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Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder; however, it remains underdiagnosed and undertreated. Although screening tools such as the Berlin questionnaire (BQ), STOP-BANG questionnaire (SBQ), STOP questionnaire (STOP), and Epworth sleepiness scale (ESS) are widely used for OSA, the findings regarding their diagnostic accuracy are controversial. Therefore, this meta-analysis investigated and compared the summary sensitivity, specificity, and diagnostic odds ratio (DOR) among the BQ, SBQ, STOP, and ESS according to the severity of OSA. Electronic databases, namely the Embase, PubMed, PsycINFO, ProQuest dissertations and theses A&I databases, and China knowledge resource integrated database, were searched from their inception to July 15, 2016. We included studies examining the sensitivity and specificity of the BQ, SBQ, STOP, and ESS against the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The revised quality assessment of diagnostic accuracy studies was used to evaluate the methodological quality of studies. A random-effects bivariate model was used to estimate the summary sensitivity, specificity, and DOR of the tools. We identified 108 studies including a total of 47 989 participants. The summary estimates were calculated for the BQ, SBQ, STOP, and ESS in detecting mild (AHI/RDI ≥ 5 events/h), moderate (AHI/RDI ≥ 15 events/h), and severe OSA (AHI/RDI ≥ 30 events/h). The performance levels of the BQ, SBQ, STOP, and ESS in detecting OSA of various severity levels are outlined as follows: for mild OSA, the pooled sensitivity levels were 76%, 88%, 87%, and 54%; pooled specificity levels were 59%, 42%, 42%, and 65%; and pooled DORs were 4.30, 5.13, 4.85, and 2.18, respectively. For moderate OSA, the pooled sensitivity levels were 77%, 90%, 89%, and 47%; pooled specificity levels were 44%, 36%, 32%, and 621%; and pooled DORs were 2.68, 5.05, 3.71, and 1.45, respectively. For severe OSA, the pooled sensitivity levels were 84%, 93%, 90%, and 58%; pooled specificity levels were 38%, 35%, 28%, and 60%; and pooled DORs were 3.10, 6.51, 3.37, and 2.10, respectively. Therefore, for mild, moderate, and severe OSA, the pooled sensitivity and DOR of the SBQ were significantly higher than those of other screening tools (P < .05); however, the specificity of the SBQ was lower than that of the ESS (P < .05). Moreover, age, sex, body mass index, study sample size, study populations, presence of comorbidities, PSG or portable monitoring performance, and risk of bias in the domains of the index test and reference standard were significant moderators of sensitivity and specificity (P < .05). Compared with the BQ, STOP, and ESS, the SBQ is a more accurate tool for detecting mild, moderate, and severe OSA. Sleep specialists should use the SBQ to conduct patient interviews for the early diagnosis of OSA in clinical settings, particularly in resource-poor countries and sleep clinics where PSG is unavailable.	Which disease risk can be estimated with the Stop-Bang questionnaire?	Although screening tools such as the Berlin questionnaire (BQ), STOP-BANG questionnaire (SBQ), STOP questionnaire (STOP), and Epworth sleepiness scale (ESS) are widely used for OSA, the findings regarding their diagnostic accuracy are controversial.
Macrophages are one of the principal host cell populations in solid tumors. They are capable, due to their plasticity, of acquiring phenotypes that either combat (M1 type) or promote (M2 type) neoplastic growth. These cells, known as tumor-associated macrophages (TAMs), play complex but pivotal roles in the outcome of photodynamic therapy (PDT) of malignant lesions. Among the various parenchymal and stromal cell populations found in tumors, TAMs have been shown to have the greatest capacity for the uptake of systemically administered photosensitizers. Both the tumor-localizing property of photosensitizers and their tumor-localized fluorescence could be partly attributed to the activity of TAMs. Since resident TAMs with accumulated high photosensitizer content will sustain high degrees of PDT damage, this population (predominantly M2 in most tumors) is selectively destroyed, and during the ensuing inflammatory reaction is replaced with newly invading macrophages of M1 phenotype. These macrophages are sentinels responding to DAMP signals from PDT-treated tumor cells and in turn are mobilized to generate a variety of inflammatory/immune mediators and opsonins. They have a critical role in contributing to the therapeutic effect of PDT by mediating disposal of killed cancer cells and by processing/presenting tumor antigens to T lymphocytes. However, TAMs accumulating in the later post-PDT phase can acquire the M2 (healing) phenotype, and could have a role in tumor recurrence by releasing factors that promote angiogenesis and the survival/proliferation of remaining cancer cells. Various therapeutic strategies modulating TAM activity in the PDT response have potential for clinical use for improving PDT-mediated tumor control.	What are TAMs in cancer therapy?	These cells, known as tumor-associated macrophages (TAMs), play complex but pivotal roles in the outcome of photodynamic therapy (PDT) of malignant lesions.
A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene was recently identified as an important cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Caucasian populations. The role of the C9ORF72 repeat expansion in ALS in Chinese populations has received little attention. We therefore performed mutation analyses in a Taiwanese cohort of 22 unrelated familial ALS (FALS) patients and 102 sporadic ALS patients of Han Chinese descent. The C9ORF72 mutation was found in 4 FALS (18.2%; 4/22) and 2 sporadic ALS patients (2.0%; 2/102). The C9ORF72 repeat numbers in the 300 healthy controls and the 118 ALS patients without the C9ORF72 mutation ranged from 3 to 15. Needle biopsy in the left frontal cortex of 1 patient with FALS-frontotemporal dementia revealed numerous cytoplasmic TAR DNA-binding protein 43 (TDP-43) inclusions and minimal neuritis, consistent with type B frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) pathology. This study clearly demonstrates the existence and importance of the C9ORF72 hexanucleotide repeat expansion in a Taiwanese ALS cohort of Chinese origin, and supports the global presence of the C9ORF72 repeat expansion in ALS.	Are mutations in the C9orf72 gene associated with macular degeneration?	GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene was recently identified as an important cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Caucasian populations.
Hashimoto's thyroiditis is a common chronic autoimmune disease characterized by the loss of thyroid follicular cells (thyrocytes) that are gradually replaced by lymphocytic infiltration and diffuse fibrosis. These morphological findings suggested that autoreactive T-cell clones were responsible for thyrocyte destruction and hypothyroidism through effector-target cytotoxic recognition. Later, autonomous interaction between thyrocyte Fas and FasL has been proposed as a major mechanism of thyrocyte depletion in Hashimoto's thyroiditis. Here, we analyze the possible role of Fas and FasL in the pathogenesis of Hashimoto's thyroiditis. We suggest that the Fas-FasL system dictates the outcome of the autoimmune response by acting on both immune and target cells.	How thyrocyte destruction is induced in autoimmune thyroiditis?	Here, we analyze the possible role of Fas and FasL in the pathogenesis of Hashimoto's thyroiditis. We suggest that the Fas-FasL system dictates the outcome of the autoimmune response by acting on both immune and target cells
Homozygous carriers of factor V Leiden have an approximately 80-fold increased risk of venous thrombosis. Also double heterozygous carriers of both the factor V Leiden and the prothrombin gene mutations are at high thrombotic risk. The magnitude of the risk of venous thrombosis in pregnant women with the two severe thrombophilic conditions has not been estimated so far. We performed a multicenter retrospective family study in women with homozygous factor V Leiden, double heterozygous factor V Leiden and the prothrombin gene mutation, and women with normal coagulation. Only relatives of index patients with thrombosis formed the study cohort. Fifteen homozygous and 39 double heterozygous women were compared to 182 women with normal coagulation. Venous thrombosis occurred in 3 of 19, 2 of 50 and 1 of 221 pregnancies, respectively. One thrombotic episode occurred in the third trimester, the remaining 5 in the postpartum. The prevalence of venous thrombosis was 15.8% (95% CI 3.4-39.6) for homozygotes. 4.0% (95% CI 0.5-13.7) for double heterozygotes and 0.5% for women with normal coagulation. The relative risk of pregnancy-related venous thrombosis was 41.3 (95% CI 4.1-419.7) for homozygous and 9.2 (95% CI 0.8-103.2) for double heterozygous carriers. In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period. On the basis of these findings we recommend that these women receive anticoagulant prophylaxis at least in the postpartum, that should perhaps be extended to the whole pregnancy in homozygous carriers.	Is thrombophilia related to increased risk of miscarriage?	In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period
Hutchinson-Gilford progeria syndrome is a rare genetic disorder, characterized by progressive premature aging and early death in the first or second decade of life, usually secondary to cardiovascular events (myocardial infarction and stroke). We report a case of a 14-year-old boy with progeria syndrome and cardiac arrest due to myocardial infarction, who was submitted to an immediate coronary angiography which revealed left main stem and three-vessel coronary artery disease. A prompt double bypass coronary artery grafting surgery was performed, and, despite successful coronary reperfusion, the patient remained in coma and brain death was declared on fourth day after surgery.	What is Progeria?	Hutchinson-Gilford progeria syndrome is a rare genetic disorder, characterized by progressive premature aging and early death in the first or second decade of life, usually secondary to cardiovascular events (myocardial infarction and stroke).
In about 30% of the patients with syndromal craniosynostosis, a genetic mutation can be traced. For the purpose of adequate genetic counseling and treatment of these patients, the full spectrum of clinical findings for each specific mutation needs to be appreciated. The Pro250Arg mutation in the FGFR3 gene is found in patients with Muenke syndrome and is one of the most frequently encountered mutations in craniosynostosis syndromes. A number of studies on the relationship between genotype and phenotype concerning this specific mutation have been published. Two Dutch families with Muenke syndrome were screened for the reported characteristics of this syndrome and for additional features. New phenotypical findings were hypoplasia of the frontal sinus, ptosis of the upper eyelids, dysplastic elbow joints with restricted elbow motion, and mild cutaneous syndactyly. Incidentally, polydactyly, severe ankylosis of the elbow, fusion of cervical vertebrae, and epilepsy were found. Upper eyelid ptosis is thought to be pathognomonic for Saethre-Chotzen syndrome but was also observed in our series of patients with Muenke syndrome. Because Muenke and Saethre-Chotzen syndrome can have similar phenotypes, DNA analysis is needed to distinguish between these syndromes, even when a syndrome diagnosis is already made in a family member.	Is there an association between Muenke Syndrome and FGFR3 gene mutation?	The Pro250Arg mutation in the FGFR3 gene is found in patients with Muenke syndrome and is one of the most frequently encountered mutations in craniosynostosis syndromes
Protein kinase casein kinase 1 (CK1) phosphorylates Ser-45 of beta-catenin, "priming" the subsequent phosphorylation by glycogen synthase-3 of residues 41, 37, and 33. This concerted phosphorylation of beta-catenin signals its degradation and prevents its function in triggering cell division. The sequence around Ser-45 does not conform to the canonical consensus for CK1 substrates, which prescribes either phosphoamino acids or acidic residues in position n-3 from the target serine. However, the beta-catenin sequence downstream from Ser-45 is very similar to a sequence recognized by CK1 in nuclear factor for activated T cells 4. The common features include an SLS motif followed two to five residues downstream by a cluster of acidic residues. Synthetic peptides reproducing residues 38-65 of beta-catenin were assayed with purified rat liver CK1 or recombinant CK1 alpha and CK1 alpha L from zebrafish. The results demonstrate that SLS and acidic cluster motifs are crucial for CK1 recognition. Pro-44 and Pro-52 are also important for efficient phosphorylation. Similar results were obtained with the different isoforms of CK1. Phosphorylation of mutants of full-length recombinant beta-catenin from zebrafish confirmed the importance of the SLS and acidic cluster motifs. A search for proteins with similar motifs yielded, among other proteins, adenomatous polyposis coli, previously found to be phosphorylated by CK1. There is a strong correlation of beta-catenin mutations found in thyroid tumors with the motifs recognized by CK1 in this protein.	List phosphorylation consensus motifs for Casein Kinase 1 (CK1)?	The common features include an SLS motif followed two to five residues downstream by a cluster of acidic residues.
Statins remain the mainstay of medical cardiovascular risk reduction because of their effectiveness in decreasing low-density lipoprotein cholesterol (LDL-C) as well as some other potentially beneficial effects. The latest US 2013 lipid guidelines essentially recommend only the prescription of a high-dose statin for the high-risk patient. However, both quite old and quite new outcomes evidence, such as reported for ezetimibe, emphasize that LDL-C lowering is, in and of itself, quite important for cardiovascular risk reduction. It appears that the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a major new contribution to this effort, especially for patients with severe familial hypercholesterolemia, proven clinical cardiovascular disease, statin intolerance, or failure to attain an acceptably low LDL-C goal despite maximum available medical management. Very recent clinical trials have proven overwhelmingly the effectiveness and safety of PCSK9 inhibitors for lowering LDL-C. Both alirocumab and evolocumab have now been approved by the US FDA and there are some initial favorable outcomes data. This review is intended to summarize available evidence and emphasize the possible clinical role of these inhibitors following the approval of alirocumab and evolocumab. Understanding the negative receptor feedback of PCSK9 and the mechanism and beneficial effect of PCSK9 inhibitors for cardiovascular risk reduction is essential for the up-to-date practitioner of cardiovascular medicine. There is every reasonable hope for significant cardiovascular benefit from these new additions to our medical cardiovascular armamentarium.	Which are the Proprotein Convertase Subtilisin Kexin 9 (PCSK9) inhibitors that are FDA approved?	Very recent clinical trials have proven overwhelmingly the effectiveness and safety of PCSK9 inhibitors for lowering LDL-C. Both alirocumab and evolocumab have now been approved by the US FDA and there are some initial favorable outcomes data.
Cardiac contractility is regulated through the activity of various key Ca(2+)-handling proteins. The sarco(endo)plasmic reticulum (SR) Ca(2+) transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of Ca(2+) by SR membranes during relaxation. Recently, the antiapoptotic HS-1-associated protein X-1 (HAX-1) was identified as a binding partner of PLN, and this interaction was postulated to regulate cell apoptosis. In the current study, we determined that HAX-1 can also bind to SERCA2. Deletion mapping analysis demonstrated that amino acid residues 575-594 of SERCA2's nucleotide binding domain are required for its interaction with the C-terminal domain of HAX-1, containing amino acids 203-245. In transiently cotransfected human embryonic kidney 293 cells, recombinant SERCA2 was specifically targeted to the ER, whereas HAX-1 selectively concentrated at mitochondria. On triple transfections with PLN, however, HAX-1 massively translocated to the ER membranes, where it codistributed with PLN and SERCA2. Overexpression of SERCA2 abrogated the protective effects of HAX-1 on cell survival, after hypoxia/reoxygenation or thapsigargin treatment. Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels. These findings suggest that HAX-1 may promote cell survival through modulation of SERCA2 protein levels and thus ER Ca(2+) stores.	Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?	The sarco(endo)plasmic reticulum (SR) Ca(2+) transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of Ca(2+) by SR membranes during relaxation.
Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23-82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC), and maximum observed plasma concentration (C) increased on days 1 and 15 with increasing pexidartinib doses, and time at C (T) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).	What is targeted by Pexidartinib?	Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This
Iron deprivation of Saccharomyces cerevisiae induces transcription of genes required for high-affinity iron uptake. AFT1 mediates this transcriptional control. In this report, the 5'-flanking region of FET3, which encodes a copper-dependent oxidase required for iron transport, was analyzed and found to contain a DNA sequence responsible for AFT1-regulated gene expression. AFT1 was capable of interacting specifically with this DNA sequence. A core element within this DNA sequence necessary for the binding of AFT1 was also determined. In vivo footprinting demonstrated occupancy of the AFT1 binding site in cells deprived of iron and not in cells grown in the presence of iron. Thus, the environmental signal resulting from iron deprivation was transduced through the regulated binding of AFT1 to the FET3 promoter, followed by the activation of transcription. A regulon of genes under the control of AFT1 could be defined. AFT1 was able to bind to a consensus binding site (PyPuCACCCPu) in the 5' region of FRE1, FRE2, FTR1, FTH1 and CCC2.	What is the function of the yeast protein Aft1?	Iron deprivation of Saccharomyces cerevisiae induces transcription of genes required for high-affinity iron uptake. AFT1 mediates this transcriptional control.
Mammalian X-chromosome inactivation is thought to be controlled by the X inactivation centre (XIC, X-controlling element -Xce-in mice). A human gene, XIST and its mouse counterpart, Xist, which map to the XIC/Xce, are expressed exclusively from inactive X chromosomes, suggesting their involvement in the process of X-inactivation. We now report the presence of Xist/XIST transcripts in newborn and adult mouse testes, and in human testicular tissue with normal spermatogenesis, but not in the testes of patients who lack germ cells. Our results indicate that while the X chromosome in males is active in somatic cells, it undergoes inactivation during spermatogenesis.	In which tissues is the lincRNA Xist expressed?	We now report the presence of Xist/XIST transcripts in newborn and adult mouse testes, and in human testicular tissue with normal spermatogenesis, but not in the testes of patients who lack germ cells.
The class I histone deacetylase (HDAC) enzymes;HDAC1,2 and 3 form the catalytic engine of at least seven structurally distinct multiprotein complexes in cells. These molecular machines play a vital role in the regulation of chromatin accessibility and gene activity via the removal of acetyl moieties from lysine residues within histone tails. Their inhibition via small molecule inhibitors has beneficial effects in a number of disease types, including the clinical treatment of hematological cancers. We have previously reported a library of proteolysis targeting chimeras (PROTACs) incorporating a benzamide-based HDAC ligand (from CI-994), with an alkyl linker and ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase that degrade HDAC1-3 at submicromolar concentrations. Here we report the addition of two novel PROTACs (JPS026 and JPS027), which utilize a ligand for the cellular inhibitor of apoptosis (IAP) family of E3 ligases. We found that both VHL (JPS004)- and IAP (JPS026)-based PROTACs degrade HDAC1-3 and induce histone acetylation to a similar degree. However, JPS026 is significantly more potent at inducing cell death in HCT116 cells than is JPS004. RNA sequencing analysis of PROTAC-treated HCT116 cells showed a distinct gene expression signature in which cell cycle and DNA replication machinery are repressed. Components of the mTORC1 and -2 complexes were also reduced, leading to an increase in FOXO3 and downstream target genes that regulate autophagy and apoptosis. In summary, a novel combination of HDAC and IAP ligands generates a PROTAC with a potent ability to stimulate apoptosis and differential gene expression in human cancer cells.	What is a PROTAC?	We have previously reported a library of proteolysis targeting chimeras (PROTACs) incorporating a benzamide-based HDAC ligand (from CI-994), with an alkyl linker and ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase that degrade HDAC1-3 at submicromolar concentrations.
Titin, the largest protein in the human body, is well known as a molecular spring in muscle cells and scaffold protein aiding myofibrillar assembly. However, recent evidence has established another important role for titin: that of a regulatory node integrating, and perhaps coordinating, diverse signaling pathways, particularly in cardiomyocytes. We review key findings within this emerging field, including those related to phosphorylation of the titin springs, and also discuss how titin participates in hypertrophic gene regulation and protein quality control.	Is Titin the largest single protein molecule found in Nature?	Titin, the largest protein in the human body, is well known as a molecular spring in muscle cells and scaffold protein aiding myofibrillar assembly.
von Hippel-Lindau (VHL) disease is an inherited multisystem familial cancer syndrome caused by mutations of the VHL gene on chromosome 3p25. A wide variety of neoplastic processes are known to be associated with VHL disease. The consequences of the VHL mutations and the pathway for tumor development continue to be elucidated. This paper will detail the variety of tumors associated with VHL disease and discuss the genetic mechanisms that lead to the predisposition for neoplasia.	What is known as Von Hippel–Lindau disease or syndrome?	von Hippel-Lindau (VHL) disease is an inherited multisystem familial cancer syndrome caused by mutations of the VHL gene on chromosome 3p25. A wide variety of neoplastic processes are known to be associated with VHL disease.
Loss-of-function alterations of INK4A are commonly observed in lymphoid malignancies, but are consistently absent in pre-B cell leukemias induced by the chimeric oncoprotein E2a-Pbx1 created by t(1;19) chromosomal translocations. We report here that experimental induction of E2a-Pbx1 enhances expression of BMI-1, a lymphoid oncogene whose product functions as a transcriptional repressor of the INK4A-ARF tumor suppressor locus. Bmi-1-deficient hematopoietic progenitors are resistant to transformation by E2a-Pbx1; however, the requirement for Bmi-1 is alleviated in cells deficient for both Bmi-1 and INK4A-ARF. Furthermore, the adverse effects of E2a-Pbx1 on pre-B cell survival and differentiation are partially bypassed by forced expression of p16(Ink4a). These results link E2a-Pbx1 with Bmi-1 on an oncogenic pathway that is likely to play a role in the pathogenesis of human lymphoid leukemias through downregulation of the INK4A-ARF gene.	Which cyclin- dependent kinase inhibitor is regulated by Bmi-1?	expression of BMI-1, a lymphoid oncogene whose product functions as a transcriptional repressor of the INK4A-ARF tumor suppressor locu
The COP9 signalosome (CSN) is a multiprotein complex that was initially identified in plants as a repressor of photomorphogenesis. It is now known to play major roles in several other developmental pathways, from auxin response to flower development. Furthermore, the COP9 signalosome shares homologies with the lid sibcomplex of the proteasome and is evolutionarily conserved from fission yeast to humans. It is important for the proper development of virtually all higher eukaryotes. In recent years, significant progress has been made in unraveling the molecular, cellular, and physiological mode of action of the COP9 signalosome. This review discusses our current understanding of the COP9 signalosome function with particular emphasis on its recently defined role in modulating a wide variety of cellular processes by regulating specific protein degradation events.	What is the role of the constitutive photomorphogenesis 9 signalosome (CSN)?	The COP9 signalosome (CSN) is a multiprotein complex that was initially identified in plants as a repressor of photomorphogenesis.
Polycistronic mRNAs transcribed from operons are resolved via the trans-splicing of a spliced-leader (SL) RNA. Trans-splicing also occurs at monocistronic transcripts. The phlyogenetically sporadic appearance of trans-splicing and operons has made the driving force(s) for their evolution in metazoans unclear. Previous work has proposed that germline expression drives operon organization in Caenorhabditis elegans, and a recent hypothesis proposes that operons provide an evolutionary advantage via the conservation of transcriptional machinery during recovery from growth arrested states. Using a modified cap analysis of gene expression protocol we mapped sites of SL trans-splicing genome-wide in the marine chordate Oikopleura dioica. Tiled microarrays revealed the expression dynamics of trans-spliced genes across development and during recovery from growth arrest. Operons did not facilitate recovery from growth arrest in O. dioica. Instead, we found that trans-spliced transcripts were predominantly maternal. We then analyzed data from C. elegans and Ciona intestinalis and found that an enrichment of trans-splicing and operon gene expression in maternal mRNA is shared between all three species, suggesting that this may be a driving force for operon evolution in metazoans. Furthermore, we found that the majority of known terminal oligopyrimidine (TOP) mRNAs are trans-spliced in O. dioica and that the SL contains a TOP-like motif. This suggests that the SL in O. dioica confers nutrient-dependent translational control to trans-spliced mRNAs via the TOR-signaling pathway. We hypothesize that SL-trans-splicing provides an evolutionary advantage in species that depend on translational control for regulating early embryogenesis, growth and oocyte production in response to nutrient levels.	What is the reason for the abundance of operons in the genome of C. elegans?	Previous work has proposed that germline expression drives operon organization in Caenorhabditis elegans, and a recent hypothesis proposes that operons provide an evolutionary advantage via the conservation of transcriptional machinery during recovery from growth arrested states.
Multiple myeloma (MM) remains incurable despite important recent advances in treatment due to its inherent resistance, characterized by highly complex and heterogeneous molecular abnormalities, as well as the support from myeloma bone marrow (BM) microenvironment. A novel therapeutic strategy that effectively targets specific molecules on myeloma cells and also potentially overcomes tumor microenvironment-mediated drug resistance and the downstream effects of genetic instability is thus urgently needed. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. DARA may, therefore, be the first mAb with significant anti-MM activity both as a monotherapy and in combination. It is currently being further evaluated both alone and in combination with conventional and novel anti-MM agents as part of prospective clinical trials. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.	Which molecule is targeted by Daratumumab?	Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM
The genome projects have unearthed an enormous diversity of genes of unknown function that are still awaiting biological and biochemical characterization. These genes, as most others, can be grouped into families based on sequence similarity. The PFAM database currently contains over 2,200 such families, referred to as domains of unknown function (DUF). In a coordinated effort, the four large-scale centers of the NIH Protein Structure Initiative have determined the first three-dimensional structures for more than 250 of these DUF families. Analysis of the first 248 reveals that about two thirds of the DUF families likely represent very divergent branches of already known and well-characterized families, which allows hypotheses to be formulated about their biological function. The remainder can be formally categorized as new folds, although about one third of these show significant substructure similarity to previously characterized folds. These results infer that, despite the enormous increase in the number and the diversity of new genes being uncovered, the fold space of the proteins they encode is gradually becoming saturated. The previously unexplored sectors of the protein universe appear to be primarily shaped by extreme diversification of known protein families, which then enables organisms to evolve new functions and adapt to particular niches and habitats. Notwithstanding, these DUF families still constitute the richest source for discovery of the remaining protein folds and topologies.	How can DUF families be deciphered?	In a coordinated effort, the four large-scale centers of the NIH Protein Structure Initiative have determined the first three-dimensional structures for more than 250 of these DUF families.
This first meta-analysis of all RCTs for the pharmacological treatment of RLS provides evidence that, besides the well-defined efficacy of dopaminergic treatment, other treatments with different pharmacological principles show efficacy in small samples and may be well-tolerated alternatives for the treatment of RLS. In the group of anticonvulsants, only the trials performed with α₂δ ligands such as gabapentin, gabapentin enacarbil, and pregabalin showed good efficacy. This indicates a specific mechanism of action of these substances in RLS. The group of iron treatments consisted of a few trials with different compounds in oral and intravenous application form, respectively. For a more differentiated evaluation of the efficacy of iron treatments further studies are necessary. The large efficacy of one opioid RCT in RLS has to be confirmed in further studies.	Is pregabalin effective for treatment of patients with restless leg syndrome?	In the group of anticonvulsants, only the trials performed with α₂δ ligands such as gabapentin, gabapentin enacarbil, and pregabalin showed good efficacy.
In mesophilic prokaryotes, the DNA-binding protein HU participates in nucleoid organization as well as in regulation of DNA-dependent processes. Little is known about nucleoid organization in thermophilic eubacteria. We show here that HU from the hyperthermophilic eubacterium Thermotoga maritima HU bends DNA and constrains negative DNA supercoils in the presence of topoisomerase I. However, while binding to a single site occludes approximately 35 bp, association of T. maritima HU with DNA of sufficient length to accommodate multiple protomers results in an apparent shorter occluded site size. Such complexes consist of ordered arrays of protomers, as revealed by the periodicity of DNase I cleavage. Association of TmHU with plasmid DNA yields a complex that is remarkably resistant to DNase I-mediated degradation. TmHU is the only member of this protein family capable of occluding a 35 bp nonspecific site in duplex DNA; we propose that this property allows TmHU to form exceedingly stable associations in which DNA flanking the kinks is sandwiched between adjacent proteins. We suggest that T. maritima HU serves an architectural function when associating with a single 35 bp site, but generates a very stable and compact aggregate at higher protein concentrations that organizes and protects the genomic DNA.	Which proteins act as histone-like molecules in prokaryotes?	We suggest that T. maritima HU serves an architectural function when associating with a single 35 bp site, but generates a very stable and compact aggregate at higher protein concentrations that organizes and protects the genomic DNA
Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene have been associated with different clinical phenotypes including Silver syndrome/spastic paraplegia 17, distal hereditary motor neuropathy type V, and Charcot-Marie-Tooth disease type 2 (CMT2) with predominant hand involvement. We studied an Italian family with a CMT2 phenotype with pyramidal signs that had subclinical sensory involvement on sural nerve biopsy. Direct sequencing analysis of the BSCL2 gene in the three affected siblings revealed an S90L mutation. This report confirms the variability of clinical phenotypes associated with a BSCL2 Ser90Leu mutation and describes the first Italian family with this mutation.	Which phenotypes are associated with heterozygous mutations of the BSCL2 gene?	Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene have been associated with different clinical phenotypes including Silver syndrome/spastic paraplegia 17,
The transcriptional coactivators CBP and P/CAF are required for activation of transcription from the IFN beta enhanceosome. We show that CBP and P/CAF acetylate HMG I(Y), the essential architectural component required for enhanceosome assembly, at distinct lysine residues, causing distinct effects on transcription. Thus, in the context of the enhanceosome, acetylation of HMG I by CBP, but not by P/CAF, leads to enhanceosome destabilization and disassembly. We demonstrate that acetylation of HMG I(Y) by CBP is essential for turning off IFN beta gene expression. Finally, we show that the acetyltransferase activities of CBP and P/CAF modulate both the strength of the transcriptional response and the kinetics of virus-dependent activation of the IFN beta gene.	Which transcription factors (TFs) participate in the formation of the interferon-beta (IFN-b) enhanceosome?	The transcriptional coactivators CBP and P/CAF are required for activation of transcription from the IFN beta enhanceosome. We show that CBP and P/CAF acetylate HMG I(Y), the essential architectural component required for enhanceosome assembly, at distinct lysine residues, causing distinct effects on transcription.
Bisphenols are increasingly recognized as environmental pollutants with endocrine-disrupting potential. Nonetheless, the study of environmental occurrence and some endocrine-disrupting activities of some bisphenols came widely into focus of research only recently. The aims of the present study were to: 1) determine the predominant bisphenols in Norwegian sewage sludge and sediment and in Czech surface waters, and 2) characterize the binding of bisphenols to a transport protein transthyretin (TTR) and their (anti-)thyroid, (anti-)progestagenic, and (anti-)androgenic activities. High-performance liquid chromatography with atmospheric pressure chemical ionization or photoionization coupled with high resolution mass spectrometry (HPLC-APCI/APPI-HRMS) and Chemically Activated LUciferase gene eXpression (CALUX) in vitro reporter gene bioassays were used to detect the target compounds and to determine endocrine-disrupting activities, respectively. Bisphenol A (BPA), 4,4'-bisphenol F (BPF), bisphenol S (BPS), and bisphenol E (BPE) were the most frequently found compounds in municipal sewage sludge. Furthermore, bisphenol TMC (BPTMC) and bisphenol AF (BPAF) frequently occurred in sediment and surface waters, respectively. BPA was the major contributor to Ʃ of bisphenols in Norwegian sewage sludge with exception of one sample where BPF predominated. We also monitored a few bisphenols in sediment but only BPTMC was found. BPA, BPAF and BPF were the dominant bisphenols in Czech surface waters. Some bisphenols have shown TTR binding potency (BPAF = BPF > BPA = BPE) and some have displayed the following endocrine-disrupting activities: anti-thyroid (BPAF), anti-progestagenic (BPTMC > BPA = BPAF), and anti-androgenic (BPAF > BPE > BPA > BPTMC > BPF > BPS). It is noteworthy that BPAF exhibited stronger or similarly potent endocrine-disrupting activities compared to BPA. Our results provide new insights into these less-studied endocrine-disrupting activities of environmentally relevant bisphenols and may be useful in prioritizing those compounds that deserve further attention in environmental monitoring and eco-toxicological research.	what is the effect of Bisphenol A in the body?	Bisphenols are increasingly recognized as environmental pollutants with endocrine-disrupting potential.
As of October 2020, there is still no specific drug to treat COVID-19 as it rages worldwide. Favipiravir, indicated for the treatment of new and re-emerging influenza infections, has been suggested to be effective against SARS-CoV-2, although this is not yet fully validated. We administered favipiravir to a 64-year-old female patient with COVID-19. Her symptoms resolved quickly after the start of treatment, with reduction of SARS-CoV-2 viral load, but she developed a fever again on day 12. Since the fever was relieved by discontinuation of favipiravir, and based on positive results with a drug-induced lymphocyte stimulation test, we diagnosed her with favipiravir-induced drug fever. A decrease in the serum concentration of favipiravir was observed along with resolution of the fever. The present case suggests that drug fever should be considered in the differential diagnosis of relapsing fever episodes in COVID-19 patients receiving favipiravir.	What is the indication for Favipiravir?	Favipiravir, indicated for the treatment of new and re-emerging influenza infections, has been suggested to be effective against SARS-CoV-2, although this is not yet fully validated.
This study provides detailed information about the diversity of multiple orc/cdc6-associated replication origins in haloarchaeal genomes, and provides novel insight into the evolution of multiple replication origins in Archaea.	Do archaeal genomes contain one or multiple origins of replication?	multiple orc/cdc6-associated replication origins in haloarchaeal genomes
Ctf4 remains a central player in DNA replication. Our findings are consistent with what has been previously reported for CTF4 function in yeast, Xenopus extracts, and human tissue culture. We show that Ctf4 function is conserved and that Drosophila can be effectively used as a model to further probe the precise function of Ctf4 as a member of the replication fork and possible roles in development.	What is the main role of Ctf4 in dna replication?	Ctf4 remains a central player in DNA replication
Mesenchymal stem cells (MSCs) can differentiate into multiple mesodermal cell types in vitro; however, their differentiation capacity is influenced by their tissue of origin. To what extent epigenetic information on promoters of lineage-specification genes in human progenitors influences transcriptional activation and differentiation potential remains unclear. We produced bisulfite sequencing maps of DNA methylation in adipogenic, myogenic, and endothelial promoters in relation to gene expression and differentiation capacity, and unravel a similarity in DNA methylation profiles between MSCs isolated from human adipose tissue, bone marrow (BM), and muscle. This similarity is irrespective of promoter CpG content. Methylation patterns of MSCs are distinct from those of hematopoietic progenitor cells (HPCs), pluripotent human embryonic stem cells (hESCs), and multipotent hESC-derived mesenchymal cells (MCs). Moreover, in vitro MSC differentiation does not affect lineage-specific promoter methylation states, arguing that these methylation patterns in differentiated cells are already established at the progenitor stage. Further, we find a correlation between lineage-specific promoter hypermethylation and lack of differentiation capacity toward that lineage, but no relationship between weak promoter methylation and capacity of transcriptional activation or differentiation. Thus, only part of the restriction in differentiation capacity of tissue-specific stem cells is programmed by promoter DNA methylation: hypermethylation seems to constitute a barrier to differentiation, however, no or weak methylation has no predictive value for differentiation potential.	Are Mesenchymal stem cells (MSC) multipotent cells?	multipotent hESC-derived mesenchymal cells (MCs)
Towards the development of a systems biology-based risk assessment approach for environmental toxicants, including tobacco products in a systems toxicology setting such as the "21st Century Toxicology", we are building a series of computable biological network models specific to non-diseased pulmonary and cardiovascular cells/tissues which capture the molecular events that can be activated following exposure to environmental toxicants. Here we extend on previous work and report on the construction and evaluation of a mechanistic network model focused on DNA damage response and the four main cellular fates induced by stress: autophagy, apoptosis, necroptosis, and senescence. In total, the network consists of 34 sub-models containing 1052 unique nodes and 1538 unique edges which are supported by 1231 PubMed-referenced literature citations. Causal node-edge relationships are described using the Biological Expression Language (BEL), which allows for the semantic representation of life science relationships in a computable format. The Network is provided in .XGMML format and can be viewed using freely available network visualization software, such as Cytoscape.	What is BEL(Biological Expression Language) used for?	e-edge relationships are described using the Biological Expression Language (BEL), which allows for the semantic representation of life science relationships in a computable format. The Networ
The 70-gene signature (MammaPrint) is a prognostic tool used to guide adjuvant treatment decisions. The aim of this study was to assess its value to predict chemosensitivity in the neoadjuvant setting. We obtained the 70-gene profile of stage II-III patients prior to neoadjuvant chemotherapy and classified the prognosis-signatures. Pathological complete remission (pCR) was used to measure chemosensitivity. Among 167 patients, 144 (86%) were having a poor and 23 (14%) a good prognosis-signature. None of the good prognosis-signature patients achieved a pCR (0/23), whereas 29/144 patients (20%) in the poor prognosis-signature group did (P = 0.015). All triple-negative tumors (n = 38) had a poor prognosis-signature. Within the non triple-negative subgroup, the response of the primary tumor remained associated with the classification of the prognosis-signature (P = 0.023). A pCR is unlikely to be achieved in tumors that have a good prognosis-signature. Tumors with a poor prognosis-signature are more sensitive to chemotherapy.	What is the clinical value of MammaPrint?	The 70-gene signature (MammaPrint) is a prognostic tool used to guide adjuvant treatment decisions
Nowadays nickel is a global problem, related to occupations (mainly metalworkers) and to life habits. The dietary intake, more than environments, is the source of a basic immune identification and also of possible complications after occupational inhalation or contact. Nickel insoluble compounds are proved to be cancerogenic. Nickel ions are very reactive with proteins and oxidant, then also potential irritant for the airways. Metallic nickel and soluble compounds are sensitizers, causing dermatitis, rhinitis and asthma. Recently a Systemic Nickel Allergy Syndrome (SNAS) has been identified in allergic subjects, with a clinical picture of urticaria, general hitching, headache, gastrointestinal troubles. SNAS may affect allergic occupational or non-occupational ones. Studies are in progress aimed to an oral treatment inducing immunotolerance. Nickel in urine seems to be the best tool for monitoring nickel absorption.	What is the systemic nickel allergy syndrome?	Recently a Systemic Nickel Allergy Syndrome (SNAS) has been identified in allergic subjects, with a clinical picture of urticaria, general hitching, headache, gastrointestinal troubles. SNAS may affect allergic occupational or non-occupational ones.
Calcitonin gene-related peptide (CGRP) is pivotal in the pathophysiology of migraine headaches and represents a promising target for migraine treatment. The humanized monoclonal antibody galcanezumab (LY2951742) binds to CGRP and may be effective in migraine prophylaxis. The primary objective was to evaluate the safety and tolerability of single and multiple doses of galcanezumab in humans. Secondary objectives included assessing the pharmacokinetics and evaluating target engagement. A double-blind, randomized, placebo-controlled study (NCT 01337596) with single escalating and multiple subcutaneous (SC) doses of galcanezumab was performed in healthy male volunteers. Single doses of 1, 5, 25, 75, 200, and 600 mg of galcanezumab ( = 7/dose) or placebo ( = 2/dose) were injected SC in six consecutive cohorts of nine subjects each. One cohort of nine subjects received multiple (4) 150 mg doses of galcanezumab or placebo every other week. Target engagement was evaluated by measuring inhibition of capsaicin-induced increase in dermal blood flow (DBF). Sixty-three subjects were randomized and included in the safety analyses. Galcanezumab was well tolerated in single doses (1-600 mg SC) and consecutive doses (150 mg SC). There was no dose-dependent difference in type or frequency of treatment-emergent adverse events, and no clinically meaningful difference when compared with placebo. Pharmacokinetics were linear. Galcanezumab induced a robust, dose-dependent, and durable inhibition of capsaicin-induced increase in DBF, supporting the continued clinical development of galcanezumab for prophylaxis in migraine patients.	What is the target of galcanezumab?	The humanized monoclonal antibody galcanezumab (LY2951742) binds to CGRP and may be effective in migraine prophylaxis.
Dynamic methylations and demethylations of histone lysine residues are important for gene regulation and are facilitated by histone methyltransferases and histone demethylases (HDMs). KDM5B/Jarid1B/PLU1 is an H3K4me3/me2-specific lysine demethylase belonging to the JmjC domain-containing family of histone demethylases (JHDMs). Several studies have linked KDM5B to breast, prostate and skin cancer, highlighting its potential as a drug target. However, most inhibitor studies have focused on other JHDMs, and inhibitors for KDM5B remain to be explored. Here, we report the expression, purification and characterization of the catalytic core of recombinant KDM5B (ccKDM5B, residues 1-769). We show that ccKDM5B, recombinantly expressed in insect cells, demethylates H3K4me3 and H3K4me2 in vitro. The kinetic characterization showed that ccKDM5B has an apparent Michaelis constant (K(m) (app) ) value of 0.5 μm for its trimethylated substrate H3(1-15)K4me3, a considerably increased apparent substrate affinity than reported for related HDMs. Despite the presence of a PHD domain, the catalytic activity was not affected by additional methylation at the H3K9 position, suggesting that in vitro chromatin cross-talk between H3K4 and H3K9 does not occur for ccKDM5B. Inhibition studies of ccKDM5B showed both in vitro and in cell inhibition of ccKDM5B by 2,4-pyridinedicarboxylic acid (2,4-PDCA) with a potency similar to that reported for the HDM KDM4C. Structure-guided sequence alignment indicated that the binding mode of 2,4-PDCA is conserved between KDM4A/C and KDM5B.	Which are the inhibitors of histone methyltransferases?	Inhibition studies of ccKDM5B showed both in vitro and in cell inhibition of ccKDM5B by 2,4-pyridinedicarboxylic acid (2,4-PDCA) with a potency similar to that reported for the HDM KDM4C.
The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored. We conclude by proposing new strategies that are built on current vaccine technologies and improved upon with novel combinatorial approaches.	Which histone mutations have been associated with pediatric gliomas?	Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored.
We have demonstrated that both high-K+ and electrical stimulation of the vagus nerves release endogenous glutamate from the vascularly-perfused rat stomach in a calcium-dependent manner. In the present study, we examined properties of calcium channel subtypes mediating endogenous glutamate release from the stomach. Application of 50 mM KCl elicited a release of glutamate, and this release was abolished in calcium-free medium. The release of glutamate was significantly inhibited by both omega-agatoxin IVA, a P/Q-type calcium channel antagonist, and isradipine, an L type calcium channel antagonist. Omega-conotoxin GVIA, an N type calcium channel antagonist and flunarizine, a nonselective T-type calcium channel antagonist were without effect. In contrast to this case of glutamate, omega-conotoxin GVIA induced a marked inhibition in the release of gastric noradrenaline. The combined treatment with omega-agatoxin IVA plus isradipine produced a marked synergistic inhibition of the glutamate release. This inhibition was, however, much less than that by cadmium. The present results suggest that P/Q and L type calcium channels coexist to regulate the release of gastric glutamate. Furthermore, it is possible that unidentified calcium channels other than P/Q and L type channels are also involved in the release of glutamate in the stomach.	What does isradipine do to L-type channels?	The release of glutamate was significantly inhibited by both omega-agatoxin IVA, a P/Q-type calcium channel antagonist, and isradipine, an L type calcium channel antagonist. Omega-conotoxin GVIA, an N type calcium channel antagonist and flunarizine, a nonselective T-type calcium channel antagonist were without effect.
DOPA was measured in the anterior pituitary and hypothalamic-hypophysial portal blood after treatment with NSD-1015, a DOPA decarboxylase inhibitor. NSD-1015 caused DOPA to accumulate in the anterior pituitary of mice and rats, and increased DOPA in the hypothalamic-hypophysial portal blood of rat. Serum prolactin was also increased. Interruption of the anterior pituitary blood supply from the hypothalamic-hypophysial system by cannulation of the entire pituitary stalk eliminated the NSD-1015-induced DOPA accumulation in the rat pituitary. We conclude that DOPA can be taken into the anterior pituitary from the portal blood of NSD-1015-treated rodents and that the anterior pituitary lacks tyrosine hydroxylase activity in both mice and rats.	Is NSD-1015 an inhibitor of Aromatic L-Amino Acid Decarboxylase?	DOPA was measured in the anterior pituitary and hypothalamic-hypophysial portal blood after treatment with NSD-1015, a DOPA decarboxylase inhibitor.
Site-specific characterisation of mucin-type O-linked glycosylation is an analytical challenge due to glycan heterogeneity, lack of glycosylation site consensus sequence and high density of occupied glycosylation sites. Here, we report the use of electron transfer dissociation (ETD) for the site-specific characterisation of densely glycosylated mucin-type O-linked glycopeptides using ESI-IT-MS/MS. Synthetic glycopeptides from the human mucin-1 (MUC-1) tandem repeat region containing a range of O-linked, tumour-associated carbohydrate antigens, namely Tn, T and sialyl T, with different glycosylation site occupancies and an increasing number of tandem repeats were studied. In addition, a glycopeptide from the anti-freeze glycoprotein of Antarctic and Arctic notothenoids, bearing four O-linked, per-acetylated T antigens was characterised. ETD MS/MS of infused or capillary LC-separated glycopeptides provided broad peptide sequence coverage (c/z·-type fragment ions) with intact glycans still attached to the Ser/Thr residues. Thus, the glycosylation sites were unambiguously determined, while simultaneously obtaining information about the attached glycan mass and peptide identity. Highly sialylated O-glycopeptides showed less efficient peptide fragmentation, but some sequence and glycosylation site information was still obtained. This study demonstrates the capabilities of ETD MS/MS for site-specific characterisation of mucin-type glycopeptides containing high-density O-linked glycan clusters, using accessible and relative low-resolution/low-mass accuracy IT MS instrumentation.	List fish anti-freeze proteins.	the anti-freeze glycoprotein of Antarctic and Arctic notothenoids,
The polycythemic strain of the spleen focus-forming virus (SFFVp) contains the most potent murine retroviral enhancer configuration known so far for gene expression in myeloerythroid hematopoietic cells. In the present study, we mapped two crucial elements responsible for the high activity of the SFFVp enhancer to an altered upstream control region (UCR) containing a GC-rich motif (5'-GGGCGGG-3') and to a unique enhancer core (5'-TGCGGTC-3'). Acquisition of these motifs accounts for half of the activity of the complete retroviral enhancer in hematopoietic cells, irrespective of the developmental stage or lineage. Furthermore, the UCR motif contains the major determinant for the enhancer activity of SFFVp in embryonic stem (ES) cells. Using electrophoretic mobility shift assays, we show that the UCR of SFFVp, but not of Friend murine leukemia virus, is targeted by the ubiquitous transcriptional activator, Sp1. The core motif of SFFVp creates a specific and high-affinity target for polyomavirus enhancer binding protein/core binding factor (PEBP/CBF) and excludes access of CAAT/enhancer binding protein. Cotransfection experiments with ES cells imply that PEBP/CBF cooperates with the neighboring element, LVb (the only conserved Ets consensus in the SFFVp enhancer), and that the Sp1 motif in the UCR stimulates transactivation through the Ets-PEBP interaction. Putative secondary structures of the retroviral enhancers are proposed based on these data.	Which is the binding site motif of Sp1?	upstream control region (UCR) containing a GC-rich motif (5'-GGGCGGG-3') and to a unique enhancer core (5'-TGCGGTC-3')