extract at concentrations 1, and 2 mg/ml did not cause any significant inhibitory effect on Ang. II-induced contraction at all Ang. II doses were used as compared to the control. In contrast, NS.HM extract at concentrations 3, and 4mg/ml produced a highly significant inhibition of contraction (P<0.01) at a dose 1 M Ang. II (for 3 and 4 mg/ml of ext.) and 30 M (for 4 mg/ml ext.). At the same time, a very highly significant (P<0.001) inhibition of contraction in aortic smooth muscle was observed at concentrations 3 DISCUSSION Hypertension is a primary risk factor for myocardial infarction (MI), stroke, vascular ailment, and chronic renal disease. It is a serious medical condition with higher intravascular pressure than normal 1. High blood pressure is, therefore, considered to be a common cause of cardiovascular problems. The hemodynamic variations seen during hypertension are influenced by different hormonal factors, among which angiotensin II (Ang II) which appears to be a critical one. 16 Ang II receptor type 1 (AT1R) is one of the key sites to which Ang II binds. AT1R promotes many intracellular signaling pathways leading to hypertension, endothelial dysfunction, vascular remodeling, and tissue injury 17. Different pathways exist for synthesizing Ang II, like Cathepsin G, Chymostatinsensitive Ang II generating enzyme (CAGE), Chymase, and Angiotensinconverting enzyme (ACE) 18. The inhibitors acting on any of these enzymes (particularly ACE) can only reduce the production of Ang II by about 30-40% 19. For this reason, recently, attention was focused on the AT1R blocking. However, the useful impacts of contemporary antihypertensive medicines are well reported; nevertheless, the preventive effects of numerous drugs are known to have various side effects. Accordingly, attention now a day is focused on the use of medicinal plants to treat many diseases. One of the most important medicinal plants used in folk medicine is N. sativa 3. It is well known that it exhibits an anti-hypertensive effect, but its exact mechanism is still in debate. Therefore, the current work was carried out for the first time so far to investigate the role of hydromethanolic (NS.HM) and aqueous (NS.Aq) extracts of N. sativa in blocking of AT1R in isolated rat's aorta. The results of the current study demonstrated for the first time that both NS.HM and NS.Aq extracts have significantly shifted Ang II dose-response curve, in Ang II induced contraction in rat's aortic rings, to the right at concentrations 3 and 4mg/ml and 4mg/ml, respectively. Furthermore, various physiological responses to different extracts reflect diverse, active ingredients in each N. sativa extract. Therefore, the results of the present work demonstrated that NS.HM (3 and 4mg/ml) has a more potent inhibitory effect than NS.Aq (only 4mg/ml) in Ang II induced contraction on aortic rings. This clearly reflects the presence of different active ingredients in each extract and different potencies and different action mechanisms. Moreover, it was observed that concentrations 1 and 2mg/ml NS.HM were unable to shift the dose-response curve of Ang II to the right. In contrast, highly significant differences were observed in Ang II doses between control and those of 3 and 4mg/ml NS.HM. This indicates that the anti-hypertensive effect of NS.HM is concentration-dependent. Furthermore, NS.Aq also inhibited the Ang II induced contraction in rat aorta in a concentrationdependent manner, but to a lesser extent. So far, four angiotensin receptors have been described: AT-1, AT-2, AT-4, and Mas receptors (AT1-7) 7,20 ; among them, AT1R is the most clinically important one, as many drugs competitively block it, thereby reducing blood pressure. Ang II, which is a bioactive peptide, activates both AT1R and AT2R 16. After binding with AT1R, Ang II switches on various intracellular signaling pathways that mediate different physiological responses, including hypertension, atherosclerosis, ventricular hypertrophy, cell proliferation, angiogenesis, matrix synthesis, aldosterone synthesis, and discharge 21. In other words, Ang II induces contraction in smooth muscle cells occurs through Gq/11-PLC-PIP2-IP3-PKC 22 and/or G12/13-GEF -ATP-Rho -ROCK MLC phosphatase 23,24. The results of the current study revealed that NS.HM extract produced a partial but the more potent effect on Ang II induced contraction than NS.Aq extract. The partial vasorelaxant effect of NS.HM and NS.Aq extracts reflect the differences in the active ingredients present in both extracts. This may be due to the inhibitory effect of their active ingredients on one or more enzymes in the signal transduction pathway. As far as we are aware, at least at the moment, no data concerning the effect of NS.HM and NS.Aq on aortic smooth muscles contracted by Ang II are available. However, a study carried out on the aorta contracted by PMA (a PKC activator) showed that in Ca2+ free solution, PMA activates PKC and induced a slowly developing sustained contraction without changing the i. However, it has been concluded that the flavonoids (pentamethyl quercetin, luteolin, kaempferol, and apigenin) competitively bind ATP binding sites and significantly inhibited the PKC 25. Furthermore, studies on ventricular cardiomyocytes demonstrated that the monoterpene thymol caused a cardio-depression in guinea pigs through inhibition of SERCA, which in turn reduced Ca2+ level in the sarcoplasmic reticulum 10,26, in which the effect was also described for skeletal muscle fibers 27. On the other hand, it has been reported that the flavonoid quercetin has a role in the inhibition of the formation of the calciumcalmodulin complex 28. However, in other observations, the vasodilation effect of quercetin by this mechanism has been rolled out 25. Another expected mechanism is calcium channel blockade. The patchclamp technique in the whole-cell configuration showed that the monoterpene carvacrol was able to inhibit the calcium ion current through the L-type Ca2+ channel in cardiomyocytes isolated from canine and human ventricles 29 |
Uganda is to administer an experimental Ebola vaccine for health workers in high-risk areas bordering the Democratic Republic of the Congo.
The vaccination programme launches on Wednesday with support from the World Health Organization, targeting 2,000 frontline workers in districts close to DRC’s North Kivu province, which is currently experiencing an outbreak of the deadly virus.
Uganda is the first country in the world to give the vaccine without an active outbreak of the disease, but is judged to be at very high risk.
In December 2000, Lukwiya, a medical superintendent of Lacor Hospital in the northern district of Gulu, died along with 12 nurses after contracting the highly contagious disease, which is transmitted through contact with body fluids.
“The public health risk of cross border transmission of Ebola to Uganda [from DRC] was assessed to be very high at the national level,” said Jane Aceng, Uganda’s health minister.
“The affected areas in the DRC [North Kivu and Ituri provinces] are about 100km from Uganda’s border districts,” she said.
There are so far 239 confirmed cases in DRC in the latest flare-up, and 174 people have died from the disease.
The vaccine, developed by Merck, is not licensed but proved effective during limited trials in west Africa, where the biggest recorded outbreak of Ebola killed 11,300 people in Guinea, Liberia and Sierra Leone from 2014 to 2016.
“This particular vaccine is currently being administered in DRC, and is highly protective and has demonstrated potency against [the Zaire strain of] Ebola virus,” said Woldemariam. |
import * as fs from "fs";
export const dartCodeExtensionIdentifier = "Dart-Code.dart-code";
export const flutterExtensionIdentifier = "Dart-Code.flutter";
export const isWin = /^win/.test(process.platform);
export const isMac = process.platform === "darwin";
export const isLinux = !isWin && !isMac;
export const isChromeOS = isLinux && fs.existsSync("/dev/.cros_milestone");
// Used for code checks and in Dart SDK urls so Chrome OS is considered Linux.
export const dartPlatformName = isWin ? "win" : isMac ? "mac" : "linux";
// Used for display (logs, analytics) so Chrome OS is its own.
export const platformDisplayName = isWin ? "win" : isMac ? "mac" : isChromeOS ? "chromeos" : "linux";
export const platformEol = isWin ? "\r\n" : "\n";
export const dartExecutableName = isWin ? "dart.exe" : "dart";
export const pubExecutableName = isWin ? "pub.bat" : "pub";
export const flutterExecutableName = isWin ? "flutter.bat" : "flutter";
export const androidStudioExecutableName = isWin ? "studio64.exe" : "studio.sh";
export const dartVMPath = "bin/" + dartExecutableName;
export const pubPath = "bin/" + pubExecutableName;
export const pubSnapshotPath = "bin/snapshots/pub.dart.snapshot";
export const analyzerSnapshotPath = "bin/snapshots/analysis_server.dart.snapshot";
export const flutterPath = "bin/" + flutterExecutableName;
export const androidStudioPath = "bin/" + androidStudioExecutableName;
export const DART_DOWNLOAD_URL = "https://dart.dev/get-dart";
export const FLUTTER_DOWNLOAD_URL = "https://flutter.io/setup/";
export const DART_TEST_SUITE_NODE_CONTEXT = "dart-code:testSuiteNode";
export const DART_TEST_GROUP_NODE_CONTEXT = "dart-code:testGroupNode";
export const DART_TEST_TEST_NODE_CONTEXT = "dart-code:testTestNode";
export const DART_DEP_PROJECT_NODE_CONTEXT = "dart-code:depProjectNode";
export const DART_DEP_PACKAGE_NODE_CONTEXT = "dart-code:depPackageNode";
export const DART_DEP_FOLDER_NODE_CONTEXT = "dart-code:depFolderNode";
export const DART_DEP_FILE_NODE_CONTEXT = "dart-code:depFileNode";
export const IS_RUNNING_LOCALLY_CONTEXT = "dart-code:isRunningLocally";
export const stopLoggingAction = "Stop Logging";
export const showLogAction = "Show Log";
export const restartReasonManual = "manual";
export const restartReasonSave = "save";
export const pubGlobalDocsUrl = "https://www.dartlang.org/tools/pub/cmd/pub-global";
export const stagehandInstallationInstructionsUrl = "https://github.com/dart-lang/stagehand#installation";
export const wantToTryDevToolsPrompt = "Dart DevTools (preview) includes additional tools for debugging and profiling Flutter apps, including a Widget Inspector. Try it?";
export const openDevToolsAction = "Open DevTools";
export const noThanksAction = "No Thanks";
export const doNotAskAgainAction = "Don't Ask Again";
export const flutterSurveyPromptWithAnalytics = "Help improve Flutter! Take our Q3 survey. By clicking on this link you agree to share feature usage along with the survey responses.";
export const flutterSurveyPromptWithoutAnalytics = "Help improve Flutter! Take our Q3 survey.";
export const takeSurveyAction = "Take Flutter Q3 Survey";
// Minutes.
export const fiveMinutesInMs = 1000 * 60 * 5;
export const tenMinutesInMs = 1000 * 60 * 10;
export const twentyMinutesInMs = 1000 * 60 * 20;
// Hours.
export const twoHoursInMs = 1000 * 60 * 60 * 2;
export const twentyHoursInMs = 1000 * 60 * 60 * 20;
export const fortyHoursInMs = 1000 * 60 * 60 * 40;
// Duration for not showing a prompt that has been shown before.
export const noRepeatPromptThreshold = twentyHoursInMs;
export const longRepeatPromptThreshold = fortyHoursInMs;
export const pleaseReportBug = "Please raise a bug against the Dart extension for VS Code.";
// Chrome OS exposed ports: 8000, 8008, 8080, 8085, 8888, 9005, 3000, 4200, 5000
export const CHROME_OS_DEVTOOLS_PORT = 8080;
export const CHROME_OS_VM_SERVICE_PORT = 8085;
export const DART_STAGEHAND_PROJECT_TRIGGER_FILE = "dart.sh.create";
export const FLUTTER_STAGEHAND_PROJECT_TRIGGER_FILE = "flutter.sh.create";
export const FLUTTER_CREATE_PROJECT_TRIGGER_FILE = "flutter.create";
export const REFACTOR_FAILED_DOC_MODIFIED = "This refactor cannot be applied because the document has changed.";
export const REFACTOR_ANYWAY = "Refactor Anyway";
export const TRACK_WIDGET_CREATION_ENABLED = "dart-code:trackWidgetCreationEnabled";
export const HAS_LAST_DEBUG_CONFIG = "dart-code:hasLastDebugConfig";
export const showErrorsAction = "Show Errors";
export const debugAnywayAction = "Debug Anyway";
export const userPromptContextPrefix = "hasPrompted.";
export const installFlutterExtensionPromptKey = "install_flutter_extension_3";
export const observatoryListeningBannerPattern: RegExp = new RegExp("Observatory (?:listening on|.* is available at:) (http:.+)");
export const observatoryHttpLinkPattern: RegExp = new RegExp("(http://[\\d\\.:]+/)");
|
Cell disruption
Methods
The production of biologically interesting molecules using cloning and culturing methods allows the study and manufacture of relevant molecules. Except for excreted molecules, cells producing molecules of interest must be disrupted. This page discusses various methods. Another method of disruption is called cell unroofing.
Bead method
A common laboratory-scale mechanical method for cell disruption uses glass, ceramic or steel beads, 0.1 to 2 mm in diameter, mixed with a sample suspended in aqueous media. First developed by Tim Hopkins in the late 1970s, the sample and bead mix is subjected to high level agitation by stirring or shaking. Beads collide with the cellular sample, cracking open the cell to release intercellular components. Unlike some other methods, mechanical shear is moderate during homogenization resulting in excellent membrane or subcellular preparations. The method, often called "beadbeating", works well for all types of cellular material - from spores to animal and plant tissues. It is the most widely used method of yeast lysis, and can yield breakage of well over 50% (up to 95%). It has the advantage over other mechanical cell disruption methods of being able to disrupt very small sample sizes, process many samples at a time with no cross-contamination concerns, and does not release potentially harmful aerosols in the process.
In the simplest example of the method, an equal volume of beads are added to a cell or tissue suspension in a test tube and the sample is vigorously mixed on a common laboratory vortex mixer. While processing times are slow, taking 3-10 times longer than that in specialty shaking machines, it works well for easily disrupted cells and is inexpensive.
Successful beadbeating is dependent not only design features of the shaking machine (which take into consideration shaking oscillations per minute, shaking throw or distance, shaking orientation and vial orientation), but also the selection of correct bead size (0.1–6 mm diameter), bead composition (glass, ceramic, steel) and bead load in the vial.
In most laboratories, beadbeating is done in batch sizes of one to twenty-four sealed, plastic vials or centrifuge tubes. The sample and tiny beads are agitated at about 2000 oscillations per minute in specially designed reciprocating shakers driven by high power electric motors. Cell disruption is complete in 1–3 minutes of shaking. Significantly faster rates of cell disruption are achieved with a beadbeater variation called SoniBeast. Differing from conventional machines, it agitates the beads using a vortex motion at 20,000 oscl/min. Larger beadbeater machines that hold deep-well microtiter plates also shorten process times, as do Bead Dispensers designed to quickly load beads into multiple vials or microplates. Pre-loaded vials and microplates are also available.
All high energy beadbeating machines warm the sample about 10 degrees/minute. This is due to frictional collisions of the beads during homogenization. Cooling of the sample during or after beadbeating may be necessary to prevent damage to heat-sensitive proteins such as enzymes. Sample warming can be controlled by beadbeating for short time intervals with cooling on ice between each interval, by processing vials in pre-chilled aluminum vial holders or by circulating gaseous coolant through the machine during beadbeating.
A different beadbeater configuration, suitable for larger sample volumes, uses a rotating fluorocarbon rotor inside a 15, 50 or 200 ml chamber to agitate the beads. In this configuration, the chamber can be surrounded by a static cooling jacket. Using this same rotor/chamber configuration, large commercial machines are available to process many liters of cell suspension. Currently, these machines are limited to processing monocellular organisms such as yeast, algae and bacteria.
Cryopulverization
Samples with a tough extracellular matrix, such as animal connective tissue, some tumor biopsy samples, venous tissue, cartilage, seeds, etc., are reduced to a fine powder by impact pulverization at liquid nitrogen temperatures. This technique, known as cryopulverization, is based on the fact that biological samples containing a significant fraction of water become brittle at extremely cold temperatures. This technique was first described by Smucker and Pfister in 1975, who referred to the technique as cryo-impacting. The authors demonstrated cells are effectively broken by this method, confirming by phase and electron microscopy that breakage planes cross cell walls and cytoplasmic membranes.
The technique can be done by using a mortar and pestle cooled to liquid nitrogen temperatures, but use of this classic apparatus is laborious and sample loss is often a concern. Specialised stainless steel pulverizers generically known as Tissue Pulverizers are also available for this purpose. They require less manual effort, give good sample recovery and are easy to clean between samples.
Advantages of this technique are higher yields of proteins and nucleic acids from small, hard tissue samples - especially when used as a preliminary step to mechanical or chemical/solvent cell disruption methods mentioned above.
High Pressure Cell Disruption
Since the 1940s high pressure has been used as a method of cell disruption, most notably by the French Pressure Cell Press, or French Press for short. This method was developed by Charles Stacy French and utilises high pressure to force cells through a narrow orifice, causing the cells to lyse due to the shear forces experienced across the pressure differential. While French Presses have become a staple item in many microbiology laboratories, their production has been largely discontinued, leading to a resurgence in alternate applications of similar technology.
Modern physical cell disruptors typically operate via either pneumatic or hydraulic pressure. Although pneumatic machines are typically lower cost, their performance can be unreliable due to variations in the processing pressure throughout the stroke of the air pump. It is generally considered that hydraulic machines offer superior lysing ability, especially when processing harder to break samples such as yeast or Gram-positive bacteria, due to their ability to maintain constant pressure throughout the piston stroke. As the French Press, which is operated by hydraulic pressure, is capable of over 90% lysis of most commonly used cell types it is often taken as the gold standard in lysis performance and modern machines are often compared against it not only in terms of lysis efficiency but also in terms of safety and ease of use. Some manufacturers are also trying to improve on the traditional design by altering properties within these machines other than the pressure driving the sample through the orifice. One such example is Constant Systems, who have recently shown that their Cell Disruptors not only match the performance of a traditional French Press, but also that they are striving towards attaining the same results at a much lower power.
Pressure Cycling Technology ("PCT"). PCT is a patented, enabling technology platform that uses alternating cycles of hydrostatic pressure between ambient and ultra-high levels (up to 90,000 psi) to safely, conveniently and reproducibly control the actions of molecules in biological samples, e.g., the rupture (lysis) of cells and tissues from human, animal, plant, and microbial sources, and the inactivation of pathogens. PCT-enhanced systems (instruments and consumables) address some challenging problems inherent in biological sample preparation. PCT advantages include: (a) extraction and recovery of more membrane proteins, (b) enhanced protein digestion, (c) differential lysis in a mixed sample base, (d) pathogen inactivation, (e) increased DNA detection, and (f) exquisite sample preparation process control.
The Microfluidizer method used for cell disruption strongly influences the physicochemical properties of the lysed cell suspension, such as particle size, viscosity, protein yield and enzyme activity. In recent years the Microfluidizer method has gained popularity in cell disruption due to its ease of use and efficiency at disrupting many different kinds of cells. The Microfluidizer technology was licensed from a company called Arthur D. Little and was first developed and utilized in the 1980s, initially starting as a tool for liposome creation. It has since been used in other applications such as cell disruption nanoemulsions, and solid particle size reduction, among others.
By using microchannels with fixed geometry, and an intensifier pump, high shear rates are generated that rupture the cells. This method of cell lysis can yield breakage of over 90% of E. coli cells.
Many proteins are extremely temperature-sensitive, and in many cases can start to denature at temperatures of only 4 degrees celsius. Within the microchannels, temperatures exceed 4 degrees celsius, but the machine is designed to cool quickly so that the time the cells are exposed to elevated temperatures is extremely short (residence time 25 ms-40 ms). Because of this effective temperature control, the Microfluidizer yields higher levels of active proteins and enzymes than other mechanical methods when the proteins are temperature-sensitive.
Viscosity changes are also often observed when disrupting cells. If the cell suspension viscosity is high, it can make downstream handling—such as filtration and accurate pipetting—quite difficult. The viscosity changes observed with a Microfluidizer are relatively low, and decreases with further additional passes through the machine.
In contrast to other mechanical disruption methods the Microfluidizer breaks the cell membranes efficiently but gently, resulting in relatively large cell wall fragments (450 nm), and thus making it easier to separate the cell contents. This can lead to shorter filtration times and better centrifugation separation.
Microfluidizer technology scales from one milliliter to thousands of liters.
Nitrogen decompression
For nitrogen decompression, large quantities of nitrogen are first dissolved in the cell under high pressure within a suitable pressure vessel. Then, when the gas pressure is suddenly released, the nitrogen comes out of the solution as expanding bubbles that stretch the membranes of each cell until they rupture and release the contents of the cell.
Nitrogen decompression is more protective of enzymes and organelles than ultrasonic and mechanical homogenizing methods and compares favorably to the controlled disruptive action obtained in a PTFE and glass mortar and pestle homogenizer. While other disruptive methods depend upon friction or a mechanical shearing action that generate heat, the nitrogen decompression procedure is accompanied by an adiabatic expansion that cools the sample instead of heating it.
The blanket of inert nitrogen gas that saturates the cell suspension and the homogenate offers protection against oxidation of cell components. Although other gases: carbon dioxide, nitrous oxide, carbon monoxide and compressed air have been used in this technique, nitrogen is preferred because of its non-reactive nature and because it does not alter the pH of the suspending medium. In addition, nitrogen is preferred because it is generally available at low cost and at pressures suitable for this procedure.
Once released, subcellular substances are not exposed to continued attrition that might denature the sample or produce unwanted damage. There is no need to watch for a peak between enzyme activity and percent disruption. Since nitrogen bubbles are generated within each cell, the same disruptive force is applied uniformly throughout the sample, thus ensuring unusual uniformity in the product. Cell-free homogenates can be produced.
The technique is used to homogenize cells and tissues, release intact organelles, prepare cell membranes, release labile biochemicals, and produce uniform and repeatable homogenates without subjecting the sample to extreme chemical or physical stress.
The method is particularly well suited for treating mammalian and other membrane-bound cells. It has also been used successfully for treating plant cells, for releasing virus from fertilized eggs and for treating fragile bacteria. It is not recommended for untreated bacterial cells. Yeast, fungus, spores and other materials with tough cell walls do not respond well to this method. |
'''
Demonstrates how to create a mmesh from scratch and to set color per vertex data.
'''
from pymxs import runtime as rt # pylint: disable=import-error
def make_pyramid_mesh(side=20.0):
'''Construct a pyramid from vertices and faces.'''
halfside = side / 2.0
return rt.mesh(
vertices=[
rt.point3(0.0, 0.0, side),
rt.point3(-halfside, -halfside, 0.0),
rt.point3(-halfside, halfside, 0.0),
rt.point3(halfside, 0.0, 0.0)
],
faces=[
rt.point3(1, 2, 3),
rt.point3(1, 3, 4),
rt.point3(1, 4, 2),
rt.point3(2, 3, 4),
])
def color_pyramid_mesh(mesh):
'''Add two color vertices, and refer them in the faces (color the pyramid).'''
rt.setNumCPVVerts(mesh, 2, True)
rt.setVertColor(mesh, 1, rt.Point3(255, 0, 0))
rt.setVertColor(mesh, 2, rt.Point3(0, 0, 255))
rt.buildVCFaces(mesh)
rt.setVCFace(mesh, 1, 1, 1, 2)
rt.setVCFace(mesh, 2, 1, 2, 2)
rt.setVCFace(mesh, 3, 2, 2, 2)
rt.setVCFace(mesh, 4, 1, 1, 1)
rt.setCVertMode(mesh, True)
rt.update(mesh)
def main():
'''Construct a pyramid and then add colors to its faces.'''
rt.resetMaxFile(rt.Name('noPrompt'))
mesh = make_pyramid_mesh()
color_pyramid_mesh(mesh)
main()
|
<reponame>Cr4ziEsT/TIL<filename>java/FastCampus/MiniPJT/guestbook/src/main/java/my/examples/guestbook/dao/GuestbookDao.java
package my.examples.guestbook.dao;
import my.examples.guestbook.servlet.Guestbook;
import java.sql.Connection;
import java.sql.Date;
import java.sql.PreparedStatement;
import java.sql.ResultSet;
import java.time.LocalDateTime;
import java.time.ZoneId;
import java.util.ArrayList;
import java.util.List;
public class GuestbookDao {
private String dbUrl = "jdbc:h2:tcp://localhost:9092/jdbc:h2:tcp://localhost/~/test;DB_CLOSE_DELAY=-1;";
private String dbId = "sa";
private String dbPassword = "";
public List<Guestbook> getGuestbookList(){
List<Guestbook> list = new ArrayList<>();
Connection conn = null;
PreparedStatement ps = null;
ResultSet rs = null;
try{
conn = DbUtil.connect(dbUrl, dbId, dbPassword);
String sql = "select id, name, content, regdate from guestbook order by id desc";
ps = conn.prepareStatement(sql);
rs = ps.executeQuery();
while(rs.next()){
Guestbook guestbook = new Guestbook();
guestbook.setId(rs.getLong(1));
guestbook.setName(rs.getString(2));
guestbook.setContent(rs.getString(3));
Date dbDate = rs.getDate(4); // java.sql.Date
LocalDateTime ldt = dbDate.toInstant().atZone(ZoneId.systemDefault()).toLocalDateTime();
guestbook.setRegate(ldt);
list.add(guestbook);
}
}catch (Exception ex){
ex.printStackTrace();
}finally{
DbUtil.close(conn,ps,rs);
}
return list;
}
public int addGuestbook(Guestbook guestbook){
int count = 0;
Connection conn = null;
PreparedStatement ps = null;
try{
conn = DbUtil.connect(dbUrl,dbId,dbPassword);
String sql = "insert into guestbook(id, name, content, regdate values (null, ?, ?, now())";
ps = conn.prepareStatement(sql);
ps.setString(1, guestbook.getName());
ps.setString(2, guestbook.getContent());
count = ps.executeUpdate();
}catch (Exception ex){
ex.printStackTrace();
}finally {
DbUtil.close(conn, ps);
}
return count;
}
public int deleteGuestbook(Long id){
int count = 0;
Connection conn = null;
PreparedStatement ps = null;
try{
conn = DbUtil.connect(dbUrl, dbId, dbPassword);
String sql = "delete from guestbook where id = ?";
ps = conn.prepareStatement(sql);
ps.setLong(1, id);
count = ps.executeUpdate();
}catch (Exception ex){
ex.printStackTrace();
}finally {
DbUtil.close(conn, ps);
}
return count;
}
}
|
#!/usr/bin/env python2
import os, time, subprocess, requests, sys, syslog
RECONFIG_CMD = "v4l2-ctl --set-fmt-video=width=1920,height=1080,pixelformat=1".split(" ")
PRIME_CMD = "v4l2-ctl --stream-to=- --stream-mmap=3 --stream-count=60".split(" ")
CAPTURE_CMD = "v4l2-ctl --stream-to=- --stream-mmap=3 --stream-count=1".split(" ")
BUS_POWER_FILE = "/sys/devices/platform/soc/3f980000.usb/buspower"
CAPTURE_INTERVAL = 5.
HEADERS = dict([[j.strip() for j in i.strip().split(":") if j.strip()] for i in os.environ.get("HEADERS", "").split(";") if i.strip()])
URL = len(sys.argv) > 1 and sys.argv[1] or "http://localhost:9000/upsydaisy"
def reconfig():
syslog.syslog("power cycling camera")
f = file(BUS_POWER_FILE, "w")
f.write("0")
f.close()
f = file(BUS_POWER_FILE, "w")
f.write("1")
f.close()
time.sleep(2.)
subprocess.call(RECONFIG_CMD, stderr=None)
subprocess.call(PRIME_CMD, stderr=None)
if __name__ == "__main__":
count = 0
devnull = file("/dev/null","w")
HEADERS['content-type'] = 'image/jpeg'
while True:
start = time.time()
try:
jpeg = subprocess.check_output(CAPTURE_CMD, stderr=devnull)
try:
res = requests.post(URL, data=jpeg, headers=HEADERS, timeout=0.1)
except:
syslog.syslog(str(sys.exc_info()[1]))
if not count % 500:
reconfig()
except KeyboardInterrupt:
raise SystemExit(0)
except:
syslog.syslog(str(sys.exc_info()[1]))
d = time.time() - start
d = d > 5. and 5. or d
d = d < 0. and 0. or d
time.sleep(5. - d)
count += 1
|
<reponame>Student-Management-System/StandaloneSubmitter
/**
* Package for handling (parsing) the error message of a the hook script.
*/
package de.uni_hildesheim.sse.submitter.svn.hookErrors; |
<gh_stars>10-100
/* Generated by RuntimeBrowser.
*/
@protocol SKUIProxyScrollViewDelegate <UIScrollViewDelegate>
@optional
- (void)scrollViewDidChangeContentInset:(SKUIProxyScrollView *)arg1;
- (void)scrollViewDidMoveToWindow:(SKUIProxyScrollView *)arg1;
@end
|
/**
* Created by Jeffrey Liu on 12/2/15.
*/
public class SendWatchMessageIntentService extends IntentService implements GoogleApiClient.ConnectionCallbacks {
private static final String TAG = "SendWatchMessage";
public static final String INPUT_EXTRA = "input extra";
private GoogleApiClient mApiClient;
public SendWatchMessageIntentService() {
super("SendWatchMessageIntentService");
}
@Override
protected void onHandleIntent(Intent intent) {
initGoogleApiClient();
NodeApi.GetConnectedNodesResult nodes = Wearable.NodeApi.getConnectedNodes(mApiClient).await();
for (Node node : nodes.getNodes()) {
MessageApi.SendMessageResult result = Wearable.MessageApi.sendMessage(
mApiClient, node.getId(), PhoneWatchClass.PHONE_TO_WATCH_MESSAGE_PATH, intent.getStringExtra(INPUT_EXTRA).getBytes()).await();
}
}
private void initGoogleApiClient() {
mApiClient = new GoogleApiClient.Builder(this)
.addApi(Wearable.API)
.build();
mApiClient.connect();
}
@Override
public void onConnected(Bundle bundle) {
Log.d(TAG, "onConnected");
}
@Override
public void onConnectionSuspended(int i) {
Log.e(TAG, "onConnectionSuspended: " + i);
}
@Override
public void onDestroy() {
if (mApiClient != null)
mApiClient.disconnect();
super.onDestroy();
}
} |
Correlation between endoscopic suspicion of gastric cancer and histology in Nigerian patients with dyspepsia. Gastric mucosal biopsies of 77 dyspeptic patients whose endoscopic features were suggestive of cancer and 56 patients with uncomplicated duodenal ulcer (DU) were subjected to histopathological analysis. Gastric cancer was confirmed in 18 (23.4%) of the 77 patients but not in 59 (76.6%). 4 (5.2%) of the 18 patients had early gastric cancer (EGC). Histopathological findings in the stomach biopsy of the 59 patients in whom cancer could not be confirmed were compared with those of the 56 patients with DU. Intestinal metaplasia (IM) was present in 32.2% of the 59 cases with endoscopic suspicion of gastric cancer and in 16.1% of the 56 DU controls (P < 0.05). Mucosa-associated lymphoid tissue (MALT) occurred in 28.8% of the cancer-resembling cases and in 12.5% of the DU patients (P < 0.05). The difference in the prevalence of gastric mucosal atrophy and Helicobacter pylori infection between the two groups (83% vs. 71.4%) did not reach statistical significance (P > 0.10). All 18 patients with gastric cancer were positive for Helicobacter pylori and the prevalence of the infection approached 95% in those with IM and MALT. This study shows that IM and MALT present with endoscopic appearances that resemble that of gastric cancer and that along with the latter, their main aetiological agent is Helicobacter pylori. |
Opening Day is nearly upon us and the weather is planning on cooperating.
Check back for daily weather updates as Opening Day approaches.
The Opening Day Parade begins at noon Thursday, along Race and Fifth streets. The Reds' game against the Pittsburgh Pirates is scheduled to begin at 4:10 p.m.
Thursday will be partly sunny, with a high near 65. Overnight temperatures will dip down to 49 and there is a chance of showers ager 3 a.m.
"The high will gradually move east of the region tonight into Wednesday. A cold front will approach the area from the northwest on Thursday, bringing increasing clouds and a chance of showers," the National Weather Service said.
Tuesday: Sunny, with a high near 52. Overnight low around 26.
Wednesday: Sunny, with a high near 61. Overnight low around 39.
Thursday: Partly sunny, with a high near 65. Overnight chance of showers, mainly after 3 a.m. Low around 50.
Friday: A chance of showers before 5 p.m. Cloudy, with a high near 65. Overnight chance of showers after 10 p.m. with a low around 52.
Saturday: Showers and a high near 62 for FC Cincinnati fans. Overnight rain showers before 4 a.m. and possible snow showers. Low around 33.
Sunday: A chance of rain and snow showers. Partly sunny, with a high near 44. Overnight low around 29. |
Chance Waters
Biography
Waters has toured in support of many of Australia's biggest hip-hop acts, including Bliss N Eso, Drapht, The Herd, Pez & 360. In 2009 he was a Featured Artist on Triple J Unearthed, an initiative run by the national youth broadcaster Triple J to expose and promote talented unsigned Australian artists – since being unearthed he has received airplay and accolades from the station. In the same year he was also awarded a front page feature on social networking website Myspace and received coverage in The Australian.
In 2011 he released the extended player Inkstains (Acoustic) an acoustic re-imagining of various songs from Inkstains including an acoustic version of the title track and lead single to his second record Infinity. The EP's single Build It Up (Acoustic) featured independent Brisbane folk band Charlie Mayfair and received airplay on triple j. To promote the EP Waters appeared on the front cover of mX in Sydney and gave an interview and live performance on the Triple J Hip Hop Show and FBi Radio. In support of the EP Waters embarked on the Hey, Where's Your DJ? east coast tour, which was billed as the first ever acoustic Australian hip hop tour and included a three-week capacity residency at Oxford Art Factory in Sydney. At the end of 2011 Waters released the Approaching Infinity mixtape, his final release under the Phatchance moniker. The release included a remix of Gotye's international hit Somebody That I Used To Know which amassed well over 100,000 plays on YouTube as well as seeing chart success on radio in Europe.
In 2012 Waters announced he was nearing completion of his follow up album Infinity and that he was relinquishing the Phatchance moniker in favour of his given name. In February 2012 he released the first single from Infinity in the form of the title track and accompanying video clip. The song received airplay on triple j and the video clip received national play on ABC's RAGE!. In support of the single Waters embarked on his first east coast tour for the year, the Approaching Infinity tour, which included a capacity show with fellow rapper Seth Sentry at The Evelyn in Melbourne and a Sydney performance at FBi Social. In May 2012 Waters released the second single from Infinity Maybe Tomorrow featuring Sydney Soul singer Lilian Blue. The song was added to the triple j hit list and achieved high rotation on the station, it was also picked up by National Geographic as the promotional music to their internationally franchised program Doomsday Preppers. The song was the 9th most added track to radio in Australia in the second week of May and peaked at No. 2 on the AIR national independent radio charts in June. The accompanying video clip was named RAGE! Indie of the Week and would later place at No. 7 in the 2012 RAGE! Top 50.
In August 2012 Chance Waters announced he was releasing his new album Infinity through the Shock Records imprint Permanent Records. The same month in an interview with Sarah Howells on triple j Waters said he was working on a new single with Bertie Blackman and that Infinity would be released on 2 November. The single, Young and Dumb was exclusively premiered on triple j on 20 September and performed live for the first time on Like a Version alongside a cover of Mumford & Sons little lion man. In November 2012 Waters was nominated for the Unearthed J Award and released his sophomore record Infinity which also signified his first top 100 album, debuting at No. 54 on the ARIA Album Charts. Young & Dumb would later go on to place at No. 45 in the Triple J Hottest 100, 2012 alongside Maybe Tomorrow at No. 89.
Chance has been booked for festivals including Sydney Big Day Out, Insert To Play, Rip It Up, The Big Pineapple Festival and Nannup Music Festival.
Natural Causes
From 2003 to 2007 Phatchance was one of the founding members of the Sydney Hip-Hop group Natural Causes the flagship act for Independent record label Nurcha Records. Prior to the collapse of Nurcha Records and the eventual collapse of the band, they played more than 70 live shows across Australia.
Natural Causes first and only release The Incidental Noise Demo was released on Nurcha Records in 2007. The first single from the release Introductions received Single of the Week on FBi Radio, Sydney's largest Independent Broadcaster.
Personal life
Chance Waters was born in Sydney but grew up in Christies Beach, South Australia after a short stint in Melbourne. At the age of twelve Waters moved back to Sydney, living in Balmain, with his single parent mother and brother. Waters completed his primary schooling at North Rocks Public School and then attended Fort Street High School in Petersham a school whose alumni includes artists and bands such as Josh Pyke, Horrorshow and Spit Syndicate.
Waters is an active vegan and is vocal in support of animal rights issues. |
With educators on the lookout for instructional materials that fit with the content and vision of the common-core standards, a new set of “publishers’ criteria” aim to influence decisions by both the developers and purchasers of such offerings for high school mathematics.
Crafted by the lead writers of the math common core, the 20-page document issued today seeks to “sharpen the alignment question” and make “more clearly visible” whether materials faithfully reflect both the letter and spirit of the math standards adopted by 45 states and the District of Columbia.
In addition, a revised set of K-8 criteria were released today, with a variety of changes to the version first put out last summer based on feedback from the field (including districts that started to use them). One notable deletion was the explicit call for elementary math textbooks to not exceed 200 pages in length (and for middle and high school texts not to exceed 500 pages). Another change was to include more precise guidance on how much time should be devoted to the “major work” of the standards, differentiating in particular the K-2 level with that for the middle grades.
Both sets of criteria are endorsed by several prominent organizations that provided feedback, including national groups representing governors, chief state school officers, state boards of education, and large urban districts, as well as Achieve, the Washington-based nonprofit that managed the process for developing the Common Core State Standards.
One of the endorsing organizations, the Council of the Great City Schools, signaled last year that more than 30 of its member districts—including Chicago, Los Angeles, and New York—would use the criteria in math (and a companion set for English/language arts) to guide their decisions in selecting materials. Also, California recently used the K-8 math criteria as part of its work to develop guidance for districts on selecting math materials.
The new high school criteria (as well as the revised K-8) drive home three core dimensions of the math standards: focus, coherence, and rigor. On the issue of focus—the notion of addressing fewer math topics in greater depth—the document sends a clear signal that materials should have a clear eye on readying students for postsecondary education.
“In any single course, students using the materials as designed spend the majority of their time developing knowledge and skills that are widely applicable as prerequisites for postsecondary education,” it says.
For more details, see Erik Robelen’s full post on the publishers’ guides on the Curriculum Matters blog. |
Diabetes in tropical Africa: a prospective study, 1981-7. I. Characteristics of newly presenting patients in Dar es Salaam, Tanzania, 1981-7. OBJECTIVE--To study the clinical characteristics of newly diagnosed diabetic patients in tropical Africa. DESIGN--Prospective study of all newly diagnosed diabetic patients registered at a major urban hospital between 1 June 1981 and 31 May 1987. SETTING--Muhimbili Medical Centre, Dar es Salaam, Tanzania. PATIENTS--1250 Patients: 874 men, 376 women. RESULTS--272 (21.8%) Patients had diabetes requiring insulin, 825 (66.0%) had diabetes not requiring insulin, and 153 (12.2%) had diabetes of uncertain type. Most patients (1103, 88.2%) presented with the classic symptoms of diabetes. The peak time of presentation of diabetic patients requiring insulin was at age 15 to 19 years. Male manual workers and peasant farmers with diabetes not requiring insulin presented at a significantly older age and had a lower body mass index than sedentary office workers. Forty six (18.1%) of the patients requiring insulin diabetes and 111 (14.4%) not requiring insulin had first degree relative with diabetes. Twenty seven per cent of patients were underweight (body mass index less than 20 kg/m2) and 14.6% were obese (body mass index greater than 30 kg/m2). Hypertension was diagnosed in 211 (26.7%) of 791 patients not requiring insulin. Nine (3.3%) of those requiring insulin may have had the protein deficient type of diabetes related to malnutrition. The fibrocalculous variety of diabetes related to malnutrition was not observed. CONCLUSIONS--Newly presenting diabetic patients in Tanzania with diabetes requiring insulin are older at presentation than those in Britain; most diabetic patients present with diabetes not requiring insulin and a smaller proportion of Tanzanian patients are obese. Most have a lower socioeconomic state than diabetic patients in Britain. There are often delays in diagnosis in Tanzania, and there is a higher incidence of death shortly after presentation. |
For years now Apple has followed a rather intelligent waterfall of its products down the pricing stack. With the arrival of every new iPhone, the previous generation gets a $100 discount from its on-contract price, and the generation before that one is offered for free on-contract. In the early days of this strategy, it was a great way to continue to build up the iOS user base without having to compete in the lower margin feature phone space. The strategy worked quite well.
During the days of the iPhone 4S the strategy made a ton of sense, as the 3GS was undoubtedly cheaper to manufacturer than the glass + metal iPhone 4 and 4S designs. No attention was paid to the impact on the iOS brand however of having a bunch of customers walking around with new 3GSes as recently as late 2011.
With the iPhone 5s however, Apple was caught in an interesting situation. The previous model leveraged the same industrial design, and it’s definitely not a cheap one at that. Capacitive touchscreen display costs increase with display size, making the iPhone 5’s display a more expensive option than its predecessor. Add in other flagship features like in-cell touch and premium construction and the iPhone 5 quickly became a device that Apple would rather not discount.
Keep in mind that Apple built its phone business much like it built its Mac business, by focusing exclusively on higher margin products. The incredible volumes that followed were a side effect of the state of the industry, not a deliberate change in business model. With its core motivations unchanged, Apple needed a solution to continue to make the 3 phone strategy work. The solution is the iPhone 5c:
The iPhone 5c leverages the entirety of the iPhone 5 hardware platform, but moves from a glass + aluminum construction down to a more cost effective glass + polycarbonate design. The iPhone 5c retains all other features of the iPhone 5 including in-cell touch, Lightning connector, the same rear facing iSight camera stack and A6 SoC. It even brings some new features to the table like sharing the same front facing FaceTime HD camera as the iPhone 5s. Other elements aren’t necessarily newer but are at least shared with the 5s platform. For example, the WiFi, cellular and BT hardware is different than the iPhone 5, but shared across the 5c and 5s. Having as many common components between Apple’s two iPhones at this point is another great way to capitalize on economies of scale.
The savings on materials however is enough to allow Apple to sell the iPhone 5c in place of the outgoing 5. With a 2-year contract Apple expects a 16GB 5c to sell for $99, and a 32GB for $199. These are exactly the same price points you’d expect the iPhone 5 to drop to after the introduction of the 5s. Anyone expecting the 5c to be Apple’s solution for volume in China or somehow compete in the feature phone space will be disappointed. At the same time, anyone who is familiar with Apple’s business will know that a low cost volume play was never in the cards.
The 5c comes in iPod touch-like packaging but still includes a pair of Apple EarPods (with remote and mic), a 5W wall adapter and a Lightning cable.
Apple iPhone 5 Apple iPhone 5c Apple iPhone 5s SoC Apple A6 Apple A6 Apple A7 Display 4-inch 1136 x 640 LCD sRGB coverage with in-cell touch RAM 1GB LPDDR2 1GB LPDDR3 WiFi 2.4/5GHz 802.11a/b/g/n, BT 4.0 Storage 16GB/32GB/64GB 16GB/32GB 16GB/32GB/64GB I/O Lightning connector, 3.5mm headphone Current OS iOS 7 Battery 1440 mAh, 3.8V, 5.45 Whr 1507 mAh, 3.8V, 5.73 Whr 1570 mAh, 3.8V, 5.96 Whr Size / Mass 123.8 x 58.6 x 7.6 mm, 112 grams 124.4 x 59.2 x 8.97 mm, 132 grams 123.8 x 58.6 x 7.6 mm, 112 grams Camera 8MP iSight with 1.4µm pixels Rear Facing
1.2MP with 1.75µm pixels Front Facing 8MP iSight with 1.4µm pixels Rear Facing
1.2MP with 1.9µm pixels Front Facing 8MP iSight with 1.5µm pixels Rear Facing + True Tone Flash
1.2MP with 1.9µm pixels Front Facing Price $199 (16GB), $299 (32GB), $399 (64GB) on 2 year contract $99 (16GB), $199 (32GB) on 2 year contract $199 (16GB), $299 (32GB), $399 (64GB) on 2 year contract
In fact if we look back at the period of netbook success during the late 2000s, Apple was often under pressure to compete in that space. Instead of putting out a low cost PC competitor, Apple eventually brought the iPad to market - a completely different device, with a very different cost structure, to compete with those lower cost PCs. I don’t know that Apple has to do the same thing here, but if you’re looking for an ultra cheap mobile computing device from Apple - it may not look like a phone.
iPhone 5c (left) vs. iPhone 5s (right)
The smartphone market is definitely maturing. We’ve passed the point of everyone being an early adopter to smartphones now encompassing a larger section of the technology buying pyramid. For people further away from the early adopter summit (further down the pyramid), carrying the absolute latest technology isn’t always at the top of the purchasing decision tree. We are seeing an increased number of smartphone manufacturers play with the use of color in their devices to go after this more mainstream market where the color of your phone may be just as important (if not more) than what SoC is inside.
Motorola recently embraced this trend by offering a huge number of color customizations on the Moto X. We’ve had brightly colored phones from HTC in the past as well, and there’s no way we can have a discussion of color without mentioning Nokia of course. With the 5c, Apple joins the ranks of smartphone companies shipping phones in pretty colors - a side benefit of the iPhone 5c being made out of a polycarbonate material.
The iPhone 5c isn’t, of course, Apple’s first polycarbonate phone. The iPhone 3G and 3GS both relied on plastics before an eventual transition to the glass + metal combination that we got with the newer iPhones.
The 5c is available in five colors: blue, white, green, yellow and pink. I was sampled a pink 5c. Color preferences can definitely get very personal, but for what it’s worth I really like the pink 5c. It’s sort of a combination of pink and coral rather than a bright pink.
The final finish on the 5c is smooth and looks a lot like what you see when you open up a can of brightly colored paint. As with all plastic/polycarbonate phones with a glossy finish, smudges are easily picked up by the iPhone 5c. The colors are light/bright enough where smudges on the device aren’t hugely distracting though, and of course the smooth back surface is easy to wipe off.
Apple offers a line of first party cases for the iPhone 5c. These are soft touch silicon rubber cases, and they are available in six different colors (white, black, blue, yellow, green and pink). Apple’s iPhone 5c cases still allow some color to shine through on the front, and are perforated with large holes to let color through on the back as well. I can’t say I’m a huge fan of the styling of the back of the case but otherwise I like them. The rubber surface is grippy and the inside of the case is made of a microfiber-like material to prevent scratching. I’ve found that the holes on the back of the case do let dirt in between the case and the phone unfortunately.
The combination of 5c color and case color is Apple’s answer to those who want even more customization on the styling of their phone. Similar to what Motorola is doing with the Moto X, the default background of your 5c will match the color you purchase.
The iPhone 5c follows largely the same shape as the iPhone 5 and 5s, but with a twist. Since the 5c’s back is built from a polycarbonate material, it’s much easier to deliver smoothly rounded corners and edges. The result is a device that feels great in hand. I’d actually argue that other than the added weight, the 5c maybe even feels better in hand than the iPhone 5/5s. The same complaints that apply to the 5/5s obviously apply to the 5c - mainly that if you want a bigger display, you’re not getting one here.
The 5c follows the same button layout as the iPhone 5/5s. Power/lock is up top, volume up/down are on the left with the silence switch and there’s a physical home button on the front of the device. Unlike the iPhone 5s, the 5c doesn’t get Touch ID so the home button looks no different than it did on the iPhone 5.
All of the buttons on the 5c feel great, something Brian noticed in his hands on with the device. The internal vibrator motor feels identical to that of the iPhone 5s, and at a slightly higher frequency compared to the original iPhone 5. Again I wouldn’t be too surprised to see as much parts bin sharing as possible between the 5s and 5c.
Display
The iPhone 5c's display is identical to that of the iPhone 5 and 5s. It's the same 4-inch 1136 x 640 Retina Display that Apple launched last year. Apple seems to multi-source the panel as the quality of the one in my 5c review sample was the best iPhone Retina Display I've ever tested. I'm presenting a subset of our display tests below, if you want more detail you can check out our iPhone 5s review:
The 5c's display is incredibly bright, has the best color reproduction of any other phone we've tested and has more than enough contrast.
Internally Apple is quite proud of the steel reinforced frame that gives the iPhone 5c its rigidity. In practice, the 5c has virtually no noticeable chassis flex. It’s an easy victory for Apple because the 5c doesn’t have to be a flagship device, and thus doesn’t have to be as thin as possible. Apple can rely on the 5s pursuing the as-thin-as-can-be market, giving the 5c room to be a bit thicker and thus feel a bit more solid. I agree with Brian in that not all plastic/polycarbonate devices have to feel cheap (see: HTC, Nokia), and the iPhone 5c definitely doesn’t. It’s a different feel than the softer/matte polycarbonate designs I’ve seen in that it’s definitely more slippery.
Battery Life
I do see some small changes in battery life results compared to the iPhone 5, but at this point I’m chalking that up to minor hardware differences in the 5c as well as the fact that we are comparing across iOS versions here (iOS 7 on the 5c vs. iOS 6 on the 5). Web browsing battery life on the 5c is quite good, but if you stress the SoC a lot or look at call time performance the 5c's behavior is mostly dictated by battery capacity, which is definitely more middle of the road rather than flagship.
CPU Performance
The performance of the 5c under iOS 7 is still quite good. I feel like Apple outpaced its own software requirements with the iPhone 5s’ A7 SoC as iOS feels pretty quick on both platforms at this point. Obviously the big downside to going with the 5c over the slightly more expensive 5s is that you lose 64-bit support and do have a much slower CPU, both of which may become more of a pain if you keep the phone for a long time.
Octane and SunSpider both have the iPhone 5c doing relatively well for a non-flagship device, but the platform's performance in Kraken is starting to look quite dated. Browsermark is arguably the most interesting test here as it attempts to present a holistic view of browser performance rather than just focusing on js subtests. Under Browsermark, the still looks quite competitive.
GPU Performance
The latest flagship smartphones have pushed GPU performance far beyond where Apple was with the PowerVR SGX 543MP3 last year. Performance at the 5c's native display resolution is still quite compelling, but if you want the platform to last for a few years in terms of usable 3D gaming life it will definitely age quicker than the 5s or any of the Adreno 320/330 based flagships we've tested.
Camera, Cellular & WiFi
Rear camera quality of the iPhone 5c is identical to the iPhone 5 as it is physically the same camera module. The front facing camera on the other hand is identical to the iPhone 5s. The result is a pair of competent shooters, but you definitely don’t get the move forward in low light performance from the 5s. I won’t go too deep into the camera analysis here as Brian did a great job of that in his piece on the original iPhone 5.
Cellular and WiFi performance seem identical between the iPhone 5c and iPhone 5s. Apple claims both platforms are using the same hardware and have roughly the same antenna layouts. The 5c’s internal steel frame plays a double role as an antenna, although we won’t know exactly how until someone tears one of these down. Just like the 5s, the 5c features the same support for up to 13 LTE bands depending on the model:
Apple iPhone 5S and 5C Banding iPhone Model GSM / EDGE Bands WCDMA Bands FDD-LTE Bands TDD-LTE Bands CDMA 1x / EVDO Rev A/B Bands 5S- A1533 (GSM)
5C- A1532 850, 900, 1800, 1900 MHz 850, 900, 1700/2100, 1900, 2100 MHz 1, 2, 3, 4, 5, 8, 13, 17, 19, 20, 25 N/A N/A 5S- A1533 (CDMA)
5C- A1532 800, 1700/2100, 1900, 2100 MHz 5S- A1453
5C- A1456 1, 2, 3, 4, 5, 8, 13, 17, 18, 19, 20, 25, 26 5S- A1457
5C- A1507 850, 900, 1900, 2100 MHz 1, 2, 3, 5, 7, 8, 20 N/A 5S- A1530
5C- A1529 1, 2, 3, 5, 7, 8, 20 38, 39, 40 Apple iPhone 5S/5C FCC IDs and Models FCC ID Model BCG-E2642A A1453 (5S) A1533 (5S) BCG-E2644A A1456 (5C) A1532 (5C) BCG-E2643A A1530 (5S) BCG-E2643B A1457 (5S) BCG-E2694A A1529 (5C) BCG-E2694B A1507 (5C)
iOS & Software
The iPhone 5c ships with iOS 7 from the factory. Apple also recently made iPhoto, iMovie and its iWork suite free for anyone who buys a new iPhone preloaded with iOS 7 (the iPhone 5c and 5s). The list includes iPhoto, iMovie, Pages, Numbers and Keynote, a pretty substantial collection given how much Apple used to charge for all of them in the past ($40 total). Apple is clearly mimicking its successful Mac strategy here, leveraging software as a way to sell hardware. I’m actually surprised the five apps don’t come preloaded on the 5c, although I wouldn’t be too shocked to see that change in the future.
Final Words
The iPhone 5c is a well built device. For all intents and purposes it is a perfect replacement for the iPhone 5. If you were planning on buying a cost reduced iPhone 5 once the 5s came out, the iPhone 5c should have no problems filling that role. Its performance, battery life and camera quality are all on par with the 5.
Apple’s return to a polycarbonate iPhone design seems to have gone quite well. The iPhone 5c is solid, doesn’t have any noticeable amount of flex and has a great in hand feel thanks to its nicely curved edges. I feel like the color options will go over very well with the 5c’s target markets. I can see many users even preferring the styling of the 5c to the 5s in those markets that aren’t feature/performance sensitive.
Personally I’d prefer the iPhone 5s simply because of its more modern platform, even if I were recommending a device for someone else not as concerned with performance. Supporting the latest ISA (which will probably stick around for a while) and OpenGL ES 3.0 are both important if you’re going to be keeping your phone for a very long time and plan on using it for more than just the basic first party apps.
As I said before though, if your plan all along was to buy an iPhone 5 - the iPhone 5c is a clear substitute good. I don’t expect that we’ll see an even cheaper version, but I am excited for what happens when the 5s hardware waterfalls into the 5c replacement next year.
Apple throwing its hat into the multi-device race marks a very important change for the company. I’ve always believed that the smartphone space would end up looking a lot like the PC industry, or in Apple’s case, the Mac business. Apple presently offers a handful of Mac notebooks, and I see no reason why Apple will stop at two with the iPhone. |
/**
* Passwords tree data.
*/
type TreeData = TreeDataItem[];
/**
* Group item in tree data.
*/
interface TreeDataItem
{
/** Group name */
name: string;
/** Icon URI */
icon?: string;
/** Password entries in this group */
entries: TreeDataEntry[];
}
/**
* Password entry in tree data.
*/
interface TreeDataEntry
{
/** Creation timestamp */
id: number;
/** Expiration timestamp */
expiration?: number;
/** Timestamps of previous versions */
history?: number[];
/** Entry name */
name: string;
/** Additional description */
description?: string;
/** URL address */
url?: string;
/** Icon URI */
icon?: string;
/** Separately encrypted data */
protected?: TreeDataEntryProtected;
}
/**
* Protected part of password enrty.
*/
interface TreeDataEntryProtected
{
/** Login name */
login: string;
/** Password */
password: string;
/** Additional data/comments */
comment?: string;
/** Attachments */
attachments?: TreeDataEntryAttachment[];
}
/**
* Attachment to password entry.
*/
interface TreeDataEntryAttachment
{
/** File name */
name: string;
/** File contents in Base64 */
data: string;
}
/**
* Module
*/
export {
TreeData as default,
TreeDataItem,
TreeDataEntry,
TreeDataEntryProtected,
TreeDataEntryAttachment,
};
|
. The abortion laws in effect and being considered in several European countries are summarized briefly (Scandinavian and Eastern European countries, Switzerland, Austria); others are more comprehensively reviewed, including dates, content and individual sponsors of proposed laws (Denmark, England, France, Belgium, Luxembourg, Holland, West Germany, Italy). Denmark and England have liberal abortion laws; Denmark permits abortion on demand up to 12 weeks but to residents only, but England performs about 25% (24,000/year) of its abortions on foreigners. Illegal abortions are estimated at 500,000-1,000,000/year in Germany, 250,000-800,000/year in France, and 30,000-50,000/year in Belgium. All of these countries have repressive abortion laws, usually prescribing 5 years in prison and/or a fine for the woman, and 5 years in prison with suspension of license for the practitioner. Convictions are rare in comparison with illegal abortions not prosecuted. A controversial conviction was that of Dr. Willy Peers, Professor of Gynecology of Brussels, who was imprisoned for performing an abortion on a mentally retarded girl raped by her father. Germany, France, Holland, and Belgium each have proposed liberal legislation during 1971-1973. A condemnation of abortion by Pope Paul has prompted 2 proposed bills in the Italian assembly which stand, however, little chance of being ennacted. |
Secondary phosphorus poisoning in dogs. Subsequent to a possum (Trichosurus vulpecula) poisoning operation purportedly using 1% phosphorus baits, six dogs with access to poisoned possums died of phosphorus poisoning. Two dogs survived, following treatment with oral copper sulphate and parenteral vitamin K. Clinical signs included depression, jaundice, vomiting and bloody diarrhoea. Post-mortem lesions included large areas of subcutaneous, interstitial and intermuscular haemorrhage, subserosal haemorrhage and liver degeneration. Free phosphorus was detected in the ingesta of three of the dogs which died up to 7 days after the last of the poison was laid. Analysis of two batches of baits used showed P levels of 1.17% and 1.24%. |
Tibial derotational osteotomies in two neuromuscular populations: comparing cerebral palsy with myelomeningocele Abstract Purpose To review the outcomes of tibial derotational osteotomies (TDOs) as a function of complication and revision surgery rates comparing a cohort of children with myelodysplasia to a cohort with cerebral palsy (CP). Methods A chart review was completed on TDOs performed in a tertiary referral centre on patients with myelodysplasia or CP between 1985 and 2013 in patients aged > 5 years with > 2 years follow-up. Charts were reviewed for demographics, direction/degree of derotation, complications and need for re-derotation. Two-sample T-tests were used to compare the characteristics of the two groups. Two-tailed chi-square tests were used to compare complications. Generalised linear logit models were used to identify independent risk factors for complication and re-rotation. Results The 153 patients (217 limbs) were included. Average follow-up was 7.83 years. Overall complication incidence was 10.14%, including removal of hardware for any reason, with a 4.61% major complication incidence (fracture, deep infection, hardware failure). After adjusting for gender and age, the risk of complication was not statistically significantly different between groups (p = 0.42) nor was requiring re-derotation (p = 0.09). The probability of requiring re-derotation was 31.9% less likely per year increase in age at index surgery (p = 0.005). Conclusion With meticulous operative technique, TDO in children with neuromuscular disorders is a safe and effective treatment for tibial torsion, with an acceptable overall and major complication rate. The risk of re-operation decreases significantly in both groups with increasing age. The association between age at initial surgery and need for re-derotation should help guide the treatment of children with tibial torsion. Introduction Rotational deformities of the tibia are common among children with myelodysplasia and cerebral palsy (CP). Unlike idiopathic tibial torsion, torsion in children with a neuromuscular disease often does not resolve without surgical intervention. 1,2 In the typically developing child, the tibia is internally rotated at birth and external tibial rotation occurs throughout growth, predictably improving with age. 3 In contrast, external tibial torsion is often progressive, more frequently requiring surgical correction, even in the idiopathic population. 2 In the neuromuscular population, dynamic muscular imbalance, weakness and, in some cases, spasticity commonly lead to progressive rotational deformity that may significantly affect brace wear in all affected patients and gait biomechanics in ambulatory patients 1,4-7 (GMFCS I-III in the CP population and lumbar or sacral levels of involvement in the myelodysplastic population). Internal tibial torsion can lead to frequent falls resulting from poor foot clearance -from the ground and from the other leg in swing. External tibial torsion can lead to hindfoot valgus, pes planus, increased valgus stress at the knee, excessive shoe wear, poor orthotic control and trophic ulceration in the myelodysplastic population who lack protective sensation. 1,4 Both internal and external torsion may result in lever arm dysfunction, which can lead to the development of crouch gait with resultant decreased velocity, poor endurance and knee pain in both populations. 5, In both groups, significant improvements in gait biomechanics have been reported following tibial derotational osteotomy (TDO). 10,11 Surgery should be considered for all tibial torsion affecting gait biomechanics (typically > 20° of absolute rotation in either direction), with the goal of improving brace tolerance, minimising brace requirement and achieving a near-normal gait pattern. 5 Yet despite documented clinical benefits, high complication rates between 5% and 33% 4,12-19 and substantial re-torsion rates between 16% and 58% 19,20 have dampened enthusiasm for surgical intervention in these populations. Nevertheless, much of the reported outcomes data are of mixed neuromuscular diagnoses without comparison among these distinctive populations. However, the aetiology and natural history of rotational deformities in these populations are not equivalent, and their response to surgical intervention may also be dissimilar, warranting deeper evaluation into these groups' surgical outcomes. Further, surgical technique and post-operative management are quite variable among previous reports. 4, As such, the goal of the present study was to review the results of derotational osteotomies as a function of complications and need for revision surgery in a population of children with myelodysplasia compared with a population of children with CP. Patients and methods A retrospective chart review was performed to identify patients with myelodysplasia or CP who underwent TDOs for tibial torsion affecting brace wear, standing transfers, gait biomechanics and/or gait velocity between 1985 and 2013. All children included in the analysis with myelodysplasia had low lumbar or sacral level involvement apart from three thoracic-level patients. Functional neurologic level was assigned by the treating surgeon based on manual muscle testing performed by the institution's department of physical therapy at the pre-operative clinical visit. All children included in the analysis with CP were classified as GMFCS I-III except for one GMFCS IV (no GMFCS V). GMFCS level was assigned by the treating surgeon based on functional capacity documented at the pre-operative clinical visit. All GMFCS levels were prospectively documented in the patient charts after 1997, when the original description of the classification system was published. 21 For those patients treated prior to 1997, GMFCS was retrospectively assigned based on a careful chart review by the treating surgeon. Retrospective assignment of GMFCS has been shown to have high inter-observer reliability and to be consistent with levels assigned at the time of evaluation. 22 All participants were aged five years or older and had at least 20° of absolute internal or external tibial torsion that interfered with gait or bracing/shoe-wear, with at least two years of follow-up. Participants were excluded from the analysis for insufficient data, age less than five years at time of index surgery and for less than two years of follow-up. Rotation was calculated by the two senior authors using thigh foot angle 1 pre-, intra-and post-operatively. All angles were obtained using a goniometer. Pre-and post-operative measurements were obtained prone and intra-operative measurements were obtained supine. Data were insufficient to determine inter-rater and intra-rater reliability. However, this has been previously described in similar studies. 11 All surgeries were performed by the two senior authors (VS, LD) at a single tertiary care paediatric referral centre. The surgical technique used has been previously described. 19 In brief, the surgery is performed supine through an anterolateral longitudinal incision overlying the distal tibia, to allow room for a four to six hole 3.5 mm or 4.5 mm limited contact direct compression plate (LC-DCP) placed proximal to the distal tibial physis. A separate direct lateral longitudinal incision overlying the fibula -at the same level as the planned tibial osteotomy -is made, and a transverse osteotomy is completed using an oscillating saw prior to TDO. The TDO is created with multiple drill holes placed in parallel and it is completed using a straight AO osteotome to limit osteonecrosis. The derotation is then performed manually, using smooth K-wires placed proximal and distal to the osteotomy site prior to osteotomy as a guide for correction, with a goal to correct to between neutral and 5° external rotation, measured by goniometer. The osteotomy is then fixed using the LC-DCP placed on the anterolateral face of the tibia in compression mode (Fig. 1). The incisions are closed with interrupted nylon sutures over a drain that remains in place for 24 hours. Intravenous antibiotics are given for 24 hours post-operatively. All patients are placed in short-leg casts and made non-weight-bearing for an average of three weeks post-operatively with an additional three weeks spent in a walking cast thereafter. Routine removal of hardware is not performed, as is done in some centres. After identification of participants, charts were reviewed for demographic information, direction of derotation, correction achieved (in degrees) at index surgery, incidence of complications, type of complication, as well as the need for re-operation. Complications included in analysis were superficial infection, deep infection/dehiscence, fracture, hardware failure and removal of hardware for any reason. Removal of hardware was performed only in patients with symptomatic hardware and was included as a complication because it necessitated a return to the operating room. Two-sample T-tests were used to compare the characteristics of the two groups. Descriptive statistics were used to determine the incidence of complications as well as need for re-operation, and two-tailed chi-square tests were used to compare incidence of complications between cohorts. Generalised linear logit models were used to identify independent risk factors for complication and need for re-derotation among the two cohorts. Demographics and surgical characteristics A total of 153 patients -64 of whom underwent bilateral osteotomies -met the criteria for inclusion, for a total of 217 limbs. Of these, 64 patients (82 limbs) had CP and 89 (135 limbs) had myelodysplasia. In total, 88 male and 65 female patients were included for analysis. Of those with spina bifida, 36 (40.45%) had L4 and proximal levels of involvement and 53 (59.55%) had L5 or sacral levels of involvement. Of those with CP, 36 (56.25%) were classified as GMFCS I or II and 28 (43.75%) were classified as GMFCS III or IV. Average age at index surgery was older in the cohort with CP compared with those with myelodysplasia (12.47 vs 9.33, p < 0.0001), with a resultant longer average follow-up for those patients with spina bifida (8.57 years (2.35 to 18.78) vs 6.76 years (2.05 to 18.76)) ( Table 1). Complications All patients went on to union despite ten tibiae (4.61%) that required prolonged casting (more than ten weeks) for delayed union (without fracture). Those patients that were casted more than ten weeks were evenly divided between the studied cohorts. The average time spent in a cast was 7.04 weeks (± 1.93 weeks) for all patients, which was, on average, shorter for patients with CP (6.63 weeks ± 1.62) compared with those with spina bifida (7.29 weeks The overall incidence of complication was 10.14%, including removal of hardware for any reason, with a 4.61% incidence of major complication including fracture, deep infection and hardware failure (Fig. 1, Table 2). All complications were Clavien-Dindo grades I-III, without any Clavien-Dindo grades IV or V. Five complications were classified as Clavien-Dindo grade I (one CP, four myelodysplasia), eight as Clavien-Dindo grade II (all myelodysplasia) and nine as Clavien-Dindo grade III (four CP, five myelodysplasia). While patients with spina bifida had higher overall complication rates than those with CP (12.6% vs 6.1%), this did not reach statistical significance (p = 0.125). Further, there was no statistically significant difference between groups when comparing major complication rate after adjusting for gender and age (odds ratio = 0.424, 95% confidence interval = 0.086 to 2.103, p = 0.292). Age at initial surgical intervention had no effect on complication rate (p = 0.798). Re-derotational surgery A total of 22 limbs (10.14%) required re-derotational surgery -21 in the myelodysplastic population (15.6%) and one in the CP cohort (1.2%). Indications for re-operation were the same as for index surgery -tibial torsion affecting gait biomechanics, velocity and/or orthotic wear. In unadjusted analysis, the risk of re-rotation requiring surgery was 93.3% less likely for patients with CP compared with those with spina bifida (0 = 0.01). However, after adjusting for age and gender, there was no statistically significant difference in re-rotation risk between the two cohorts (p = 0.093). The odds of requiring re-derotational osteotomy were 31.9% less likely per year increase in age at index surgery (p = 0.0048) after adjusting for disease group, gender, direction corrected and magnitude of correction. This was independently true for both cohorts. Length of follow-up was comparable between those that required re-derotation and those that did not (7.38 years vs 7.58 years, on average). Resultantly, this variable was not directly controlled for in this model. There was no association between degree of initial rotation and need for re-derotation (p = 0.608), nor was there an association between direction of rotation and need for re-derotation (p = 0.278). However, there was a trend toward overcorrection following external derotational osteotomies (7.1%) and under-correction following internal derotational osteotomies (6.3%) at final follow-up. Neither GMFCS nor neurologic level of involvement reached statistical significance in predicting need for re-derotational osteotomy in each respective cohort. Discussion While the aetiology of rotational abnormalities in children with CP and spina bifida are dissimilar, the effect of tibial torsion on children with overall poor musculoskeletal control and weakness results in similar natural history, progressive deformity and resultant disability. Both internal and external rotational deformities can significantly alter standing tolerance and gait patterns in patients with CP and spina bifida wherein surgical correction is necessary to maintain and/or improve ambulatory status. In fact, previous authors have reported significant improvements in gait kinematics and kinetics in both populations following TDO. 10,11 Further, despite dissimilar underlying disease processes, response to surgical management of tibial torsion in terms of complications and need for re-derotational osteotomy are similar between populations when using our previously published surgical technique. 19 This method results in an overall acceptable complication rate of 10.14% and a major complication rate of 4.61%, with no appreciable difference in major complication risk between groups. Further, the overall risk of need for re-derotational surgery in this population was 10.14%, with a negative linear relationship between age at index surgery and need for re-derotational osteotomy in both groups. Theoretically, the myelodysplastic population would be expected to have significantly higher complication rates given the underlying disease process and resultant lack of protective sensation. Likewise, the overall muscular imbalance in the CP population could theoretically increase this cohort's risk for re-rotation. Yet, we did not find any appreciable difference in major complication or need for re-derotation rates between groups. Hardware failure 0 2 (1.5) We attribute this relatively consistent complication and re-operation rate to our surgical technique: metaphyseal level osteotomy, the use of drill holes and osteotome to reduce osteonecrosis with osteotomy, rigid fixation and compression at the osteotomy site, concomitant fibular osteotomy and the use of non-absorbable, interrupted sutures for closure over a drain. While many experienced neuromuscular orthopaedic surgeons do not routinely perform concomitant fibular osteotomies in every case, we believe that consistently performing a fibular osteotomy does not increase complication risk or add significant time or complexity to the case. Further, we believe that the addition of the fibular osteotomy better preserves the relationship of the syndesmosis and likely contributes to the durability of our results compared with previously published series in which fibular osteotomies were not routinely performed. Furthermore, in direct comparison to previously published complication rates following TDO in neuromuscular populations, we report an overall favourable major complication rate for this population (4.61 vs 5.3%). 14 Notably, there was a statistically insignificant trend toward higher complication risk in our spina bifida population compared with our CP population, as would be expected. However, this complication rate (12.6%) remains lower than those of earlier reports (28% to 33%) 1,4,18 in isolated populations of spina bifida. It is additionally important to note that if removal of hardware was not included as a complication, the CP population would have an overall complication rate of only 1.2% compared with 10.4% in the myelodysplastic population, but the major complication rate would remain constant in both groups. In addition to our low complication rate, both studied populations had relatively low re-derotation rates (overall 10.14%). In contrast to these findings, two recent publications reported high rates of late over-correction following external TDOs 23 and high rates of late under-correction following internal TDOs 20 in patients with CP. With an average follow-up of 7.83 years (2.05 to 18.78), we found more durable results following both internal and external rotational osteotomies in both populations. However, there was a noted trend toward over-correction following external derotational osteotomies (overall 7.14% of patients) and under-correction following internal derotational osteotomies (overall 6.31% of patients) in our cohort. These trends paralleled those reported by Er et al, but were significantly smaller in magnitude (56% and 58%, respectively) 20,23 despite similar length of follow-up. We attribute these durable, long-term results to our inclusion of a concomitant fibular osteotomy in all cases and our use of rigid internal fixation. While diagnosis, degree of derotation and direction of derotation did not directly affect the incidence of rerotation, there was a statistically significant association between age at surgery and need for re-derotation. The risk for re-derotational osteotomy was 31.9% less likely per year increase in age at index surgery following both internal and external rotational osteotomies, independent of degree of initial derotation, diagnosis or gender. While our overall results were durable in achieving long-standing correction in the majority of patients, younger children have great remodelling potential regardless of surgical technique and mode of fixation. And while this remodelling potential with an associated high re-operation incidence has been previously reported, 18,23 this report is the first to stratify risk of recurrence by age at index surgery, which may be helpful for operative planning and preoperative counselling. Although this is the first direct comparison between myelodysplastic patients and children with CP following TDO, it was limited primarily by its retrospective nature. Given the limitations of a retrospective review, data were insufficient to determine accuracy or inter-observer error. However, this has been previously described in similar studies. 11 In addition, concomitant surgeries were not taken into consideration nor controlled for. Given that many children with neuromuscular diseases and tibial torsion require multiple surgeries for lower limb deformity and gait disturbance and that many of these surgeries are performed simultaneously, it was clinically irrelevant to control for the possibility of concurrent soft-tissue procedure or concomitant lower extremity osteotomies. Further, we do not report on functional or subjective outcomes data including gait analysis data. However, previous reports, including that of the senior author (LD), have previously demonstrated improvements in gait parameters following derotational osteotomy for tibial torsion in similar populations. 10,11 And while our average follow-up was 7.83 years, our cohort included patients with as little as two years of follow-up, which may have led to an under-representation of late recurrences in these patients. Lastly, the study cohort is limited to the patients that were operated on during the included time period and, as a result, we may be underpowered to answer all clinical questions. However, this remains the largest series of TDOs secondary to a neuromuscular disease process reported in the literature to date. Despite limitations, given the relatively favourable, consistent complication profile as well as the short-term and presumed long-term benefits of TDO for tibial torsion in patients with myelodysplasia and cerebral palsy, TDO should be strongly considered for patients with appropriate indications. While we previously reported similarly encouraging results in a purely myelodysplastic population, this comparison further reflects the safety and efficacy of TDO using rigid internal fixation and concomitant fibular osteotomy for children with non-idiopathic tibial torsion. FUNDING STATEMENT No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. OA LICENCE TEXT This article is distributed under the terms of the Creative Commons Attribution-Non Commercial 4.0 International (CC BY-NC 4.0) licence (https://creativecommons.org/ licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed. ETHICAL STATEMENT Each listed author declares that he/she has no conflicts of interest. This study received no external or internal funding. All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board, and given the retrospective nature of the study, a waiver of informed consent was granted. |
Analysis of the Court's Decision on Criminal Actions Harding Outbreak Management with Lawrence Friedman Theory Perspective The forced retrieval of the bodies of COVID-19 patients from the hospital occurred during the COVID-19 outbreak, such as the case that occurred in the Surabaya District Court Decision No. 1857/Pid.sus /2021/PN.Sby, in which the decision explains that the defendants forced the bodies of Covid-19 patients to be taken from the hospital and improperly managed the bodies, as in the decision the perpetrators who committed these acts by The panel of judges were declared legally and convincingly guilty of committing a crime: "Intentionally obstructing the implementation of epidemic control". This study is to find out the judge's considerations in imposing criminal penalties on perpetrators of crimes that hinder the prevention of epidemics in Decision No. 1857/Pid.sus/2021/PN. Sby and the analysis of the judge's decision were viewed from the perspective of Lawrence Friedman's Legal System Theory. Based on the results of the study, it is known that the judge's consideration in imposing a sentence on the perpetrator of a criminal act hinders the prevention of the epidemic in Decision No. 1857/Pid.sus/2021/PN. Sby is that the actions of the Defendants caused unrest in the community. According to Lawrence Meir Friedman, a legal sociologist from Stanford University, the effectiveness and success of law enforcement depend on 3 (three) elements of the legal system, namely: 1) the substance of the law, related to legislation; 2) the legal structure (structure of law), concerning law enforcement officers; 3) Based on the results of the study, it is known that the judge's consideration in imposing a sentence on the perpetrator of a criminal act hinders the prevention of the epidemic in Decision No. 1857/Pid.sus/2021/PN.Sby is that the actions of the Defendants caused unrest in the community. According to Lawrence Meir Friedman, a legal sociologist from Stanford University, the effectiveness and success of law enforcement depend on 3 (three) elements of the legal system, namely: 1) the substance of the law, related to legislation; 2) the legal structure (structure of law), concerning law enforcement officers; 3) Based on the results of the study, it is known that the judge's consideration in imposing a sentence on the perpetrator of a criminal act hinders the prevention of the epidemic in Decision No. 1857/Pid.sus/2021/PN.Sby is that the actions of the Defendants caused unrest in the community. According to Lawrence Meir Friedman, a legal sociologist from Stanford University, the effectiveness and success of law enforcement depend on 3 (three) elements of the legal system, namely: 1) the substance of the law, related to legislation; 2) the legal structure (structure of law), concerning law enforcement officers; 3) Sby is that the actions of the Defendants caused unrest in the community. According to Lawrence Meir Friedman, a legal sociologist from Stanford University, the effectiveness and success of law enforcement depend on 3 (three) elements of the legal system, namely: 1) the substance of the law, related to legislation; 2) the legal structure (structure of law), concerning law enforcement officers; 3) Sby is that the actions of the Defendants caused unrest in the community. According to Lawrence Meir Friedman, a legal sociologist from Stanford University, the effectiveness and success of law enforcement depend on 3 (three) elements of the legal system, namely: 1) the substance of the law, related to legislation; 2) the legal structure (structure of law), concerning law enforcement officers; 3) legal culture (legal culture), is a living law (living law) that adopted in a society. The Judge's Decision Number: Number: 1857/Pid.sus/2021/PN. Sby is one of the efforts to carry out law enforcement so that it runs effectively and successfully. |
AN ORIGINAL manuscript written in Dublin by Nobel Prize- winning physicist Erwin Schrödinger has resurfaced after almost 60 years.
The short manuscript was prepared in 1955 for publication in the King’s Hospital school magazine. The five-page manuscript reveals an unexpectedly humorous side to the Austrian-born scientist, who also held Irish citizenship.
Schrödinger is viewed as one of the fathers of quantum mechanics. For the general public he is perhaps better known for his attempt to explain his theories using “Schrödinger’s Cat”, a cat that can be both alive and dead at the same time.
His willingness to write for the school’s magazine, Blue Coat, arose because of his friendship with a teacher at King’s Hospital, Ronnie Anderson, said the school’s headmaster Michael Hall.
Schrödinger published his manuscript in the December 1955 edition of Blue Coat, writing it in the form of a dialogue involving three speakers, said Trinity College Dublin’s Prof Jonathan Coleman, who now owns the typescript.
Oddly, while Schrödinger was writing about the start of quantum mechanics in the early 1900s, his speakers were from the 16th century and a time when none of the ideas would have made any sense. The character Salviati attempts to explain the oddities associated with quantum mechanics, while Simplicio refuses to believe that such things could possibly be true.
Ronnie Anderson kept the original typescript for some years before giving it to a young physics teacher who had joined the school, David Clarke, Mr Hall said. He in turn held on to it for several more decades before inviting a past pupil, Prof Coleman, to judge a science competition.
“I went to King’s Hospital and was invited to come back and talk to the kids,” he said. “At the end of the day he [Clarke] gave me the document.” Prof Coleman is now considering what to do with the typescript. “It had been sitting on a shelf for 40 years and before that, sitting on another shelf for 20 years,” he said.
The text of Schrödinger’s manuscript is now available at the kingshospital.iewebsite. |
Analysis of Strain Fields in Silicon Nanocrystals Strain has a crucial effect on the optical and electronic properties of nanostructures. We calculate the atomistic strain distribution in silicon nanocrystals up to a diameter of 3.2 nm embedded in an amorphous silicon dioxide matrix. A seemingly conflicting picture arises when the strain field is expressed in terms of bond lengths versus volumetric strain. The strain profile in either case shows uniform behavior in the core, however it becomes nonuniform within 2-3 \AA distance to the nanocrystal surface: tensile for bond lengths whereas compressive for volumetric strain. We reconsile their coexistence by an atomistic strain analysis. The low dimensional forms of silicon embedded in silica have strong potential as an optical material. Such heterogeneous structures inherently introduce the strain as a degree of freedom for optimizing their optoelectronic properties. It was realized earlier that strain can be utilized to improve the carrier mobility in bulk silicon based structures. This trend has been rapidly transcribed to lower dimesional structures, starting with two-dimensional silicon structures. Recently for silicon nanowires, there have been a number of attempts to tailor their optical properties through manipulating strain. Futhermore, recent studies have revealed that the strain can become the major factor restricting the crystallization of the nanolayers. It depends on several factors, most important of which are the lattice mismatch between the constituents, size of the NCs, and the growth conditions, such as the details of the growth procedure. In summary, for improving the optical and electronic properties of nanocrystals (NCs), the strain engineering has become an effective tool to be exploited. A critical challenge in this regard is to analyze the strain state of the Si NCs embedded in silica. The close relations between strain and optical or electronic properties in Si NCs have very recently become the center of attention. There still remains much to be done in order to understand strain in nanostructures at the atomistic level. As pioneered by Tsu et al. Raman spectroscopy can be an effective experimental tool for determining the strain state of the Si NCs. Specifically, recent Raman studies reported that the Si NCs may be under a thermal residual strain and this can be reduced by overall annealing at high temperatures or by local laser annealing. Due to small density difference between Si NC and the surrounding a-SiO 2, a limited information can be gathered about its structure using transmission electron microscopy (TEM) or even * Electronic address: [email protected] Electronic address: [email protected] Electronic address: [email protected] high resolution TEM techniques. Especially, molecular dynamics simulations with realistic interaction potentials present an opportunity, by providing more detailed critical information then the best imaging techniques currently available and clarify the analysis of experimental results. Along this direction, previously we focused on Si-Si bond length distribution and reported that Si-Si bond lengths are stretched upto 3% just below the surface of Si NCs embedded in amorphous SiO 2 which has also been very recently confirmed. In this Letter, we analyze the volumetric and bond length strain distributions in Si NCs, in particular demonstrate that both compressive volumetric strain and tensile bond length strain coexist within the same Si NC. We accomplish this by performing trajectory analysis on model samples (with ca. 5000 atoms) simulated via molecular dynamics using a reliable and accurate as well as reactive force field. The simulation details are similar to our previous work, except the way we construct the Si NC in glass matrix. Instead of deleting all glass atoms within a predetermined radius, we remove the glass atoms after rigorously defining the surface of the nanocrystal through the Delaunay triangulation method. In this way, we have constructed NCs embedded in glass matrix with diameters ranging from 2.2 nm to 3.2 nm without introducing built-in strain to the system. In this diameter range we observe similar trends in strain, volumetric strain, and bond length distribution etc., therefore, we present only the figures of the system for a typical NC of radius 2.6 nm. In the language of geometry, strain is defined through an affine transformation that maps the undeformed state to deformed state, which is called deformation gradient. Several methods to derive discrete form of deformation gradient from atomic positions are reported. In the method proposed by Pryor et al., the atomistic strain tensor is derived from local transformation matrix that transforms nearest neighbors of a certain atom from its undeformed state to the deformed one. From the MD simulations, using positions of NC atoms, we first extract each atoms displacement vector from its unde- Distance to the Surface () formed site which is determined by positioning an ideal tetrahedron to the local environment. Using these displacement vectors, we construct deformation matrix and derive the atomistic strain tensor from this local deformation tensor. The first invariant of strain tensor corresponds to the hydrostatic strain. As an alternative measure to hydrostatic strain, we calculate volumetric strain by considering volume change of a tetrahedron from its undeformed counterpart. A third measure as we have used in our previous report, is the bond length strains. To verify our results we have calculated strain distribution in NC region for all mentioned measures. We have plotted all three of them in Fig. 1. The results of volumetric strain are very close to hydrostatic strain which is the trace of strain tensor calculated with aferomentioned technique. In these results, we observe a net compressive behavior of strain just under the surface and a uniform tensile strain of about 1% at the core of NC. Si-Si bonds are stretched by about 1% in the core region in agreement with the hydrostatic and volumetric strains, however, just under the surface, Si-Si bonds are stretched up to 3% where hydrostatic and volumetric strain results indicate compressive strain state. The bond-stretch in Si-Si bonds due to oxidation has been shown earlier by us using molecular dynamics simulations which was also confirmed by other approaches. Occurrence of compressive volumetric strain and stretched bond lengths in the same outer region may initially seem contradicting. However, stretching of bonds does not imply that the system is under tensile hydrostatic strain as well. Consider a tetrahedron formed by a Si atom and its four Si neighbors (A, B, C, D) as shown in upper inset of Fig. 2. In the ideal case, the solid angle () subtended by each triangular face of this tetrahedron should be equal to 180. Under a uniform deformation, bond lengths will also be stretched, while the solid angles remain unchanged. However, under a nonuniform deformation, the change in three solid angles causes a decrease in the volume of the tetrahedron while increasing or preserving the bond lengths. Hence, a combination of stretched bond lengths with deformed solid angles may end up with an overall reduction of the volume of the tetrahedron. This explains the coexistance of compressive volumetric strain and stretched bond lengths at the region just below the surface of NCs. To better visualize the nature of the deformation of the Si NCs, we consider the orientational variation of the solid angles of the tetrahedral planes. As illustrated in the lower inset of Fig. 2, the two important directions are the unit normal (n S ) of the tetrahedron face subtending the solid angle under consideration, and the local outward surface normal (n NC ) of the NC. It is clearly seen from Fig. 2 that solid angles subtended by tetrahedra faces oriented outward to the NC surface are increased up to 220, whereas those facing inward to the NC core are decreased down to 160. This dependence is a clear evidence of how oxidation affects strain distribution close to the interface. To further quantify the atomistic strain in the highly critical region within 3 distance to the interface, we classify the average bond length and hydrostatic strain behaviors into three categories. Figure 3 displays the percentage as well as the bonding details of each category. In top-left, we illustrate most common type with a share of 53.0% which is responsible for the opposite behavior in Fig. 1 where average bond lengths of center Si atoms to its four nearest neighbors are stretched but net atomistic strain at this atom is compressive. In this case solid angles facing toward the oxide region is increased to 270 due to oxygen bonds of Si neighbors. Although these oxygen bonds stretched Si-Si bonds to 2.41, net strain on center Si atom is -2.7%. In the top-right part of the Fig. 3 we illustrate second most often case with a percentage of 42.0%, where average bond lengths and atomistic strain show similar behavior; bond lengths are stretched and net hydrostatic strain is tensile. In this case oxidation somewhat uniformly deforms the bonds so that solid angles are still around 180 which is the value for the unstrained case. Finally, as shown at bottom of Fig. 3, a very small percentage of atoms (5.0%) in the region beneath the surface have shortened bond lengths and compressive atomistic strain. In summary, we study the strain state of Si NCs in silica matrix with diameters in 2 to 3.2 nm. The structure is assumed to be free from any thermal built-in strains. The core region of the NC is observed to be under a uniform 1% tensile strain, where both bond length and volumetric strain measures are in agreement. However, towards the NC interface, while the Si-Si bonds become more stretched, the hydrostatic strain changes in the compressive direction. In the interpretation of the indirect strain measurements eg. from spectroscopy, this dual character needs to be taken into consideration. We explain these two behaviors using the solid angle deformation of the tetrahedral-bonded Si atoms, and demonstrate that it is ultimately caused by the oxygen atoms at the interface. An equally important finding is that the overall strain profile within the Si NCs is quite nonuniform. As very recently emphasized, within the context of centrosymmetric materials, like silicon, such strain gradients locally break the inversion symmetry and may lead to profound physical consequences. This work has been supported by the Turkish Scientific and Technical Council TBTAK with the Project No. 106T048 and by the European FP6 Project SEM-INANO with the Contract No. NMP4 CT2004 505285. The visit of Tahir agn to Bilkent University was facilitated by the TBTAK BDEB-2221 program. TC also acknowledges the support of NSF-IGERT. |
Editorial Preface on the Special Issue The Symposium M entitled New Routes to Inorganic Materials, Films and Nanocrystals was one of the 18 symposia of International Conference on Materials for Advanced Technologies held at Suntec Singapore International Convention and Exhibition Centre, Singapore, in July 16, 2007 whis was attended by about 2500 delegates. The Symposium M was attended by over 140 registered participants from 23 countries. This 5-day fully packed symposium had two parallel sessions, 29 keynote and invited talks, 65 oral contributions and 70 poster presentations. This symposium covered a wide range of topics on synthesis, properties and applications of inorganic bulk materials, inorganic thin films and nanocrystals of metals, alloys, metal oxides, sulfides and selenides. However majority of presentations were centered on nanomaterials and their applications. New routes to nanocrystals range from solution methods, sonochemical & microwave route, laser ablation and combustion methods to single molecular precursors methods. Application aspects include energy storage (battery) materials, molecular imaging and therapy, photocatalysis, photovoltaics, coatings, magnetic materials, ceramics, optoelectronics, hard materials (harder than diamond), The symposium also featured two poster sessions with two ICMAT 2007 best poster prizes awarded to Jency Thomas (Indian Institute of Technology, New Delhi) and J.W. Li (Tokyo Institute of Technology) and an honorary mention to I.F. Li (National Cheng Kund University, Taiwan). Another Best Poster Award sponsored by the Journal of Materials Chemistry, a Royal Society of Chemistry journal was awarded to Lu Tian (National University of Singapore). Peer reviewed papers presented at the symposium will be published in two special issues in this journal. We would like to thank all the authors who have contributed to their work presented in the symposium. We hope that the papers in these issues on diversified areas of materials synthesis and characterization will benefit the readers of this journal. |
# -*- encoding: utf-8
from datetime import datetime
import collections
import itertools
import re
from bs4 import BeautifulSoup, Tag
import requests
from .works import Work
ReadingHistoryItem = collections.namedtuple(
'ReadingHistoryItem', ['work_id', 'last_read'])
class User(object):
def __init__(self, username, password, sess=None):
self.username = username
if sess == None:
sess = requests.Session()
req = sess.get('https://archiveofourown.org')
soup = BeautifulSoup(req.text, features='html.parser')
authenticity_token = soup.find('input', {'name': 'authenticity_token'})['value']
req = sess.post('https://archiveofourown.org/user_sessions', params={
'authenticity_token': authenticity_token,
'user_session[login]': username,
'user_session[password]': password,
})
# Unfortunately AO3 doesn't use HTTP status codes to communicate
# results -- it's a 200 even if the login fails.
if 'Please try again' in req.text:
raise RuntimeError(
'Error logging in to AO3; is your password correct?')
self.sess = sess
def __repr__(self):
return '%s(username=%r)' % (type(self).__name__, self.username)
def bookmarks_ids(self):
"""
Returns a list of the user's bookmarks' ids. Ignores external work bookmarks.
User must be logged in to see private bookmarks.
"""
api_url = (
'https://archiveofourown.org/users/%s/bookmarks?page=%%d'
% self.username)
bookmarks = []
num_works = 0
for page_no in itertools.count(start=1):
# print("Finding page: \t" + str(page_no) + " of bookmarks. \t" + str(num_works) + " bookmarks ids found.")
req = self.sess.get(api_url % page_no)
soup = BeautifulSoup(req.text, features='html.parser')
# The entries are stored in a list of the form:
#
# <ol class="bookmark index group">
# <li id="bookmark_12345" class="bookmark blurb group" role="article">
# ...
# </li>
# <li id="bookmark_67890" class="bookmark blurb group" role="article">
# ...
# </li>
# ...
# </o
ol_tag = soup.find('ol', attrs={'class': 'bookmark'})
for li_tag in ol_tag.findAll('li', attrs={'class': 'blurb'}):
num_works = num_works + 1
try:
# <h4 class="heading">
# <a href="/works/12345678">Work Title</a>
# <a href="/users/authorname/pseuds/authorpseud" rel="author">Author Name</a>
# </h4>
for h4_tag in li_tag.findAll('h4', attrs={'class': 'heading'}):
for link in h4_tag.findAll('a'):
if ('works' in link.get('href')) and not ('external_works' in link.get('href')):
work_id = link.get('href').replace('/works/', '')
bookmarks.append(work_id)
except KeyError:
# A deleted work shows up as
#
# <li class="deleted reading work blurb group">
#
# There's nothing that we can do about that, so just skip
# over it.
if 'deleted' in li_tag.attrs['class']:
pass
else:
raise
# The pagination button at the end of the page is of the form
#
# <li class="next" title="next"> ... </li>
#
# If there's another page of results, this contains an <a> tag
# pointing to the next page. Otherwise, it contains a <span>
# tag with the 'disabled' class.
try:
next_button = soup.find('li', attrs={'class': 'next'})
if next_button.find('span', attrs={'class': 'disabled'}):
break
except:
# In case of absence of "next"
break
return bookmarks
def bookmarks(self):
"""
Returns a list of the user's bookmarks as Work objects.
Takes forever.
User must be logged in to see private bookmarks.
"""
bookmark_total = 0
bookmark_ids = self.bookmarks_ids()
bookmarks = []
for bookmark_id in bookmark_ids:
work = Work(bookmark_id, self.sess)
bookmarks.append(work)
bookmark_total = bookmark_total + 1
# print (str(bookmark_total) + "\t bookmarks found.")
return bookmarks
def reading_history(self):
"""Returns a list of articles in the user's reading history.
This requires the user to turn on the Viewing History feature.
This generates a series of ``ReadingHistoryItem`` instances,
a 2-tuple ``(work_id, last_read)``.
"""
# TODO: What happens if you don't have this feature enabled?
# URL for the user's reading history page
api_url = (
'https://archiveofourown.org/users/%s/readings?page=%%d' %
self.username)
for page_no in itertools.count(start=1):
req = self.sess.get(api_url % page_no)
soup = BeautifulSoup(req.text, features='html.parser')
# The entries are stored in a list of the form:
#
# <ol class="reading work index group">
# <li id="work_12345" class="reading work blurb group">
# ...
# </li>
# <li id="work_67890" class="reading work blurb group">
# ...
# </li>
# ...
# </ol>
#
ol_tag = soup.find('ol', attrs={'class': 'reading'})
for li_tag in ol_tag.findAll('li', attrs={'class': 'blurb'}):
try:
work_id = li_tag.attrs['id'].replace('work_', '')
# Within the <li>, the last viewed date is stored as
#
# <h4 class="viewed heading">
# <span>Last viewed:</span> 24 Dec 2012
#
# (Latest version.)
#
# Viewed once
# </h4>
#
h4_tag = li_tag.find('h4', attrs={'class': 'viewed'})
date_str = re.search(
r'[0-9]{1,2} [A-Z][a-z]+ [0-9]{4}',
h4_tag.contents[2]).group(0)
date = datetime.strptime(date_str, '%d %b %Y').date()
yield work_id, date
except KeyError:
# A deleted work shows up as
#
# <li class="deleted reading work blurb group">
#
# There's nothing that we can do about that, so just skip
# over it.
if 'deleted' in li_tag.attrs['class']:
pass
else:
raise
# The pagination button at the end of the page is of the form
#
# <li class="next" title="next"> ... </li>
#
# If there's another page of results, this contains an <a> tag
# pointing to the next page. Otherwise, it contains a <span>
# tag with the 'disabled' class.
try:
next_button = soup.find('li', attrs={'class': 'next'})
if next_button.find('span', attrs={'class': 'disabled'}):
break
except:
# In case of absence of "next"
break
|
This invention relates to a microphone comprising a housing formed by a cap sealed to a substrate and a MEMS (microelectromechanical systems) die mounted on the substrate. It also relates to a method of manufacturing such a microphone.
This type of microphone, known as a MEMS microphone, can be divided into top-port microphones (with the acoustic inlet port on the top side of the housing and the contacts on the bottom side) and bottom-port microphones (with the acoustic inlet port and contacts on the bottom side).
A cross-section through a bottom-port microphone is shown in FIG. 1. A MEMS die 1 is mounted on a laminate base 2 along with an application specific integrated circuit (ASIC) 3. An acoustic inlet port 4 allows sound pressure waves to move a membrane 5, which forms part of the MEMS die 1. In response to the motion of the membrane 5, its capacitance varies, and this variation in capacitance is detected and processed by ASIC 3. An output signal from ASIC 3 is made available at contacts on the laminate base 2. The volume trapped between the membrane 5 and the cap 6 is relatively large and does not affect the compliance of the membrane 5 significantly. The microphone is therefore quite sensitive and exhibits a high signal-to-noise ratio (SNR). In this design of microphone, the contacts and acoustic inlet port are both provided on the laminate base 2. This can be quite restrictive in some applications, for example if it is desired to have the acoustic inlet port on the opposite side from the contacts.
FIG. 2 shows a cross-section through a top-port design of microphone, in which the acoustic inlet port 4 is provided in the cap 6 rather than in the laminate base 2, thereby overcoming this restriction. This type of device suffers, however, from some significant problems. Specifically, it has a lower sensitivity and SNR due to the small volume behind the membrane (i.e. the volume trapped between the membrane 5, MEMS die side walls and the laminate base 2). This small volume significantly affects the compliance of the membrane 5.
Furthermore, the reliability of the device is poor relative to the bottom-port design. This is because the acoustic inlet port 4 (which has a rather large diameter in the region of 500 μm) exposes the microphone components to the environment. The components are very sensitive to moisture, especially the MEMS die 1, which has circuit impedances in the TΩ range. The reliability can be improved somewhat by application of a hydrophobic varnish to seal ultra-high impedance areas from moisture, but this would have to be done after assembly and wirebonding. As an example, the SPU0410HR5H PB top-port microphone has been found to comply with the Moisture Sensitivity Level Assessment MSLA2a reliability standard, whereas the equivalent bottom-port microphone complies with MSLA1, indicating an improved resilience to moisture. Furthermore, ingress of moisture is not the only concern; dust or other particles entering the acoustic inlet port 4 can also significantly degrade the microphone performance.
Another top-port design is shown in FIG. 3. This is identical to the design of FIG. 2, apart from a channel 7 formed in the laminate base 2. The channel 7 forms an extension to the chamber behind the membrane 5, thereby increasing the volume behind it. This has the effect of enhancing the sensitivity and SNR. However, it has no effect on the poor reliability and it is expensive to manufacture the channel 7. |
async def _trnNodeToNodeedit(self, node, model, fname=None, chknodes=True):
buid = node[0]
ndef = node[1]['ndef']
edits = []
if ndef is not None:
fname = ndef[0]
fval = ndef[1]
if fname[0] == '*':
fname = fname[1:]
else:
err = {'mesg': f'Unable to parse form name {fname}', 'node': node}
return err, None
if chknodes:
try:
mform = model.form(fname)
stortype = mform.type.stortype
except asyncio.CancelledError:
raise
except Exception as e:
err = {'mesg': f'Unable to determine stortype for {fname}: {e}'}
return err, None
else:
mform = None
stortype = self._destGetFormStype(fname)
if stortype is None:
err = {'mesg': f'Unable to determine stortype for {fname}'}
return err, None
if chknodes:
normerr = None
try:
formnorm, _ = mform.type.norm(fval)
if fval != formnorm:
if mform.type.subof == 'inet:addr' and fval.startswith('host://'):
logger.debug(f'Skipping norm failure on inet:addr type host: {fval}')
else:
normerr = {'mesg': f'Normed form val does not match inbound {fname}, {fval}, {formnorm}'}
if buid != s_common.buid((fname, fval)):
normerr = {'mesg': f'Calculated buid does not match inbound {buid}, {fname}, {fval}'}
except asyncio.CancelledError:
raise
except Exception as e:
normerr = {'mesg': f'Buid/norming exception {e}: {buid}, {fname}, {fval}'}
pass
if normerr is not None:
normerr['node'] = node
return normerr, None
edits.append((s_layer.EDIT_NODE_ADD, (fval, stortype), ()))
if fname is None:
err = {'mesg': f'No form name available for {buid}'}
return err, None
for sprop, sval in node[1]['props'].items():
sprop = sprop.replace('*', '')
if sprop[0] == '.':
stortype = self._destGetPropStype(None, sprop)
else:
stortype = self._destGetPropStype(fname, sprop)
if stortype is None:
err = {'mesg': f'Unable to determine stortype for sprop {sprop}, form {fname}'}
return err, None
edits.append((s_layer.EDIT_PROP_SET, (sprop, sval, None, stortype), ()))
for tname, tval in node[1]['tags'].items():
tnamenorm = tname[1:]
edits.append((s_layer.EDIT_TAG_SET, (tnamenorm, tval, None), ()))
for tname, tprops in node[1]['tagprops'].items():
tnamenorm = tname[1:]
for tpname, tpval in tprops.items():
try:
tptype = model.tagprops.get(tpname)
stortype = tptype.base.stortype
except asyncio.CancelledError:
raise
except Exception as e:
err = {'mesg': f'Unable to determine stortype for tagprop {tpname}: {e}'}
return err, None
edits.append((s_layer.EDIT_TAGPROP_SET,
(tnamenorm, tpname, tpval, None, stortype), ()))
return None, (buid, fname, edits) |
Metabolism of aflatoxin B1 and identification of the major aflatoxin B1-DNA adducts formed in cultured human bronchus and colon. Aflatoxin B1 and benzo(a)pyrene were activated by both cultured human bronchus and human colon as measured by binding to cellular DNA and protein. The binding of aflatoxin B1 to DNA was dose dependent, and the level of binding was higher in cultured human bronchus than it was in the colon. When compared to aflatoxin B1, the binding level of benzo(a)pyrene to both bronchial and colonic DNA was generally higher. The major adducts formed in both tissues by the interaction of aflatoxin B1 and DNA were chromatographically identical to 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1 (Structure 1) with the guanyl group and hydroxy group in trans-position and an adduct which has been tentatively identified by other investigators as 2,3-dihydro-2-(N5-formyl-2',5',6'-triamino-4'-oxo-N5-pyrimidyl)-3-hydroxyaflatoxin B1 (Structure 11). Seventy % of the radioactivity associated with bronchial DNA was found in these two peaks, and the ratio of radioactivity between the peaks was nearly 1. In colonic DNA, the ratio between Structures 1 and 11 was approximately 2. These observations add aflatoxin B1 to the list of chemical procarcinogens metabolized by cultured human tissues and in which the carcinogen-DNA adducts are similar to the adducts formed in animal tissue susceptible to the carcinogenic action of aflatoxin B1. |
Iran's parliament has ratified a budget allowing the government to ration petrol.
Rationing is needed to curb the cost of imports and subsidies.
Despite being Opec's number two crude producer, Iran lacks refinery capacity and imports more than 40% of the 60 to 70 million litres of petrol it burns each day.
European and Asian petrol traders closely watch Iran for any fluctuations in demand.
Heavily subsidised petrol sells for as little as nine cents a litre, adding to the congestion and pollution in Iran's biggest cities. Subsidies are a strain on state coffers.
In a session broadcast live on state radio, 120 parliamentarians voted for the motion to pave the way for rationing in the year to March 2007 and 59 voted against.
Hamidreza Haji-Babaee, the parliament's deputy speaker, said: "The government will be allowed to ... impose petrol rationing if it finds that necessary and design an appropriate price for any extra consumption above the ration."
Iran's government was also obliged by the bill to improve public transport before imposing rationing.
Iran's conservative government draws its support from among the poor who regard cheap and plentiful petrol as a national right making the imposition of rationing a tough political decision. |
<gh_stars>0
/*
Package multiglob implements a multi-pattern glob matcher.
It accepts multiple glob-based patterns and produces a matcher that determines which,
if any pattern matches. It's radix tree based for maximal efficiency.
*/
package multiglob
|
A computer system for the quantification of coronary artery stenoses-design of the human computer interface A low-cost, clinically usable system has been developed for the objective assessment of the severity of coronary artery stenoses from single-view angiograms. The system is based on a desktop computer with incorporated frame grabber. Images are captured by means of a video camera. Both diameter and densitometric cross-sectional area measurements can be made on a selected artery segment. Particular attention has been paid to the design of an appropriate man-machine interface, suitable for clinical use. Software tools have been developed for this purpose. They facilitate an iterative approach to program development and also provide for the needs of both the experienced and inexperienced user. The stenosis analysis system has been tested by using phantoms constructed in Perspex. These are designed to simulate arteries of various diameters and also an asymmetric stenosis. Results show good agreement with measurements for videodensitometry; however, diameter measurements are hampered by the unreliability of the edge detection algorithm, particularly when severe stenoses are encountered.<<ETX>> |
Development and Characterization of New Monoclonal Antibodies Against Porcine Interleukin-17A and Interferon-Gamma Current research efforts require a broad range of immune reagents, but those available for pigs are limited. The goal of this study was to generate priority immune reagents for pigs and pipeline them for marketing. Our efforts were aimed at the expression of soluble swine cytokines and the production of panels of monoclonal antibodies (mAbs) to these proteins. Swine interleukin-17A (IL-17A) and Interferon-gamma (IFN) recombinant proteins were produced using yeast expression and used for monoclonal antibody (mAb) production resulting in panels of mAbs. We screened each mAb for cross-species reactivity with orthologs of IL-17A or IFN and checked each mAb for inhibition by other related mAbs, to assign mAb antigenic determinants. For porcine IL-17A, the characterization of a panel of 10 mAbs identified eight different antigenic determinants; interestingly, most of the mAbs cross-reacted with the dolphin recombinant ortholog. Likewise, the characterization of a panel of nine anti-PoIFN mAbs identified four different determinants; most of the mAbs cross-reacted with dolphin, bovine, and caprine recombinant orthologs. There was a unique reaction of one anti-PoIFN mAb that cross-reacted with the zebrafish recombinant ortholog. The IL-17A mAbs were used to develop a quantitative sandwich ELISA detecting the yeast expressed protein as well as native IL-17A in stimulated peripheral blood mononuclear cell (PBMC) supernatants. Our analyses showed that phorbol myristate acetate/ionomycin stimulation of PBMC induced significant expression of IL-17A by CD3+ T cells as detected by several of our mAbs. These new mAbs expand opportunities for immunology research in swine. Current research efforts require a broad range of immune reagents, but those available for pigs are limited. The goal of this study was to generate priority immune reagents for pigs and pipeline them for marketing. Our efforts were aimed at the expression of soluble swine cytokines and the production of panels of monoclonal antibodies (mAbs) to these proteins. Swine interleukin-17A (IL-17A) and Interferon-gamma (IFNg) recombinant proteins were produced using yeast expression and used for monoclonal antibody (mAb) production resulting in panels of mAbs. We screened each mAb for crossspecies reactivity with orthologs of IL-17A or IFNg and checked each mAb for inhibition by other related mAbs, to assign mAb antigenic determinants. For porcine IL-17A, the characterization of a panel of 10 mAbs identified eight different antigenic determinants; interestingly, most of the mAbs cross-reacted with the dolphin recombinant ortholog. Likewise, the characterization of a panel of nine anti-PoIFNg mAbs identified four different determinants; most of the mAbs cross-reacted with dolphin, bovine, and caprine recombinant orthologs. There was a unique reaction of one anti-PoIFNg mAb that cross-reacted with the zebrafish recombinant ortholog. The aIL-17A mAbs were used to develop a quantitative sandwich ELISA detecting the yeast expressed protein as well as native IL-17A in stimulated peripheral blood mononuclear cell (PBMC) supernatants. Our analyses showed that phorbol myristate acetate/ionomycin stimulation of PBMC induced significant expression of IL-17A by CD3+ T cells as detected by several of our mAbs. These new mAbs expand opportunities for immunology research in swine. INTRODUCTION Immunological research in pigs remains hindered by limited reagent availability. Two cytokines of interest are interleukin-17A (IL-17A) and interferon-gamma (IFNg). The IL-17 family is best known for its important role in host defense and immune pathology. Six members of the IL-17 family, annotated as IL-17A through IL-17F, have been identified. IL-17A is an essential player in host disease defense; aberrant expression of IL-17A can lead to many autoimmune diseases and cancers. IL-17A signaling enhances production of proinflammatory molecules in multiple cell types. T helper 17 (Th17) cells (a subset of CD4+ T cells) and gdT cells are major producers of IL-17A although other cell subsets have been indicated. The IFN family is best known for its important role in host immune response to infections, pathogens, and various diseases. IFNg (the only type II IFN) is produced by many cell types, including, CD4+ T helper cell type 1 (Th1) lymphocytes, CD8+ cytotoxic lymphocytes, Natural Killer (NK) cells, NKT cells, and professional antigen-presenting cells: monocyte/macrophage, dendritic cells, and B cells. IFNg plays a major role in the fight against viruses, intracellular bacteria, and tumors, and is generally anti-inflammatory in allergy and asthma. In pigs, IFNg has been reported to play an important role in the remodeling of uterine endometrial epithelium and in promoting cell adherence during implantation. As reported herein, we describe the development and characterization of panels of monoclonal antibodies (mAbs) to porcine IL-17A or IFNg. The characterization of these new reagents includes antigen specificity, cross-clone inhibition, cross-species reactivity, intracellular staining in pig peripheral blood mononuclear cells (PBMCs), and successful development of a soluble protein detection assay. Development and Characterization of Anti-Porcine IL-17A and Anti-Porcine IFNg mAbs Recombinant cytokine proteins were cloned and expressed in Pichia pastoris by Kingfisher Biotech, (Saint Paul, MN). At a contract facility, cytokine specific hybridomas were produced using BALB/c mice that were immunized subcutaneously twice at 4-week intervals (50 mg/dose) with swine IL-17A recombinant protein (rPoIL-17A; Kingfisher Biotech, Saint Paul, MN) or swine IFNg recombinant protein (rPoIFNg; Kingfisher Biotech, Saint Paul, MN). Once antibodies were detected in the serum, mice were injected with a final intravenous boost of rPoIL-17A or rPoIFNg, and hybridoma fusion conducted. The primary hybridoma supernatants were screened for specificity by ELISA; supernatants positive for rPoIL-17A or rPoIFNg, but negative for anti-carbohydrate reactivity, were cloned and expanded for mAb production and purification. A panel of 9 anti-PoIFNg (aPoIFNg) mAbs and 10 anti-PoIL-17A (aPoIL-17A) mAbs were selected for further characterization and validation by ELISA for specific binding, determinant reactivity, and intracellular staining ( Table 1). Screening of mAbs for Specific Determinant Reactivity Protein A purified aPoIL-17A or aPoIFNg mAbs were biotinylated according to the manufacturer's instructions using the EZ-Link ™ Sulfo-NHS-LC-Biotin reagent (ThermoFisher Scientific, Waltham, MA). Purified aPoIL-17A or aPoIFNg mAbs were incubated in ELISA plates precoated with purified rPoIL-17A or rPoIFNg. The subsequent binding of biotin-labeled aPoIL-17A or aPoIFNg mAbs was determined with Streptavidin-Horseradish Peroxidase conjugate (SAv-HRP) (Thermo Fisher Scientific, Waltham, MA). Percent inhibition of the binding of biotin-labeled mAb with a 100-fold excess of each purified (non-biotinylated) mAb was calculated. Antigenic determinants were assigned based on mAb cross-inhibition and binding to cross-species orthologs. Screening of mAbs for Cross-Species Reactivity With Recombinant Orthologs ELISAs were performed as noted in section ELISA Screening of Hybridoma Supernatants and mAb Characterization. Plates were coated with every available yeast expressed recombinant protein ortholog from different species (Kingfisher Biotech, Saint Paul, MN) and reactivity compared to that with rPoIL-17A or rPoIFNg. Specifically, biotin-labeled anti-PoIL-17A mAbs were tested for binding to 13 rPoIL-17A orthologs from bovine, canine, mouse, dolphin, ovine, feline, zebrafish, human, caprine, rabbit, monkey, equine, and guinea pig; anti-PoIFNg mAbs were tested against rPoIFNg from the same species, except for guinea pig, which was replaced by murine. Any cross-species reaction whose ELISA OD was at equal or higher than 0.5 was considered positive. Development of Sandwich ELISA for Quantitation of IL-17A Sets of purified aPoIL-17A mAbs were tested to determine the optimal set of mAbs for quantitation of IL-17A. Capture mAbs were diluted in sodium carbonate buffer at optimal concentration (5 g/l) to coat ELISA plates (Thermo Fisher Scientific, Rochester, NY). Recombinant PoIL-17A (rPoIL-17A) (Kingfisher Biotech, Saint Paul, MN) was diluted serially from 0-100,000 pg/ml in PBS-BSA and added to wells for 1 hr to test for standard curve sensitivity. Biotinylated aPoIL-17A mAbs were added to each well at 0.1 g/ml for 1 hr. After washing, SAv-HRP was added, and reactivity measured with SureBlue Reserve TMB Peroxidase Substrate. Once the best standard curves were established, reactivity with native PoIL-17A was tested using supernatants from stimulated peripheral blood mononuclear cells (PBMCs) and compared to media control. PBMC Isolation and Stimulation for Cytokine Production PBMCs were separated from pig blood by density centrifugation using a Lymphocyte Separation Medium LymphoSepTM (MP Biomedicals, Solon, OH) and used fresh or frozen in liquid nitrogen until thawed for in vitro cultures. Frozen and fresh PBMC from multiple pigs were used for the studies conducted at BARC and OSU. All cell cultures were conducted in blastogenic medium . All cultures were incubated at 37°C/5% CO 2. Native PoIL-17A was prepared from PBMC cultured in 6 well plates at 4 x 10 6 cells/well. Cells were cultured in blastogenic medium with phytohemagglutinin (PHA) at 10 mg/ml or phorbol myristate acetate and ionomycin (PMA/Iono) at 50 ng/ml and 500 ng/ml, respectively, to induce cytokine production. Cells were incubated for 24 or 48 hrs in a 37°C humidified CO 2 incubator, then harvested and centrifuged. Supernatants were collected, aliquoted, and stored at -20°C until use for ELISA assay and not refrozen after use. Cell Culture for Immunostaining and Flow Cytometric Analyses Purified aPoIL-17A or aPoIFNg mAbs were labeled with AF647 according to the manufacturer's instructions using the Alexa Fluor ® 647 Protein Labeling Kit (ThermoFisher Scientific, Waltham, MA). For cell culture, frozen PBMCs were thawed and cultured overnight in blastogenic medium in 6 well plates at 4 x 10 6 cells/well. Cells were stimulated for 5 hrs with BD Leukocyte Activation Cocktail (BD Biosciences, San Diego, CA), which is a ready-to-use polyclonal cell activation mixture containing PMA/Iono, and a protein transport inhibitor (Brefeldin A). For cell surface staining, Fc receptors were first blocked for 30 min at 4°C in complete Flow Cytometry Medium (FCM) . For dead/viable cell exclusion, the cells were stained with the fixable viability stain 520 (FVS) (BD Biosciences, San Diego, CA) in PBS for 7 min at 37°C and washed twice with PBS-BSA. Alternatively, the cells were stained with the VivaFix cell viability dye (Bio-Rad, Hercules, CA) in PBS for 30 min at room temperature, then washed twice with PBS-BSA. For intracellular staining, after staining for dead/viable cell exclusion as noted above, Fc receptors were blocked for 30 min at 4°C in complete FCM. The cells were then stained with PEconjugated aPoCD3 mAb (BD Biosciences, San Diego, CA) for 30 min at 4°C in normal FCM, fixed for 30 min at 4°C in Fixation & Permeabilization Buffer (BD Biosciences, San Diego, CA), washed twice with 1x Permeabilization Buffer (BD Biosciences, San Diego, CA), and labeled with AF647-conjugated aPoIL-17A or aPoIFNg mAb ( Table 1) for 30 min at 4°C in 1x Permeabilization Buffer. The cells were washed twice with 1x Permeabilization Buffer and re-suspended in normal FCM. For flow cytometric analyses, data on labeled cells were acquired either on an Accuri C6 or an Accuri C6 Plus flow cytometer (BD Biosciences, San Diego, CA) and analyzed using FlowJo Software, version 10.7.1 (BD Biosciences, San Jose, CA), gating on live lymphocytes and live T cells. BLAST and Multiple Sequence Alignments Single best sequence homologs for each immunogen were retrieved from NCBI protein BLAST searches (https://blast. ncbi.nlm.nih.gov/Blast.cgi), performed restricting hits to a single sequence and using all other default settings. Corresponding swine reference amino acid sequences were BLAST queries. Hits corresponding to species of interest were aligned using the NCBI COBALT tool (https://www.ncbi.nlm. nih.gov/tools/cobalt/cobalt.cgi) with default settings. Data Analysis ELISA data were analyzed using Microsoft Excel program (Microsoft Software, Redmond, WA). The mean ODs of duplicates were plotted using GraphPad Prism 5 software (GraphPad Software, La Jolla, CA). Any cross-species reaction whose optical density (OD) was equal to, or higher than, 0.5 was considered positive. The lower and upper sensitivity limits of the sandwich ELISA were determined as the first data point which detects reactivity above background level, and the upper sensitivity limit was determined as the apex point on the standard curve. Flow Cytometry data were analyzed using FlowJo Software version 10.7.1 (BD Biosciences, San Jose, CA), gating on live lymphocytes and for some analyses on live CD3+ T cells. Characterization of Anti-IL-17A mAb Antigenic Determinants To define individual antigenic determinants that are recognized by each of the 10 aPoIL-17A mAbs, a competition ELISA was used to measure the ability of excess unlabeled mAb to inhibit the binding of each biotin-labeled mAb to the target rPoIL-17A. Shown in Table 1 is the complete list of antibodies used in these studies. Table 2 notes percent inhibition of the binding of biotinlabeled mAbs by a 100-fold excess of the unlabeled mAbs. Several biotin-labeled mAbs (aPoIL-17A-2.4, -2.5, -2.6, and -2.8) were inhibited by self and most other aPoIL-17A mAbs, whereas a few others (aPoIL-17A-1.1, -1.2) were inhibited by no or a few other mAbs. Sequence Alignments for Porcine IL-17A Proteins We performed a BLAST search on porcine IL-17A proteins to see whether amino-acid sequences that are shared with several orthologous proteins we tested, may correlate with the crossspecies reactivity patterns we observed in this study (Supplementary Figure 1). Next to each sequence name is a percentage identity value with respect to the aligned region. For porcine IL-17A, the closest ortholog is bovine (83% identity), then ovine, caprine, and dolphin, all of which with 81% identity. Despite the highest sequence identity mAb reactivity with the rBoIL-17A ortholog was relatively low; higher reactivity was found with equine and human rIL-17A with 74% and 72% sequence identity, respectively, to porcine IL-17A. Characterization of Anti-IFNg mAb Antigenic Determinants As with IL-17A, porcine IFNg antigenic determinants recognized by each of the nine aPoIFNg mAbs were defined by competition ELISA, testing 100-fold excess unlabeled aPoIFNg mAbs capacity to competitively inhibit binding of biotin-labeled aPoIFNg mAbs to rPoIFNg. As shown in Table 3, for aPoIFNg mAbs, half of the unlabeled aPoIFNg mAbs inhibited the binding of self biotin-labeled mAbs (aPoIFNg- 1.1, -17.1, -21.3, -23.2). The other inhibition patterns were heterogeneous, ranging from none, weak to medium, or strong. There were also some mAbs that failed to inhibit self (aPoIFNg-35.1 and -45.2) ( Table 3). Cross-Reactivity of Anti-IFNg mAbs With Orthologous Recombinant Proteins and Determinant Assignments We used a direct ELISA to assess the ability of the aPoIFNg mAbs to react with orthologous rIFNg proteins. Fourteen orthologous rIFNg proteins from different species were tested. Based on the binding patterns (Figure 2), four determinants (A-E) representing potential antigenic determinants emerged ( Table 3). For group A, one mAb (aPoIFNg-1.1) was the only mAb that unexpectedly cross-reacted with zebrafish rIFNg protein. Most of the aPoIFNg mAbs showed a strong cross-reactivity with orthologous rIFNg proteins from dolphin, bovine, caprine, and ovine. Three aPoIFNg mAbs (aPoIFNg-23.2, -24.1, -35.1) also cross-reacted weakly with human and equine rIFNg and were assigned as Group B. Group C: Represented by aPoIFNg-17.1 and -21.3, these mAbs crossreacted with canine, dolphin, bovine, ovine and caprine rIFNg and had strong cross inhibition patterns. Group D: Represented by aPoIFNg-27.3; -34.2 and -45.2, these mAbs cross-reacted with bovine, ovine, caprine, dolphin, and canine rIFNg. No aPoIFNg mAb cross-reactivity was detected with rabbit, chicken, or mouse rIFNg, and only weak reactivity was seen with feline and monkey rIFNg. Sequence Alignments for Porcine IFNg Proteins Shown in Supplemental Figure 2 are multiple sequence alignments against porcine IFNg. Next to each sequence name is a percentage identity value with respect to the aligned region. For porcine IFNg, the closest sequence homologies are with dolphin (80.7% identity), then bovine, ovine, and caprine, all of which with 77-78% identity. This sequence homology may explain why most of our new mAbs cross-reacted with bovine, ovine, caprine, equine, canine, feline, dolphin, and human IFNg. However, it cannot explain the unique cross-reactivity of one mAb, aPoIFNg-1.1, with zebrafish. Indeed, zebrafish IFNg protein was the least identical to porcine IFNg protein, with only 25% identity. Sandwich ELISA and Quantitation of IL-17A We established an IL-17A sandwich ELISA using rPoIL-17A standard curves and testing several sets of mAbs based on their 30-60% <30% Self Shown are percent inhibition of the binding of biotinylated anti-PoIFNg mAbs by a 100-fold excess of the unlabeled anti-PoIFNg mAbs. Numbers in yellow reflect self inhibition, in orange >60% inhibition, gray 30-60% inhibition, and blue <30% inhibition. The cross-species reactivities summarized and assigned determinant groups noted. NT: Not Tested. different determinant reactivities. As shown in Figure 3A, three of the best performing mAb pairs were compared with aPoIL-17A-2.6 mAb as the capture mAb, and aPoIL-17A-1.1 mAb as the detection mAb (2.6/1.1 pair) proving to be the most sensitive pair at detecting rPoIL-17A with a lower sensitivity limit of 100-300 pg/ml and an upper limit of 3,000 pg/ml. The reverse mAb pair (1.1/2.6) and a different pair (1.2/1/1) were less sensitive with a lower limit of 300 pg/ml and an upper limit of 10,000 pg/ ml. We did not test our newly developed anti-IFNg mAbs for development of a sandwich ELISA because such assays are already commercially available from both R&D Systems and BD Biosciences. Subsequent experiments were performed using the aPoIL-17A-2.6/-1.1 pair. We investigated the ELISA sensitivity for rPoIL-17A detection in PBS+BSA versus pig serum. As shown in Figure 3B, the lower sensitivity limit for the PBS+BSA curve was at 300 pg/ml, while the lower limit was around 1,000 pg/ml in the samples containing pig serum at 10% and 20%. There was an increasingly higher background with increasing concentrations of pig serum. This may make it more difficult to use this assay with samples containing >20% pig serum, because the PBS+BSA standard curve had better background levels. Thus, it is recommended to use samples containing no more than 20% pig serum to maintain the sensitivity of the assay. Next, we needed to affirm the reactivity of the assay with native porcine IL-17A. As shown in Figure 3C, the aPoIL-17A-2.6/1.1 mAb pair was sensitive for detecting IL-17A in supernatants from cultured pig PBMC. This was evidenced by the low background levels in the cell culture medium only and the supernatant from unstimulated cells (BM) compared to the detection of native porcine IL-17A in supernatants from PHA or PMA/Iono-stimulated PBMC. More IL-17A was expressed in supernatants from PBMC stimulated with PHA or PMA/Iono for 48 hrs compared to supernatants from PBMC stimulated with PHA or PMA/Iono for 24 hrs. Intracellular Staining of Pig PBMCs With AF647 Labeled Anti-PoIL-17A mAbs We tested the ability of newly produced mAbs to specifically bind porcine IL-17A intracellularly. Several of the tested aPoIL-17A mAbs stained well and our analyses showed that PMA/ ionomycin stimulation induced significant expression of IL-17A by CD3+ T cells. As shown in Figure 4, gating on live lymphocytes, the tested aPoIL-17A mAbs showed a clear population of T cells expressing IL-17A. Repeated assays revealed aPoIL-17A-2.5, -2.6, and -2.10 to be the most reliable mAbs. The mean frequency of IL-17A expressing CD3+ T cells from PBMCs was 1.33 ± 0.36%. Using aHuIL-17-SCPL1362 mAb as a positive control, our data confirmed a previous report that it cross-reacted with pig cells, staining 0.64 ± 0.19% CD3+ T cells after PMA/Iono stimulation. As shown in Figure 4 three of our mAbs, aPoIL-17A-2.5, -2.6, and -2.10 stained 1.01, 1.19 and 1.03% PMA/ionomycin stimulated cells, respectively. One mAb, aPoIL-17A-2.8, only stained 0.69% of those same cells. We also compared our mAbs with aBoIL-17A-2A mAb, which we confirmed was cross-reactive with swine IL-17A (data are not shown). DISCUSSION We report herein, the establishment of new panels of hybridomas that secrete aPoIL-17A and aPoIFNg mAbs. The binding specificity of these mAbs has been characterized by direct ELISA, sandwich ELISA, and flow cytometry. IL-17A is an ideal drug target because of its broad involvement in many host defense mechanisms by inducing proinflammatory cytokines and chemokines that participate in neutrophil and macrophage recruitment to the site of injury. Indeed, recent reports have shown that IL-17A plays a role in skin wound healing and gut epithelial repair while aIL-17A and aIFNg mAbs have been developed to treat psoriasis and lymphohistiocytosis, respectively, in humans, with favorable outcomes. IL-17A and IFNg are therefore ideal targets for the future development of therapeutic antibodies to test using the pig biomedical model, to affirm the cytokine's involvement in many host-defense mechanisms. All mAbs showed a strong binding specificity to their target porcine antigen and various levels of cross-clone inhibition. Additionally, mAbs yielded several binding patterns when tested on orthologous cytokines, suggesting binding of different antigenic determinants on the corresponding porcine target. The fact that there were some aPoIFNg mAbs that failed to inhibit self ( Table 3), suggests that these mAbs may react with different determinants on rPoIFNg. Highly specific mAbs often have varying potencies against antigen orthologs, which can affect the efficacy of these molecules in different animal models of disease. Usually, mAbs bind non-linear epitopes that depend on the precise three-dimensional arrangement of a constellation of amino acids. For this reason, mAbs raised against a specific antigen from any given species often do not cross-react with orthologs of that antigen from other species, and when they do, the binding potency may vary depending on the origin of the antigen that was used to test the mAbs. We found similar variations in this study when we tested the crossreactivity of our new mAbs against 13 species orthologs. Some aPoIL-17A mAbs reacted strongly with multiple mammalian species, such as aPoIL-17A determinant H ( Table 2), others showed no cross-species reactions, such as aPoIL-17A determinant B & E ( Table 2). Still other mAbs showed unique reactions, such as aPoIFNg determinant A reactivity on zebrafish rIFNg ( Table 3). Some cross inhibitions were strong such as aPoIFNg determinant C where aPoIFNg-17.1 and aPoIFNg-21.3 fully cross inhibited each other but yet had very different inhibition by aPoIFNg-45.2 ( Table 3). The assignment of antigen determinant groups was not an easy task. Even though determinants were assigned based on mAb cross-clones inhibition and binding to cross-species orthologs, some were heterogeneous within the same determinant group (Tables 2, 3). Additional studies are needed to elucidate whether these mAb antigenic determinants represent true epitopes. The crossreaction of these mAbs with orthologous cytokines may provide needed reagents for several other species. Further analyses are needed to determine whether some of these mAbs are neutralizing, i.e., block IL-17A or IFNg binding to the target receptor. The key to the success of a sandwich ELISA is to identify an appropriate pair of capture and detection antibodies. Such an antibody pair should be highly specific and sensitive to accurately quantify a low level of antigens (pg/ml). We noted that there was higher background with increasing concentrations of pig serum, preventing optimal PoIL-17A detection, but good sensitivity with samples from cell supernatants. It may be more difficult to use this assay with samples containing higher concentrations of pig serum (higher than 10-20% pig serum). Notably, our newly developed aPoIL17A sandwich ELISA successfully detected native PoIL-17A in PBMC supernatants. The highest level of IL-17A was detected in PBMCs stimulated with the mitogen PHA after 48 hrs ( Figure 3C). These data show that PHA was more successful in initiating cytokine IL-17A release from porcine PBMC than PMA/Iono, and that with increased stimulant incubation time, more cytokine is released with both stimulants. We did not test our newly developed anti-IFNg mAbs in a sandwich ELISA because this assay is already commercially available. For the tested aPoIL-17A mAbs, we describe a robust IL-17A flow cytometry-based assay to quantify and phenotype IL-17Aspecific CD3+ T cells ex-vivo using cryopreserved PBMCs. Our intracellular staining data for PoIL-17A affirmed that several of our new aPoIL-17A mAbs appeared to be slightly better than the cross reactive aHuIL-17A-SCPL1362 mAb at detecting CD3+IL-17A+ cells, indicating that the anti-porcine mAbs may detect a broader range of IL-17A+ cells. Panels of these mAbs are being shared with colleagues to affirm whether this difference is found in vivo. MAbs are being shared via Material Transfer Agreements (MTAs; mAb commercialization is underway with our Technology Transfer Office. The availability of these mAbs that detect cytokines by ELISA and flow cytometry will help dissect host response to pathogens and vaccines in swine. Comparative flow cytometric analyses of lymphocyte subsets may reveal differences in expression of IL-17A by CD4, CD8, and gd T cells in swine. In addition, some of our mAbs may be useful for other species because they crossreacted with their recombinant ortholog antigens. More studies are needed to elucidate this issue. In conclusion, we have developed and characterized new panels of aPoIL-17A and aPoIFNg mAbs. These mAbs provide the research community with new tools for the characterization of IL-17A-producing cells in pigs and the quantification of secreted IL-17A in vitro. DATA AVAILABILITY STATEMENT The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author. AUTHOR CONTRIBUTIONS JLu, JLa, GR conceptualized the study and secured funding for the project. JL and YS provided the cloned cytokines. JM, KW, VP, and OF conducted the experiments and performed the data analyses. All authors assisted in the review of the manuscript and consented to publication. All authors read and approved the final manuscript. |
<reponame>EleveShi/apollo
/*
* Copyright 2022 Apollo Authors
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*
*/
package com.ctrip.framework.apollo.common.dto;
import java.util.Date;
/**
* @author <NAME>(<EMAIL>)
*/
public class InstanceConfigDTO {
private ReleaseDTO release;
private Date releaseDeliveryTime;
private Date dataChangeLastModifiedTime;
public ReleaseDTO getRelease() {
return release;
}
public void setRelease(ReleaseDTO release) {
this.release = release;
}
public Date getDataChangeLastModifiedTime() {
return dataChangeLastModifiedTime;
}
public void setDataChangeLastModifiedTime(Date dataChangeLastModifiedTime) {
this.dataChangeLastModifiedTime = dataChangeLastModifiedTime;
}
public Date getReleaseDeliveryTime() {
return releaseDeliveryTime;
}
public void setReleaseDeliveryTime(Date releaseDeliveryTime) {
this.releaseDeliveryTime = releaseDeliveryTime;
}
}
|
def check_for_command_presence(self, job_id: str, command_id: str):
if command_id not in self.known_commands:
new_command = CommandStatus(job_id, command_id)
self.known_commands[command_id] = new_command |
<reponame>oneyoungg/oneyoung<filename>oneyoung-common/src/main/java/top/oneyoung/common/result/ResultCode.java
package top.oneyoung.common.result;
import lombok.Getter;
/**
* 错误码枚举类
*
* @author oneyoung
*/
@Getter
public enum ResultCode {
/**
* SYSTEM ERROR
*/
SYSTEM_ERROR("SYSTEM ERROR"),
/**
* PARAM_ERROR
*/
PARAM_ERROR("PARAM_ERROR");
private final String code;
ResultCode(String code) {
this.code = code;
}
}
|
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