Split (2)

train · 34.7k rows

Subsets and Splits

No community queries yet

The top public SQL queries from the community will appear here once available.

context stringlengths 5 6.31k ⌀	question stringlengths 13 640	answer stringlengths 4 2.42k ⌀
These data suggest that low FT3 levels are not predictive for mortality in a subgroup of stable HD patients who could survive more than 12 months.	Is low T3 syndrome a prognostic marker in patients with renal insufficiency?	These data suggest that low FT3 levels are not predictive for mortality in a subgroup of stable HD patients who could survive more than 12 months.
Fusobacterium necrophorum is a gram-negative anaerobic bacterium that is the causative agent of the invasive disease Lemierre's syndrome. In addition, it is also associated with peritonsillar abscess formation and otitis media in small children. Recent research has shown that F. necrophorum may be involved in pharyngotonsillitis especially in adolescent and young adults and that it may be the second most common bacterial cause of pharyngotonsillitis after Streptococcus pyogenes (Group A streptococci). Peritonsillar abscesses and Lemierre's syndrome due to F. necrophorum are also found in this age group, suggesting that they may be complications of F. necrophorum pharyngotonsillitis. In this review we present the present knowledge about the role of F. necrophorum in pharyngotonsillitis with special emphasis on the age distribution. We argue that F. necrophorum is an important pathogen involved in pharyngotonsillitis in the age group of 13-40 years of age and we urge clinical microbiology labs to set up the appropriate techniques to be able to detect F. necrophorum from throat swabs.	Is fusobacterium associated with Lemierre's syndrome?	Fusobacterium necrophorum is a gram-negative anaerobic bacterium that is the causative agent of the invasive disease Lemierre's syndrome.
Cryptic unstable transcripts (CUTs) are rapidly degraded by the nuclear exosome. However, the mechanism by which they are recognized and targeted to the exosome is not fully understood. Here we report that the MTREC complex, which has recently been shown to promote degradation of meiotic mRNAs and regulatory ncRNAs, is also the major nuclear exosome targeting complex for CUTs and unspliced pre-mRNAs in Schizosaccharomyces pombe. The MTREC complex specifically binds to CUTs, meiotic mRNAs and unspliced pre-mRNA transcripts and targets these RNAs for degradation by the nuclear exosome, while the TRAMP complex has only a minor role in this process. The MTREC complex physically interacts with the nuclear exosome and with various RNA-binding and RNA-processing complexes, coupling RNA processing to the RNA degradation machinery. Our study reveals the central role of the evolutionarily conserved MTREC complex in RNA quality control, and in the recognition and elimination of CUTs.	Which proteins control the degradation of cryptic unstable transcripts (CUTs) in yeast?	The MTREC complex specifically binds to CUTs, meiotic mRNAs and unspliced pre-mRNA transcripts and targets these RNAs for degradation by the nuclear exosome, while the TRAMP complex has only a minor role in this process
Low efficiency of gene transfer is the main obstacle for a clinically effective gene therapy at the level of the pluripotent hematopoietic stem cell. Another important aspect of stem cell gene therapy, the actual expression of the transduced genes, has only been investigated adequately in very few studies, mainly for globin genes. Transcriptional silencing and position effects due to negative effects of surrounding chromatin on the expression of randomly integrated vector sequences may seriously jeopardize the success of current gene therapy strategies, even if transduction efficiency can be significantly improved. We propose the incorporation of chromatin insulators in the design of gene therapy vectors to overcome the problem of position effects. Chromatin insulators are protein-binding DNA elements that lack intrinsic promoter/enhancer activity but shelter genes from transcriptional influence of surrounding chromatin. The best characterized insulators are from Drosophila. We hypothesize that the important cellular function of chromatin organization is evolutionarily conserved and that human homologs to Drosophila insulator binding proteins such as the suppressor of Hairy-wing exist and can be cloned. Using these putative proteins, it should be possible to identify corresponding minimal binding sites with insulator activity. The design and incorporation of effective chromatin insulator sequences in the next generation of gene therapy vectors should lead to improved and more predictable expression of therapeutic transgenes and constitute an important step toward clinically effective gene therapy.	Why are insulators necessary in gene therapy vectors?	We propose the incorporation of chromatin insulators in the design of gene therapy vectors to overcome the problem of position effects. Chromatin insulators are protein-binding DNA elements that lack intrinsic promoter/enhancer activity but shelter genes from transcriptional influence of surrounding chromatin.
Glucocorticoids (GCs) are widely used to treat acute graft-versus-host disease (aGvHD) due to their immunosuppressive activity, but they also reduce the beneficial graft-versus-leukemia (GvL) effect of the allogeneic T cells contained in the graft. Here, we tested whether aGvHD therapy could be improved by delivering GCs with the help of inorganic-organic hybrid nanoparticles (IOH-NPs) that preferentially target myeloid cells. IOH-NPs containing the GC betamethasone (BMP-NPs) efficiently reduced morbidity, mortality, and tissue damage in a totally MHC mismatched mouse model of aGvHD. Therapeutic activity was lost in mice lacking the GC receptor (GR) in myeloid cells, confirming the cell type specificity of our approach. BMP-NPs had no relevant systemic activity but suppressed cytokine and chemokine gene expression locally in the small intestine, which presumably explains their mode of action. Most importantly, BMP-NPs delayed the development of an adoptively transferred B cell lymphoma better than the free drug, although the overall incidence was unaffected. Our findings thus suggest that employing IOH-NPs could diminish the risk of relapse associated with GC therapy of aGvHD patients while still allowing to efficiently ameliorate the disease.	What is the mode of action of dexamethasone?	Glucocorticoids (GCs) are widely used to treat acute graft-versus-host disease (aGvHD) due to their immunosuppressive activity, but they also reduce the beneficial graft-versus-leukemia (GvL) effect of the allogeneic T cells contained in the graft.
Circadian clock genes regulate 10-15% of the transcriptome, and might function as tumor suppressor genes. Relatively little is known about the circadian clock in tumors and its effect on surrounding healthy tissues. Therefore, we compared the 24-hr expression levels of key circadian clock genes in liver and kidney of healthy control mice with those of mice bearing C26 colorectal tumor metastases in the liver. Metastases were induced by injection of C26 colorectal carcinoma cells into the spleen. Subsequently, tumor, liver and kidney tissue was collected around the clock to compare circadian rhythmicity. Expression levels of five clock genes (Rev-Erbα, Per1, Per2, Bmal1 and Cry1) and three clock-controlled genes (CCGs; Dbp, p21 and Wee1) were determined by qRT-PCR. Liver and kidney tissue of healthy control mice showed normal 24-hr oscillations of all clock genes and CCGs, consistent with normal circadian rhythmicity. In colorectal liver metastases, however, 24-hr oscillations were completely absent for all clock genes and CCGs except Cry1. Liver and kidney tissue of tumor-bearing mice showed a shift in clock periodicity relative to control mice. In the liver we observed a phase advance, whereas in the kidney the phase was delayed. These data show that hepatic metastases of C26 colon carcinoma with a disrupted circadian rhythm phase shift liver and kidney tissue clocks, which strongly suggests a systemic effect on peripheral clocks. The possibility that tumors may modify peripheral clocks to escape from ordinary circadian rhythms and in this way contribute to fatigue and sleep disorders in cancer patients is discussed.	List core circadian clock genes.	Expression levels of five clock genes (Rev-Erbα, Per1, Per2, Bmal1 and Cry1)
Sox proteins are transcriptional regulators with a high-mobility-group domain as sequence-specific DNA-binding domain. For function, they generally require other transcription factors as partner proteins. Sox proteins furthermore affect DNA topology and may shape the conformation of enhancer-bound multiprotein complexes as architectural proteins. Recent studies suggest that Sox proteins are tightly regulated in their expression by many signalling pathways, and that their transcriptional activity is subject to post-translational modification and sequestration mechanisms. Sox proteins are thus ideally suited to perform their many different functions as transcriptional regulators throughout mammalian development. Their unique properties also cause Sox proteins to escape detection in many standard transcription assays. In melanocytes, studies have so far focused on the Sox10 protein which functions both during melanocyte specification and at later times in the melanocyte lineage. During specification, Sox10 activates the Mitf gene as the key regulator of melanocyte development. At later stages, it ensures cell-type specific expression of melanocyte genes such as Dopachrome tautomerase. Both activities require cooperation with transcriptional partner proteins such as Pax-3, CREB and eventually Mitf. If predictions can be made from other cell lineages, further functions of Sox proteins in melanocytes may still lie ahead.	Which transcription factors are essential for the melanocyte lineage?	In melanocytes, studies have so far focused on the Sox10 protein which functions both during melanocyte specification and at later times in the melanocyte lineage.
Use of gene therapy for heart failure is gaining momentum as a result of the recent successful completion of phase II of the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, which showed clinical safety and efficacy of an adeno-associated viral vector expressing sarco-endoplasmic reticulum calcium ATPase (SERCA2a). Resorting to gene therapy allows the manipulation of molecular targets not presently amenable to pharmacologic modulation. This short review focuses on the molecular targets of heart failure gene therapy that have demonstrated translational potential. At present, most of these targets are related to calcium handling in the cardiomyocyte. They include SERCA2a, phospholamban, S100A1, ryanodine receptor, and the inhibitor of the protein phosphatase 1. Other targets related to cAMP signaling are reviewed, such as adenylyl cyclase. MicroRNAs are emerging as novel therapeutic targets and convenient vectors for gene therapy, particularly in heart disease. We propose a discussion of recent advances and controversies in key molecular targets of heart failure gene therapy.	Which genes have been proposed as potential candidates for gene therapy of heart failure?	Use of gene therapy for heart failure is gaining momentum as a result of the recent successful completion of phase II of the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, which showed clinical safety and efficacy of an adeno-associated viral vector expressing sarco-endoplasmic reticulum calcium ATPase (SERCA2a).
Given the limited efficacy and potential disadvantages of erythropoiesis-stimulating agents (ESAs) in treating anemia of chronic kidney disease (CKD), the development of better alternative therapies has become a priority. The primary purpose of this study is to investigate the effects of polysaccharide (ASP) and its underlying mechanism in the treatment of renal anemia. In the present study, we found that ASP could enhance hypoxic induction of EPO in Hep3B cells, with a mechanism that involved the stabilization of HIF-2α protein. In parallel, ASP rescued the inhibition of EPO, induced by proinflammatory factor TNF-α through blocking GATA2 and NF-κB activation. In a rat model of adenine-induced anemia of CKD, oral administration of ASP corrected anemia and alleviated renal damage and inflammation. By increasing the accumulation of HIF-2α protein and reducing the expression of NF-κB and GATA2 as well as pro-inflammatory cytokines, ASP stimulated both renal and hepatic EPO production, and resulted in an elevation of serum EPO. The restoration of EPO production and EPOR mRNA expression with ASP treatment activated EPOR downstream JAK2/STAT5 and PI3K/Akt signaling, induced their target genes, such as Bcl-xL, Fam132b and Tfrc, and increased Bcl-2/Bax ratio in bone marrow-derived mononuclear cells of CKD rats. Furthermore, we found that ASP suppressed hepatic hepcidin expression, mobilized iron from spleen and liver and increased serum iron. These findings demonstrate that ASP elicits anti-anemic action by restoring EPO production and improving iron availability in the setting of CKD in rats.	Is the TFR1 gene dispensable for erythropoiesis?	The restoration of EPO production and EPOR mRNA expression with ASP treatment activated EPOR downstream JAK2/STAT5 and PI3K/Akt signaling, induced their target genes, such as Bcl-xL, Fam132b and Tfrc, and increased Bcl-2/Bax ratio in bone marrow-derived mononuclear cells of CKD rats.
Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose. The PK profile of peginesatide (0.1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life. The peginesatide PK profile following a single i.v. dose is consistent with the sustained erythropoiesis. Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i.e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2.1 mg/kg. Microautoradiography analysis at 48 hours postdose revealed uniform and high distribution of radioactivity in the bone marrow and splenic red pulp with less extensive distribution in the renal cortex (glomeruli, associated ducts, interstitial cells). Radioactivity in the kidney was most prominent in the outer medullary and papillary interstitium. At 2 weeks after dosing, cumulative radioactivity recovery in the urine and feces was 60 and 7% of the administered dose, respectively, with most of the radioactivity associated with the parent molecule. In conclusion, the PK characteristics are consistent with a PEGylated peptide of a 45-kDa molecular mass, specifically low volume of distribution and long half-life. Drug was localized principally to hematopoietic sites, and nonspecific tissue retention was not observed. The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine.	What is the mechanism of action of peginesatide?	Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis.
Epithelial-mesenchymal transition (EMT) has recently been studied to elucidate mechanisms of the liver metastatic process. We investigated EMT in the process of liver metastasis and the effects of chemotherapy on EMT cells as therapeutic strategy for colorectal liver metastasis. We used the CT26 murine colorectal carcinoma cell line to create an in vivo mouse liver metastasis model. Liver tumors were stained immuno-histochemically. Expression of proteins associated with TGF-β/Smad and hepatocyte growth factor (HGF)/c-Met pathways were investigated by western blotting. Cells with c-Met mRNA knockdown by siRNA techniques showed clearly reduced liver metastases compared with regular cells at 21 days. TGF-β and HGF induced EMT expression, but signal transduction was quite different. TGF-β induced ERK, but not Akt phosphory-lation. HGF mediated both ERK and Akt phosphorylation. Akt inhibitor blocked Akt phosphorylation but did not affect TGF-β-induced activation of ERK, Snail and Slug. U-0126 did not reduce Snail activity by TGF-β at a concentration to block ERK phosphorylation. However, Akt inhibitor and U-0126 completely inhibited HGF-induced Slug activation. 5-FU mediated cell death in the EMT process induced by TGF-β more effectively than HGF. ERK/Akt signaling, but not the Smad pathway, may be one of the main processes in HGF-induced EMT, despite the Smad pathway, but not ERK/Akt, being critical for TGF-β-induced EMT. The MAPK/Akt pathway is indispensable in HGF/c-Met signaling. The ERK/Akt pathway particularly may be critical in the HGF-induced EMT process. However, long-term use of chemotherapeutic agents may induce drug resistance and distant metastases through EMT-related signaling pathway activation.	Is c-met involved in the activation of the Akt pathway?	HGF mediated both ERK and Akt phosphorylation.
We propose that DMT1 deficiency negatively affects metabolism and life span of mature erythrocytes; two other aspects of defective erythropoiesis which contribute to the pathophysiology of the disease.	Could divalent metal transporter 1 deficiency lead to anemia?	We propose that DMT1 deficiency negatively affects metabolism and life span of mature erythrocytes; two other aspects of defective erythropoiesis which contribute to the pathophysiology of the disease.
Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease. At least eight complementation groups (FA-A to FA-H) have been identified. Previously, we studied mutations of the FANCA gene, responsible for FA-A, and found pathogenic mutations in 12 of 15 unclassified Japanese FA patients. Here, we further studied an additional 5 FA patients for sequence alterations of the FANCA gene and found pathogenic mutations in 2 of them. We further analyzed mutations of the FANCC and FANCG genes, responsible for FA-C and FA-G, respectively, in the remaining 6 FA patients. Although there was no alterations in the FANCC gene in these 6 patients, two novel mutations of the FANCG gene, causing aberrant RNA splicing, were detected in 2 FA patients. One was a base substitution from G to C of the invariant GT dinucleotides at the splice donor site of intron 3, resulting in the skipping of exon 3, as well as the skipping of exons 3 and 4. The other was a base substitution from C to T in exon 8, creating a nonsense codon (Q356X). This mutation resulted in the exclusion of a sequence of 18 nucleotides containing the mutation from the mRNA, without affecting the splicing potential of either the authentic or the cryptic splice donor site. Collectively, 14 of the 20 unclassified Japanese FA patients belong to the FA-A group, 2 belong to the FA-G group, and none belongs to the FA-C group.	Is Fanconi anemia presented as a genetically and clinically heterogeneous disease entity?	Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease.
Uterine leiomyomas represent the most common form of benign gynecological tumors affecting 20-40% of women during their life. Several therapeutic options are available for treating these patients. The use of medical treatment for myomas has largely grown in the last years, in particular for women who would refuse, postpone or are not candidates for surgery. In the last years, the clinical investigation of gonadotropin-releasing hormone (GnRH) antagonists (GnRH-ants) has emerged. This class of drugs exerts pure competitive antagonistic activity on the GnRH receptor at the pituitary gland, producing an immediate stop in the release of gonadotropins and sex steroids. Relugolix is an orally active nonpeptide GnRH-ant, recently licensed for marketing in Japan for the treatment of symptoms related to uterine myomas. Currently, several phase III clinical trials are ongoing to evaluate this molecule in this setting in the U.S. and Europe.	Which disease can be treated with Relugolix.	Relugolix is an orally active nonpeptide GnRH-ant, recently licensed for marketing in Japan for the treatment of symptoms related to uterine myomas.
Epithelial ovarian cancer (EOC) is one of the leading causes of cancer deaths in women worldwide. Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in sumoylation-mediated cellular pathways. Although sumoylation plays a key role in DNA repair and tumorgenesis, whether Ubc9 is involved in EOC progression remains unknown. In the present study, we constructed Ubc-9 expressed recombined plasmid pEGFP-N1-Ubc9. The mRNA levels of Ubc9 were confirmed in human ovarian cell lines before and after transfection with pEGFP-N1-Ubc9 or small interfering RNA (siRNA) targeted Ubc9 by real-time polymerase chain reaction (PCR). The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to observe the effect of Ubc9 on cell proliferation. The protein levels of Ubc9, and proliferation-related signals Akt and physphorylated Akt were determined by Western blot. Our results showed that proliferation of EOC cells increased significantly in Ubc9 overexpressing cells, but decreased in Ubc9 knockdown cells. The physphorylation of Akt showed similar trends. In addition, the inhibitor of PI3K/Akt signaling pathway, LY294002, dramatically inhibited the growth of Ubc9 overexpressing cells. Therefore, Ubc9 gene plays an important role in cell proliferation in EOC through PI3K/Akt signaling pathway.	What is the role of the UBC9 enzyme in the protein sumoylation pathway?	Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in sumoylation-mediated cellular pathways.
Asbestos exposure causes asbestosis and malignant mesothelioma, disorders which remain difficult to cure. We focused on alveolar macrophages (AM) and natural killer (NK) cells in asbestosis and mesothelioma, respectively, and examined their functions upon exposure to asbestos or in patients with mesothelioma. Exposure to asbestos caused rat AM to exhibit high production of transforming growth factor-beta (TGF-β) with prolonged survival in the absence of other cells, not simultaneously with the apoptosis caused by asbestos. The NK cell line showed impaired cytotoxicity with altered expression of activating receptors upon exposure to asbestos, and primary NK cells in culture with asbestos and peripheral blood NK cells in mesothelioma shared a decrease in expression of NKp46, a representative activating receptor. The AM finding indicates that AM contribute to asbestosis by playing a direct role in the fibrogenic response, as well as the inflammatory response. The response of NK cells indicates that exposure to asbestos has an immune-suppressive effect, as well as a tumorigenic effect. Our studies therefore reveal novel effects of asbestos exposure on AM and tumor immunity, which may represent valuable information for construction of a strategy for prevention and cure of asbestosis and malignant mesothelioma.	Is mesothelioma caused by asbestos exposure?	Asbestos exposure causes asbestosis and malignant mesothelioma, disorders which remain difficult to cure.
Drug and alcohol abuse continue to be commonly encountered problems in most patient populations. To deal effectively with these problems, the primary care physician must have a thorough knowledge of the pharmacology of commonly abused drugs and the adjunctive agents used in treatment. Management of alcoholism may involve a range of medical interventions, including the treatment of alcohol intoxication, the use of benzodiazepines for alcohol withdrawal, and possibly the short-term administration of disulfiram to maintain sobriety. Successful management of cocaine or amphetamine abuse requires an understanding of the powerful reinforcing properties of these drugs and the unique problems that arise in the recovery period. Barbiturate intoxication and withdrawal are potentially life-threatening events requiring skilled in-patient treatment. Prolonged use of benzodiazepines can lead to drug dependence; successful withdrawal involves gradual dosage reduction. Acute intoxication from marijuana or hallucinogenic drugs may occasionally result in adverse reactions requiring medical intervention, but significant withdrawal reactions are rare. Management of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid antagonists. Promising new pharmacologic approaches are now being successfully applied to the management of opioid dependence. An acceptance of nicotine as the addictive component of tobacco smoke has led to the development of nicotine gum as substitution therapy for cigarette smoking. Successful pharmacologic management of overdose or withdrawal is often the prerequisite for effective long-term treatment and recovery.	Which medication should be administered when managing patients with suspected acute opioid overdose?	Management of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid antagonists.
In vitro selection of nucleic acid binding species (aptamers) is superficially similar to the immune response. Both processes produce biopolymers that can recognize targets with high affinity and specificity. While antibodies are known to recognize the sequence and conformation of protein surface features (epitopes), very little is known about the precise interactions between aptamers and their epitopes. Therefore, aptamers that could recognize a particular epitope, a peptide fragment of human immunodeficiency virus type I Rev, were selected from a random sequence RNA pool. Several of the selected RNAs could bind the free peptide more tightly than a natural RNA ligand, the Rev-binding element. In accord with the hypothesis that protein and nucleic acid binding cusps are functionally similar, interactions between aptamers and the peptide target could be disrupted by sequence substitutions. Moreover, the aptamers appeared to be able to bind peptides with different solution conformations, implying an induced fit mechanism for binding. Just as anti-peptide antibodies can sometimes recognize the corresponding epitope when presented in a protein, the anti-peptide aptamers were found to specifically bind to Rev.	What is the role of peptide aptamers?	Moreover, the aptamers appeared to be able to bind peptides with different solution conformations, implying an induced fit mechanism for binding.
Background Exploding head syndrome (EHS) is characterized by loud noises or a sense of explosion in the head during sleep transitions. Though relatively common, little is known about its characteristic symptoms or associated features. Methods A cross-sectional study of 49 undergraduates with EHS was performed. A clinical interview established diagnosis. Results The most common accompanying symptoms were tachycardia, fear, and muscle jerks/twitches with the most severe associated with respiration difficulties. Visual phenomena were more common than expected (27%). EHS episodes were perceived as having a random course, but were most likely to occur during wake-sleep transitions and when sleeping in a supine position. Only 11% reported EHS to a professional, and 8% of those with recurrent EHS attempted to prevent episodes. Conclusions EHS episodes are complex (Mean (M) = 4.5 additional symptoms), often multisensorial, and usually associated with clinically-significant fear. They are rarely reported to professionals and treatment approaches are limited.	Is there a disease or condition called Exploding Head Syndrome?	Exploding head syndrome (EHS) is characterized by loud noises or a sense of explosion in the head during sleep transitions.
Signaling photoreceptors mediate diverse organismal adaptations in response to light. As light-gated protein switches, signaling photoreceptors provide the basis for optogenetics, a term that refers to the control of organismal physiology and behavior by light. We establish as novel optogenetic tools the plasmids pDusk and pDawn, which employ blue-light photoreceptors to confer light-repressed or light-induced gene expression in Escherichia coli with up to 460-fold induction upon illumination. Key features of these systems are low background activity, high dynamic range, spatial control on the 20-μm scale, independence from exogenous factors, and ease of use. In optogenetic experiments, pDusk and pDawn can be used to specifically perturb individual nodes of signaling networks and interrogate their role. On the preparative scale, pDawn can induce by light the production of recombinant proteins and thus represents a cost-effective and readily automated alternative to conventional induction systems.	Optogenetics refers to the study of gene expression optimization	As light-gated protein switches, signaling photoreceptors provide the basis for optogenetics, a term that refers to the control of organismal physiology and behavior by light.
Expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) is used to select patients and analyze responses to anti-PD-1/L1 antibodies. The expression of PD-L1 is regulated in different ways, which leads to a different significance of its presence or absence. PD-L1 positivity may be a result of genetic events leading to constitutive PD-L1 expression on cancer cells or inducible PD-L1 expression on cancer cells and noncancer cells in response to a T cell infiltrate. A tumor may be PD-L1 negative because it has no T cell infiltrate, which may be reversed with an immune response. Finally, a tumor that is unable to express PD-L1 because of a genetic event will always be negative for PD-L1 on cancer cells.	What is the difference between PD-1 and PD-L1?	Expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) is used to select patients and analyze responses to anti-PD-1/L1 antibodies.
The protein of the gustavus (gus) gene has a typical SOCS box domain and repeats in the splA and RyR (SPRY) domains. GUS can interact with Vasa and is necessary for the specification of germ cells. We cloned two zebrafish genes, SSB-1 and SSB-4 (SPRY domain SOCS box proteins). Phylogenetic analysis shows that zebrafish SSB-1 and SSB-4 are clustered into clades of SSB-1-like and SSB-4-like genes from other species. RT-PCR analysis of tissues revealed that zebrafish SSB-1 and -4 are expressed in the ovary and testis. We investigated the spatial expression patterns of zebrafish SSB-1 and -4 in embryos from the two-cell stage to 72 h postfertilization (hpf) using whole-mount in situ hybridization. SSB-1 and -4 transcripts were present in all blastomeres during the early embryonic stages, but the genes differ in their expression pattern. SSB-4 mRNA was located in the region of the primordial germ cells in 24 and 72 hpf embryos, but SSB-1 mRNA was not detected at these stages. We hypothesize that SSB-4 plays a role in the early development of germ cells.	What are the biological roles proposed for proteins containing the SPRY domain?	We hypothesize that SSB-4 plays a role in the early development of germ cells
Hakaru Hashimoto described 4 patients with a hitherto unknown cause for goitre, struma lymphomatosa, a century ago. He was careful to distinguish this from Riedel thyroiditis but it has become clear that fibrosis and atrophy of the thyroid are indeed components of Hashimoto thyroiditis, and in rare cases IgG4-related sclerosing disease may be an outcome. Although the cause of the lymphocytic infiltration was unknown to Hashimoto, we now know through the pioneering studies of N.R. Rose and E. Witebsky [J Immunol 1956;76:417-427] that this condition is the archetype for autoimmune destruction as a disease mechanism. In the last two decades in particular, there has been huge interest in unravelling the genetic basis for this and related autoimmune disorders. The list of polymorphisms associated with autoimmune thyroid disease grows each year, and in the case of vitiligo, which is frequently found in association with thyroid autoimmunity, we know that 27 separate susceptibility loci account for less than 20% of the heritability of this condition. Environmental and existential factors may turn out to be just as complex in number and in interactions. We can thus imagine a 'Swiss cheese' model for the causation of autoimmune thyroid disease, in which the effects of cumulative weaknesses line up - like the holes in slices of cheese - to allow the catastrophic event of autoimmune destruction to occur.	Which antibodies cause Riedel thyroiditis?	He was careful to distinguish this from Riedel thyroiditis but it has become clear that fibrosis and atrophy of the thyroid are indeed components of Hashimoto thyroiditis, and in rare cases IgG4-related sclerosing disease may be an outcome.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early demise. Cognitive development is normal. Data on 10 of our own cases and 132 cases from literature are presented. The incidence in the last century in the Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were failure to thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy (20%). Mean age at diagnosis was 2.9 years. Growth in weight was more disturbed than growth in height, and growth delay started already prenatally. Mean height > 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis was wide-spread but not expressed, except in the viscerocranium, and remained limited to membranous formed bone. Lipodystrophy is generalized, only intra-abdominal fat depositions remain present. Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronary dysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble sometimes the findings in elderly persons, but can also be much more limited. Loss of smooth muscle cells seems the most important finding. Mean age of demise was 12.6 years. Patients can be subdivided in patients with classical HGPS, which follows an autosomal dominant pattern of inheritance, (almost) all cases representing spontaneous mutations, and in non-classical progeria, in whom growth can be less retarded, scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is more expressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance of non-classical progeria is most probably autosomal recessive. The cause of HGPS is an abnormally formed Lamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing (ZMPSTE24 gene mutations). Of 34 LMNA mutations found in progeria patients, there were 26 classical p.G608G mutations (76%). Pathogenesis is most likely to follow several different pathways. Potential therapeutic strategies are developed along these lines and include RNA interference techniques and inhibition of the dominant-negative influence of abnormally formed Lamin A on polymerization with normally formed Lamin A.	Is progeria caused by an autosomal recessive gene?	Pattern of inheritance of non-classical progeria is most probably autosomal recessive.
In a double-blind placebo-controlled prospective clinical trial we studied the efficacy and safety of the benzodiazepine antagonist, flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). In the remaining 7 patients, needing two series of injections of flumazenil (up to 2.0 mg), GCS did not rise significantly and coma was related to intoxications with nonbenzodiazepine sedatives, flunitrazepam and in one patient, encephalitis. In the 10 patients receiving placebo, the GCS did not change. A significant increase in the GCS from 5.5 to 10.8 (p less than 0.001) was, however, observed when flumazenil (up to 1.0 mg) was given after placebo. In patients with EEG monitoring the changes in waveform pattern paralleled the clinical response. Effects could be detected within 1-2 min after flumazenil injection and lasted up to 45 min. There were no adverse reactions or benzodiazepine withdrawal symptoms. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. The use of flumazenil is of diagnostic value in mixed-drug intoxications or coma of unknown origin and is of therapeutic importance for reversal of benzodiazepine intoxications.	Which drug should be used as an antidote in benzodiazepine overdose?	In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01).
Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is an important, highly conserved, regulator of cell growth. Ancient among the signals that regulate mTORC1 are nutrients. Amino acids direct mTORC1 to the surface of the late endosome/lysosome, where mTORC1 becomes receptive to other inputs. However, the interplay between endosomes and mTORC1 is poorly understood. Here, we report the discovery of a network that links mTORC1 to a critical component of the late endosome/lysosome, the V-ATPase. In an unbiased screen, we found that mTORC1 regulated the expression of, among other lysosomal genes, the V-ATPases. mTORC1 regulates V-ATPase expression both in cells and in mice. V-ATPase regulation by mTORC1 involves a transcription factor translocated in renal cancer, TFEB. TFEB is required for the expression of a large subset of mTORC1 responsive genes. mTORC1 coordinately regulates TFEB phosphorylation and nuclear localization and in a manner dependent on both TFEB and V-ATPases, mTORC1 promotes endocytosis. These data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.	Which transcription factor is considered as a master regulator of lysosomal genes?	These data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.
Septins are guanosine-5'-triphosphate-binding proteins involved in wide-ranging cellular processes including cytokinesis, vesicle trafficking, membrane remodelling and scaffolds, and with diverse binding partners. Precise roles for these structural proteins in most processes often remain elusive. Identification of small molecules that inhibit septins could aid in elucidating the functions of septins and has become increasingly important, including the description of roles for septins in pathogenic phenomena such as tumorigenesis. The plant growth regulator forchlorfenuron, a synthetic cytokinin known to inhibit septin dynamics, likely represents an informative probe for septin function. This report deals with septins of the human blood fluke Schistosoma mansoni and their interactions with forchlorfenuron. Recombinant forms of three schistosome septins, SmSEPT5, SmSEPT7.2 and SmSEPT10, interacted with forchlorfenuron, leading to rapid polymerization of filaments. Culturing developmental stages (miracidia, cercariae, adult males) of schistosomes in FCF at 50-500 μM rapidly led to paralysis, which was reversible upon removal of the cytokinin. The reversible paralysis was concentration-, time- and developmental stage-dependent. Effects of forchlorfenuron on the cultured schistosomes were monitored by video and/or by an xCELLigence-based assay of motility, which quantified the effect of forchlorfenuron on fluke motility. The findings implicated a mechanism targeting a molecular system controlling movement in these developmental stages: a direct effect on muscle contraction due to septin stabilization might be responsible for the reversible paralysis, since enrichment of septins has been described within the muscles of schistosomes. This study revealed the reversible effect of forchlorfenuron on both schistosome motility and its striking impact in hastening polymerization of septins. These novel findings suggested routes to elucidate roles for septins in this pathogen, and exploitation of derivatives of forchlorfenuron for anti-schistosomal drugs.	What are Septins?	Septins are guanosine-5'-triphosphate-binding proteins involved in wide-ranging cellular processes including cytokinesis, vesicle trafficking, membrane remodelling and scaffolds, and with diverse binding partners
Alpha-synuclein (a-syn) can aggregate and form toxic oligomers and insoluble fibrils which are the main component of Lewy bodies. Intra-neuronal Lewy bodies are a major pathological characteristic of Parkinson's disease (PD). These fibrillar structures can act as seeds and accelerate the aggregation of monomeric a-syn. Indeed, recent studies show that injection of preformed a-syn fibrils (PFF) into the rodent brain can induce aggregation of the endogenous monomeric a-syn resulting in neuronal dysfunction and eventual cell death. We injected 8 μg of murine a-syn PFF, or soluble monomeric a-syn into the right striatum of rats. The animals were monitored behaviourally using the cylinder test, which measures paw asymmetry, and the corridor task that measures lateralized sensorimotor response to sugar treats. In vivo PET imaging was performed after 6, 13 and 22 weeks using [C]DTBZ, a marker of the vesicular monoamine 2 transporter (VMAT2), and after 15 and 22 weeks using [C]UCB-J, a marker of synaptic SV2A protein in nerve terminals. Histology was performed at the three time points using antibodies against dopaminergic markers, aggregated a-syn, and MHCII to evaluate the immune response. While the a-syn PFF injection caused only mild behavioural changes, [C]DTBZ PET showed a significant and progressive decrease of VMAT2 binding in the ipsilateral striatum. This was accompanied by a small progressive decrease in [C]UCB-J binding in the same area. In addition, our histological analysis revealed a gradual spread of misfolded a-syn pathology in areas anatomically connected to striatum that became bilateral with time. The striatal a-syn PFF injection resulted in a progressive unilateral degeneration of dopamine terminals, and an early and sustained presence of MHCII positive ramified microglia in the ipsilateral striatum and substantia nigra. Our study shows that striatal injections of a-syn fibrils induce progressive pathological synaptic dysfunction prior to cell death that can be detected in vivo with PET. We confirm that intrastriatal injection of a-syn PFFs provides a model of progressive a-syn pathology with loss of dopaminergic and synaptic function accompanied by neuroinflammation, as found in human PD.	Please summarize the relationship between a-syn and cell death.	Alpha-synuclein (a-syn) can aggregate and form toxic oligomers and insoluble fibrils which are the main component of Lewy bodies. Intra-neuronal Lewy bodies are a major pathological characteristic of Parkinson's disease (PD). These fibrillar structures can act as seeds and accelerate the aggregation of monomeric a-syn. Indeed, recent studies show that injection of preformed a-syn fibrils (PFF) into the rodent brain can induce aggregation of the endogenous monomeric a-syn resulting in neuronal dysfunction and eventual cell death.
Chronic wasting disease (CWD) is a fatal, emerging disease of cervids associated with transmissible protease-resistant prion proteins. The potential for CWD to cause dramatic declines in deer and elk populations and perceived human health risks associated with consuming CWD-contaminated venison have led wildlife agencies to embark on extensive CWD control programs, typically involving culling to reduce deer populations. We characterized the spatial distribution of CWD in white-tailed deer (Odocoileus virginianus) in Wisconsin to facilitate CWD management. We found that CWD prevalence declined with distance from a central location, was locally correlated at a scale of 3.6 km, and was correlated with deer habitat abundance. The latter result is consistent with patterns expected for a positive relationship between density and prevalence of CWD. We recommend management activities focused on culling in geographic areas with high prevalence to have the greatest probability of removing infected individuals. Further research is needed to elucidate the factors involved in CWD spread and infection rates, especially the role of density-dependent transmission.	What is Chronic Wasting Disease (CWD) in deer?	Chronic wasting disease (CWD) is a fatal, emerging disease of cervids associated with transmissible protease-resistant prion proteins.
The sarcoplasmic reticulum calcium pump (SERCA) and its regulator, phospholamban, are essential components of cardiac contractility. Phospholamban modulates contractility by inhibiting SERCA, and this process is dynamically regulated by β-adrenergic stimulation and phosphorylation of phospholamban. Herein we reveal mechanistic insight into how four hereditary mutants of phospholamban, Arg(9) to Cys, Arg(9) to Leu, Arg(9) to His, and Arg(14) deletion, alter regulation of SERCA. Deletion of Arg(14) disrupts the protein kinase A recognition motif, which abrogates phospholamban phosphorylation and results in constitutive SERCA inhibition. Mutation of Arg(9) causes more complex changes in function, where hydrophobic substitutions such as cysteine and leucine eliminate both SERCA inhibition and phospholamban phosphorylation, whereas an aromatic substitution such as histidine selectively disrupts phosphorylation. We demonstrate that the role of Arg(9) in phospholamban function is multifaceted: it is important for inhibition of SERCA, it increases the efficiency of phosphorylation, and it is critical for protein kinase A recognition in the context of the phospholamban pentamer. Given the synergistic consequences on contractility, it is not surprising that the mutants cause lethal, hereditary dilated cardiomyopathy.	Which protein kinases have been found to phosphorylate Phospholamban and affect its biological activity?	Deletion of Arg(14) disrupts the protein kinase A recognition motif, which abrogates phospholamban phosphorylation and results in constitutive SERCA inhibition.
AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. We report here that AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress. These findings uncover a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.	Under which conditions does AMPK phosphorylate TSC2?	AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress.
Several neurodegenerative diseases such as transmissible spongiform encephalopathies, Alzheimer's and Parkinson's diseases are caused by the conversion of cellular proteins to a pathogenic conformer. Despite differences in the primary structure and subcellular localization of these proteins, which include the prion protein, α-synuclein and amyloid precursor protein (APP), striking similarity has been observed in their ability to seed and convert naïve protein molecules as well as transfer between cells. This review aims to cover what is known about the intracellular trafficking of these proteins as well as their degradation mechanisms and highlight similarities in their movement through the endocytic pathway that could contribute to the pathogenic conversion and seeding of these proteins which underlies the basis of these diseases.	What are prions?	Several neurodegenerative diseases such as transmissible spongiform encephalopathies, Alzheimer's and Parkinson's diseases are caused by the conversion of cellular proteins to a pathogenic conformer.
To date, there have been a limited number of useful biomarkers for the screening and monitoring of B-cell non-Hodgkin's lymphoma (B-NHL), which leads to the impetus to discover novel biomarkers for the disease. In the present study, gas chromatography-mass spectrometry (GC-MS) combined with head-space solid-phase micro-extraction (HS-SPME) was employed to analyze the volatile metabolites in the urine samples of 131 subjects. The subjects were divided into 4 main groups: Aggressive B-NHL, indolent B-NHL, benign lymphatic diseases patients and healthy volunteers. The differences of the concentrations of the potential biomarkers among the groups were assessed by non-parametric Wilcoxon's test. The ability of the potential biomarkers to discriminate between the four aforementioned groups was evaluated by receiver operating characteristic curves (ROC). The present study indicated that 4-heptanone, 2-methylpyrazine, 2-methylbutanal, 2,6-dimethyl-7-octen-2-ol and decanoic acid may serve as potential biomarkers for B-NHL. The area under the curve (AUC) values of single potential biomarker ranged from 0.634 to 0.901. The diagnostic models established with combined biomarkers exhibited higher diagnostic values (AUC, 0.824-0.968) compared with the models established with single biomarkers. The present study indicated that urinary volatile metabolites might be potential biomarkers for screening and monitoring of B-NHL.	List blood marker for Non-Hodgkin lymphoma.	To date, there have been a limited number of useful biomarkers for the screening and monitoring of B-cell non-Hodgkin's lymphoma (B-NHL), which leads to the impetus to discover novel biomarkers for the disease.
Factor V Leiden is a well-recognized etiology of venous thrombosis, but reports of stroke in patients with this mutation are few. Marijuana smoking has rarely been associated with thrombosis of cerebral and renal arteries and may be due to a direct toxic effect on the endothelium. Reported here is the case of a previously healthy young man who smoked marijuana on a daily basis and had an occipital lobe stroke; he was found to be heterozygous for factor V Leiden. This case suggests that marijuana smoking may increase the risk of arterial thrombosis in otherwise healthy individuals who are heterozygous for factor V Leiden.	Is marijuana use associated with increased risk for stroke?	Reported here is the case of a previously healthy young man who smoked marijuana on a daily basis and had an occipital lobe stroke; he was found to be heterozygous for factor V Leiden.
Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.	Which molecule is targeted by the drug Gevokizumab?	Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies
Angiogenesis is regulated by the highly coordinated function of various proteins with pro- and antiangiogenic functions. Proangiogenic factors include vascular endothelial growth factor (VEGF), fibroblast growth factor, platelet-derived growth factor, insulin-like growth factor, transforming growth factor, angiopoietins, and several chemokines; antiangiogenic factors include thrombospondin-1, angiostatin, and endostatin. Matrix metalloproteinases display a dual role in vascular development. Notch signaling affects remodeling of the primary vascular network of uniformly sized vessels into functionally and morphologically distinct arteries, veins, and capillaries. Tumors, described as 'wounds that never heal', lose the appropriate balance among these factors. Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we highlight recent advances in our understanding of the regulation of tumor angiogenesis and discuss the potential of molecular targeting as a new therapeutic approach.	Is endostatin a proangiogenic factor?	antiangiogenic factors include thrombospondin-1, angiostatin, and endostatin
This study evaluated the correlation and agreement between the Bispectral Index (BIS) or A-line Autoregressive Index (AAI) and a clinical scoring system, the Ramsay Sedation Scale (RSS), in 40 patients after elective cardiac surgery and admission to the intensive care unit. All patients received sedation with propofol according to the study protocol. BIS, AAI and RSS were documented at two different levels of sedation: deep sedation RSS 4 - 6; and slight sedation/extubation RSS 2 - 3. Both the BIS and AAI agreed well with the RSS (eta-coefficients of 0.902 and 0.836, respectively, for mean overall RSS stages). The systems agreed well among each other (overall intra-class correlations of 0.670 for consistency and 0.676 for absolute agreement). There was significant discrimination between RSS 2 - 3 and RSS 4 - 6 with BIS and AAI (BIS mean difference of 24.73, 95% confidence intervals [CI] 21.08 - 28.37; AAI mean difference of 20.90, 95% CI 14.64 - 27.16). In conclusion, BIS and AAI correlated well with RSS overall and also at different levels of sedation.	Is Propofol used for short-term sedation?	All patients received sedation with propofol according to the study protocol.
Scoring functions are a critically important component of computer-aided screening methods for the identification of lead compounds during early stages of drug discovery. Here, we present a new multigrid implementation of the footprint similarity (FPS) scoring function that was recently developed in our laboratory which has proven useful for identification of compounds which bind to a protein on a per-residue basis in a way that resembles a known reference. The grid-based FPS method is much faster than its Cartesian-space counterpart, which makes it computationally tractable for on-the-fly docking, virtual screening, or de novo design. In this work, we establish that: (i) relatively few grids can be used to accurately approximate Cartesian space footprint similarity, (ii) the method yields improved success over the standard DOCK energy function for pose identification across a large test set of experimental co-crystal structures, for crossdocking, and for database enrichment, and (iii) grid-based FPS scoring can be used to tailor construction of new molecules to have specific properties, as demonstrated in a series of test cases targeting the viral protein HIVgp41. The method is available in the program DOCK6.	List programs suitable for protein docking	the method yields improved success over the standard DOCK energy function for pose identification across a large test set of experimental co-crystal structures, for crossdocking, and for database enrichment
The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV+ CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.	Is there any role of Dlx1 and Dlx2 transcription factors in cortical interneurons?	Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input.
Unlike the Peyer's patches of rats and mice, which are considered to be secondary lymphoid organs, the ileal Peyer's patch of sheep is thought to be responsible for the primary generation of B cells, like the bursa of Fabricius of birds. The ileal Peyer's patch of sheep shows prenatal maturation, antigen-independent lymphopoiesis, a rate of lymphocyte production larger than that of the thymus, and involution at a young age. Follicles contain few T cells and have an IgM+, relatively immature B lymphocyte population, as judged by B-cell differentiation markers. The follicle-associated epithelium of the ileal Peyer's patch is of a special type that sheds carbonic anhydrase-rich, 50-nanometer membrane-bounded particles (carbonic anhydrase-reactive particles; CAP) into the intercellular spaces. The CAP filter into the follicle centre and are taken up by lymphocytes. They represent the epithelial (bursa-like) element in an otherwise mesenchymal stroma of reticular cells embedding the follicle lymphocytes. Transepithelial transport of macromolecules, with the formation of multivesicular body-like cytoplasmic vacuoles, appears to be the basis for CAP formation. The jejunal Peyer's patches are devoid of CAP, persist in the adult animal, contain M cells with clusters of B cells in the follicle-associated epithelium, and have many CD4+ lymphocytes in the follicles and in the interfollicular areas. Aggregates of lymphoid follicles in the large intestine resemble the jejunal Peyer's patches with respect to their lymphocyte population and the ileal Peyer's patch with respect to their follicle-associated epithelium.	Where is the body would the Peyer's patches be found	The jejunal Peyer's patches are devoid of CAP, persist in the adult animal, contain M cells with clusters of B cells in the follicle-associated epithelium, and have many CD4+ lymphocytes in the follicles and in the interfollicular areas.