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Baloxavir marboxil is an orally available prodrug of baloxavir acid. Japan was the first country to approve baloxavir marboxil as a treatment for influenza. The antiviral mechanism of action of baloxavir is unique; the drug blocks initiation of viral mRNA synthesis, thus preventing proliferation of the influenza virus. A single oral dose of baloxavir is usually well tolerated; it hastens alleviation of influenza symptoms and shortens the duration of viral shedding. However, novel influenza variants exhibiting over 10-fold reductions in baloxavir susceptibility emerged in baloxavir-treated patients. Although further clinical investigation is required to explore this issue, baloxavir may revolutionize our understanding of influenza virus biology.	Is Baloxavir effective for influenza?	A single oral dose of baloxavir is usually well tolerated; it hastens alleviation of influenza symptoms and shortens the duration of viral shedding.
Pharmacogenetic testing for HLA-B*5701 is cost-effective only if abacavir-based treatment is as effective and costs less than tenofovir-based treatment.	Which pharmacogenetic test is available for abacavir?	Pharmacogenetic testing for HLA-B*5701 is cost-effective only if abacavir-based treatment is as effective and costs less than tenofovir-based treatment.
Neonates do experience pain and its management is necessary in order to prevent long-term, as well as, short-term effects. The most common source of pain in the neonatal intensive care unit (NICU) is caused by medically invasive procedures. NICU patients have to endure trauma, medical adhesive related skin injuries, heel lance, venipuncture and intramuscular injection as well as nasogastric catheterization besides surgery. A cornerstone in pain assessment is the use of scales such as COMFORT, PIPP-R, NIPS and N-PASS. This narrative review provides an up to date account of neonate pain management used in NICUs worldwide focusing on non-pharmacological methods. Non-steroidal anti-inflammatory drugs have well established adverse side effects and opioids are addictive thus pharmacological methods should be avoided if possible at least for mild pain management. Non-pharmacological interventions, particularly breastfeeding and non-nutritive sucking as primary strategies for pain management in neonates are useful strategies to consider. The best non-pharmacological methods are breastfeeding followed by non-nutritive sucking coupled with sucrose sucking. Regrettably most parents used only physical methods and should be trained and involved for best results. Further research in NICU is essential as the developmental knowledge changes and neonate physiology is further uncovered together with its connection to pain.	What are the most common pain scales used to measure pain in neonates?	A cornerstone in pain assessment is the use of scales such as COMFORT, PIPP-R, NIPS and N-PASS.
Sumoylation is a post-translational modification that plays an important role in a wide range of cellular processes. Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation. Ubc9 has been implicated in a variety of human malignancies. In order to exploit the therapeutic potential of Ubc9, we have identified the potential site to target for rational drug design using molecular modeling approaches. The structural information derived was then used to prioritize hits from a small-molecule library for biological assay using a virtual screening protocol that involves shape matching with a known inhibitor inhibitors and docking of a small-molecule library utilizing computational approaches that incorporate both ligand and protein flexibility. Nineteen compounds were acquired from different chemical vendors and were tested for Ubc9 inhibitory activity. Five compounds showed inhibitory activity against Ubc9, out of which one compound was selected for further optimization. A similarity search was then carried out to retrieve commercially available derivatives, which were further acquired and assayed, resulting in two compounds with acceptable potency. These two compounds can be used as starting points for the development of more potent inhibitors of Ubc9 targeting the predicted site.	What is the role of the UBC9 enzyme in the protein sumoylation pathway?	Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation.
DNA double-strand breaks (DSBs) can induce chromosomal aberrations and carcinogenesis and their correct repair is crucial for genetic stability. The cellular response to DSBs depends on damage signaling including the phosphorylation of the histone H2AX (γH2AX). However, a lack of γH2AX formation in heterochromatin (HC) is generally observed after DNA damage induction. Here, we examine γH2AX and repair protein foci along linear ion tracks traversing heterochromatic regions in human or murine cells and find the DSBs and damage signal streaks bending around highly compacted DNA. Given the linear particle path, such bending indicates a relocation of damage from the initial induction site to the periphery of HC. Real-time imaging of the repair protein GFP-XRCC1 confirms fast recruitment to heterochromatic lesions inside murine chromocenters. Using single-ion microirradiation to induce localized DSBs directly within chromocenters, we demonstrate that H2AX is early phosphorylated within HC, but the damage site is subsequently expelled from the center to the periphery of chromocenters within ∼ 20 min. While this process can occur in the absence of ATM kinase, the repair of DSBs bordering HC requires the protein. Finally, we describe a local decondensation of HC at the sites of ion hits, potentially allowing for DSB movement via physical forces.	What happens to H2AX upon DNA bouble strand breaks?	he cellular response to DSBs depends on damage signaling including the phosphorylation of the histone H2AX (γH2AX). However, a lack of γH2AX formation in heterochromatin (HC) is generally observed after DNA damage induction. Here, we examine γH2AX and repair protein foci along linear ion tracks traversing heterochromatic regions in human or murine cells and find the DSBs and damage signal streaks bending around highly compacted DNA.
Transcript elongation can be interrupted by a variety of obstacles, including certain DNA sequences, DNA-binding proteins, chromatin, and DNA lesions. Bypass of many of these impediments is facilitated by elongation factor TFIIS through a mechanism that involves cleavage of the nascent transcript by the RNA polymerase II/TFIIS elongation complex. Highly purified yeast RNA polymerase II is able to perform transcript hydrolysis in the absence of TFIIS. The "intrinsic" cleavage activity is greatly stimulated at mildly basic pH and requires divalent cations. Both arrested and stalled complexes can carry out the intrinsic cleavage reaction, although not all stalled complexes are equally efficient at this reaction. Arrested complexes in which the nascent transcript was cleaved in the absence of TFIIS were reactivated to readthrough blocks to elongation. Thus, cleavage of the nascent transcript is sufficient for reactivating some arrested complexes. Small RNA products released following transcript cleavage in stalled ternary complexes differ depending upon whether the cleavage has been induced by TFIIS or has occurred in mildly alkaline conditions. In contrast, both intrinsic and TFIIS-induced small RNA cleavage products are very similar when produced from an arrested ternary complex. Although alpha-amanitin interferes with the transcript cleavage stimulated by TFIIS, it has little effect on the intrinsic cleavage reaction. A mutant RNA polymerase previously shown to be refractory to TFIIS-induced transcript cleavage is essentially identical to the wild type polymerase in all tested aspects of intrinsic cleavage.	Which RNA polymerase II subunit carries RNA cleavage activity?	Highly purified yeast RNA polymerase II is able to perform transcript hydrolysis in the absence of TFIIS.
A cis-acting DNA regulatory element 3' to the A gamma-globin gene contains eight distinct regions of DNA-protein interaction distributed over 750 bp of DNA. The sequences of two foot-printed regions (sites I and IV) are A-T rich and generate a highly retarded complex on gel shift analysis with nuclear extract from human erythroleukemia (K562) cells. We have purified a 98-kD protein that reproduces this gel shift. Tryptic cleavage and peptide sequence analysis demonstrated that the 98-kD protein is identical to a recently cloned protein, special A-T-rich binding protein 1 (SATB1), that binds selectively to nuclear matrix/scaffold-associated regions of DNA (MARs/SARs). We have shown by functional analysis that the 3' A gamma regulatory element associates with the nuclear matrix. SATB1 mRNA was identified in K562 cells, and reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated its transcript in several other hematopoietic lines. Antisera to SATB1 caused ablation of the gel shift complex generated by both the crude nuclear extract and the purified 98-kD protein with the site I oligonucleotide. Furthermore, oligonucleotides that bind SATB1 inhibited formation of the site I gel shift complex when added as excess unlabeled competitor. An immunoblot analysis of the site I gel shift complex documented the presence of SATB1. Binding of SATB1 to two sites within the 3' A gamma regulatory element and its MAR/SAR activity suggests that this element may influence gene expression through interaction with the nuclear matrix.	Is SATB1 positioned close to AT-rich sequences?	Tryptic cleavage and peptide sequence analysis demonstrated that the 98-kD protein is identical to a recently cloned protein, special A-T-rich binding protein 1 (SATB1)
The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. The birth prevalence is approximately one in 10,000 live births, accounting for 8-10% of patients with coronal synostosis. Although MS is a relatively common diagnosis in patients with craniosynostosis syndromes, with autosomal dominant inheritance, there has been no report of MS, in an affected Korean family with typical cephalo-facial morphology that has been confirmed by molecular studies. Here, we report a familial case of MS in a female patient with a Pro250Arg mutation in exon 7 (IgII-IGIII linker domain) of the FGFR3 gene. This patient had mild midfacial hypoplasia, hypertelorism, downslanting palpebral fissures, a beak shaped nose, plagio-brachycephaly, and mild neurodevelopmental delay. The same mutation was confirmed in the patient's mother, two of the mother's sisters and the maternal grandfather. The severity of the cephalo-facial anomalies was variable among these family members.	What symptoms characterize the Muenke syndrome?	The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene.
1. Sometimes called "lazy eye," amblyopia is poor vision in an eye that did not develop normal sight during early childhood. Amblyopia is common, affecting approximately 2 or 3 out of every 100 people. The best time to correct amblyopia is during infancy or early childhood. 2. Amblyopia has three major causes: strabismus (misaligned eyes), unequal focus (refractive error), and cloudiness in the normally clear eye tissues. 3. To correct amblyopia, a child must be made to use the weak eye. This is usually done by patching or covering the strong eye. Amblyopia cannot be cured by treating the cause alone; the weaker eye must be made stronger in order to see normally.	Does Amblyopia affect the eye?	To correct amblyopia, a child must be made to use the weak eye.
A chemical screen designed to identify novel inducers of autophagy led to the discovery that signal transducer and activator of transcription 3 (STAT3) inhibitors can potently stimulate the autophagic flux. Although STAT3 is best known as a pro-inflammatory and oncogenic transcription factor, mechanistic analyses revealed that autophagy is regulated by the cytoplasmic, not nuclear, pool of STAT3. Cytoplasmic STAT3 normally interacts with the eukaryotic translation initiation factor 2, subunit 1α, 35kDa (EIF2S1/eIF2α) kinase 2/protein kinase, RNA-activated (EIF2AK2/PKR), a sensor of double-stranded RNA. This interaction, which could be recapitulated using recombinant proteins in pull-down experiments, involves the catalytic domain of EIF2AK2 as well as the SH2 domain of STAT3, which can adopt a fold similar to that of EIF2S1. Thus, STAT3 may act as a competitive inhibitor of EIF2AK2. Indeed, pharmacological or genetic inhibition of STAT3 stimulates EIF2AK2-dependent EIF2S1 phosphorylation and autophagy. Conversely, the overexpression of wild-type STAT3 as well as of STAT3 mutants that cannot be phosphorylated by JAK2 or are excluded from the nucleus inhibits autophagy. However, STAT3 mutants that fail to interact with EIF2AK2 are unable to suppress autophagy. Both STAT3-targeting agents (i.e., Stattic, JSI-124 and WP1066) and EIF2AK2 activators (such as the double-strand RNA mimetic polyinosinic:polycytidylic acid) are capable of disrupting the inhibitory interaction between STAT3 and EIF2AK2 in cellula, yet only the latter does so in cell-free systems in vitro. A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex as well as the phosphorylation of mitogen-activated protein kinase 8/c-Jun N-terminal kinase 1 (MAPK8/JNK1) and EIF2S1. These results reveal an unsuspected crosstalk between cellular metabolism (fatty acids), pro-inflammatory signaling (STAT3), innate immunity (EIF2AK2), and translational control (EIF2S1) that regulates autophagy.	Is STAT3 involved in EIF2AK2-dependent suppression of autophagy?	These results reveal an unsuspected crosstalk between cellular metabolism (fatty acids), pro-inflammatory signaling (STAT3), innate immunity (EIF2AK2), and translational control (EIF2S1) that regulates autophagy
The H1N1 2009 virus is pandemic in many countries. The genome of this virus contains eight segments. Among the eight segments maximum numbers of mutation occur at the segment 1 and segment 4 which codes for PB2 subunit and hemagglutinin (HA) and less number of mutations occur in segment 6 which codes for neuraminidase (NA) protein. Neuraminidase (NA) inhibitors (Oseltamivir and Zanamivir) are presently used as an anti-flu drugs. In the present study, the in silico efficacy of different drugs was tested against the swine flu virus. 3D structures of neuraminidase (NA) proteins of H1N1 2009 were generated using Geno3D. The 3D structure of H1N1 1918 was downloaded from PDB. Interaction study was done using Arguslab 4 and PyMol view. Oseltamivir and Zanamivir have good number of interactions with H1N1 2009 virus and the scoring function also support to this result. When compared with the 1918 H1N1 viral protein, 2009 H1N1 NA protein shows more number of interaction and good scoring function. The RMSD value of before and after docking are found to be same at 0.04A° for both the drugs. The force field energy of NA protein 2009 was found to be -15603.529 KJ/mol before docking. The force field energy was found to be decreased after docking at -17620.740 KJ/mol with Tamiflu and -17652.242 KJ/mol with Zanamivir. The number of interaction and scoring function shows that Oseltamivir and Zanamivir will be able to effectively control the present pandemic H1N1 virus 2009.	What is the function of Oseltamivir when administered during flu?	Neuraminidase (NA) inhibitors (Oseltamivir and Zanamivir) are presently used as an anti-flu drugs.
Care for patients with Duchenne muscular dystrophy (DMD) is poorly standardised. There are many interventions in different systems which are known to improve outcomes in DMD but these are not uniformly applied. This leads to inequality in access to treatment, as well as problems for planning controlled trials of future therapeutics. A worldwide effort is underway to generate care guidelines for DMD, which involves the Centre for Disease Control in the USA and the TREAT-NMD network of excellence for neuromuscular diseases in Europe. In advance of the full consensus document, TREAT-NMD has worked on the generation of brief standards of care for DMD, which are presented here and are available via the TREAT-NMD website (http://www.treat-nmd.eu). Guidelines are presented for diagnostics, neurological follow up, gastrointestinal and nutritional issues, respiratory and cardiac care as well as orthopaedics, rehabilitation, psychosocial interventions and oral care.	Elaborate on the TREAT-NMD initiative for DMD patients	In advance of the full consensus document, TREAT-NMD has worked on the generation of brief standards of care for DMD, which are presented here and are available via the TREAT-NMD website (http://www.treat-nmd.eu). Guidelines are presented for diagnostics, neurological follow up, gastrointestinal and nutritional issues, respiratory and cardiac care as well as orthopaedics, rehabilitation, psychosocial interventions and oral care.
Netherton syndrome is a severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome. Here we describe the intron-exon organization of the gene and characterize the SPINK5 mutations in patients from 21 families of different geographic origin, using denaturing high performance liquid chromatography and direct sequencing. We identified 18 mutations, of which 13 were novel and seven (39%) were recurrent. The majority of the mutations were clustered between exons 1-8 and exons 21-26. They comprised four nonsense mutations (22%), eight frameshift insertions or deletions (44%), and six splice-site defects (33%). All mutations predict the formation of premature termination codons. Northern blot analysis showed variable reduction of SPINK5 mutant transcript levels, suggesting variable efficiency of nonsense-mediated mRNA decay. Seven patients were homozygotes, eight were compound heterozygotes, and five were heterozygotes with only one identifiable SPINK5 mutation. Five mutations, one of which resulted in perinatal lethal disease in three families, were associated with certain ethnic groups. We also describe 45 intragenic polymorphisms in the patients studied. The clinical features of erythroderma, trichorrhexis invaginata, and atopic manifestations were present in the majority of affected individuals and ichthyosis linearis circumflexa was seen in 12 out of 24 patients. Interfamilial and intrafamilial variation in disease severity was observed, with no clear correlation between mutations and phenotype, suggesting that the degree of severity may be affected by other factors.	Mutations in which gene and which protein are associated with Netherton syndrome?	Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome. Here we describe the intron-exon organization of the gene and characterize the SPINK5 mutations in patients from 21 families of different geographic origin, using denaturing high performance liquid chromatography and direct sequencing.
Genome editing has attracted wide interest for the generation of cellular models of disease using human pluripotent stem cells and other cell types. CRISPR-Cas systems and TALENs can target desired genomic sites with high efficiency in human cells, but recent publications have led to concern about the extent to which these tools may cause off-target mutagenic effects that could potentially confound disease-modeling studies. Using CRISPR-Cas9 and TALEN targeted human pluripotent stem cell clones, we performed whole-genome sequencing at high coverage in order to assess the degree of mutagenesis across the entire genome. In both types of clones, we found that off-target mutations attributable to the nucleases were very rare. From this analysis, we suggest that, although some cell types may be at risk for off-target mutations, the incidence of such effects in human pluripotent stem cells may be sufficiently low and thus not a significant concern for disease modeling and other applications.	Is TALEN being used on stem cells?	Using CRISPR-Cas9 and TALEN targeted human pluripotent stem cell clones, we performed whole-genome sequencing at high coverage in order to assess the degree of mutagenesis across the entire genome.
TAL1/SCL (hereafter referred to as TAL1) is a critical transcription factor required for hematopoiesis in which hematopoietic stem cells commit and differentiate to different lineages. During this process, transcription of many genes is turned on and off in part by epigenetic mechanisms. TAL1 has recently been shown to differentially recruit LSD1 and other histone modifying complexes to regulate its target genes. Here, we focus primarily on epigenetic mechanisms that are regulated by TAL1 during normal and malignant hematopoiesis. We discuss how different histone modifying enzymes are recruited by TAL1 and how these enzymatic activities mediate the activating or repressive function of TAL1. Finally, we further explore the possible mechanisms by which dysregulation of the recruitment and activity of histone modifying enzymes contribute to leukemogenesis.	What is the role of lysine-specific demethylase 1 (LSD1) in hematopoiesis?	TAL1 has recently been shown to differentially recruit LSD1 and other histone modifying complexes to regulate its target genes
Previous work has demonstrated that fusion of a luciferase to an opsin, to create a luminescent opsin or luminopsin, provides a genetically encoded means of manipulating neuronal activity via both chemogenetic and optogenetic approaches. Here we have expanded and refined the versatility of luminopsin tools by fusing an alternative luciferase variant with high light emission, Gaussia luciferase mutant GLucM23, to depolarizing and hyperpolarizing channelrhodopsins with increased light sensitivity. The combination of GLucM23 with Volvox channelrhodopsin-1 produced LMO4, while combining GLucM23 with the anion channelrhodopsin iChloC yielded iLMO4. We found efficient activation of these channelrhodopsins in the presence of the luciferase substrate, as indicated by responses measured in both single neurons and in neuronal populations of mice and rats, as well as by changes in male rat behavior during amphetamine-induced rotations. We conclude that these new luminopsins will be useful for bimodal opto- and chemogenetic analyses of brain function.	Are Luminopsins a fusion proteins of luminol and Rhodopsin ?	Here we have expanded and refined the versatility of luminopsin tools by fusing an alternative luciferase variant with high light emission, Gaussia luciferase mutant GLucM23, to depolarizing and hyperpolarizing channelrhodopsins
Miller Fisher syndrome (MFS), a variant of Guillain-Barré syndrome, is a rare disorder typically characterized by a triad of ataxia, areflexia, and ophthalmoplegia, which may have a highly variable clinical presentation. We report a case of MFS in a 45-year-old female presenting with sphenoid sinusitis and sixth nerve palsy. She underwent endoscopic sphenoid sinusotomy without improvement, had postoperative deterioration, was diagnosed with MFS, and was treated with intravenous immunoglobulin with complete response. Because of the potential severity of Guillain-Barré syndrome, great vigilance should be taken when examining sixth nerve palsies to prevent misdiagnosis and delay in treatment of the MFS variant of this disease.	Is the Miller-Fisher syndrome considered to be a variant of Guillain-Barré?	Miller Fisher syndrome (MFS), a variant of Guillain-Barré syndrome, is a rare disorder typically characterized by a triad of ataxia, areflexia, and ophthalmoplegia, which may have a highly variable clinical presentation.
Feline coronavirus (FCoV) is an etiological agent that causes a benign enteric illness and the fatal systemic disease feline infectious peritonitis (FIP). The FCoV spike (S) protein is considered the viral regulator for binding and entry to the cell. This protein is also involved in FCoV tropism and virulence, as well as in the switch from enteric disease to FIP. This regulation is carried out by spike's major functions: receptor binding and virus-cell membrane fusion. In this review, we address important aspects in FCoV genetics, replication and pathogenesis, focusing on the role of S. To better understand this, FCoV S protein models were constructed, based on the human coronavirus NL63 (HCoV-NL63) S structure. We describe the specific structural characteristics of the FCoV S, in comparison with other coronavirus spikes. We also revise the biochemical events needed for FCoV S activation and its relation to the structural features of the protein.	The virus that causes FIP, Feline Infectious Peritonitis belongs to what family?	Feline coronavirus (FCoV) is an etiological agent that causes a benign enteric illness and the fatal systemic disease feline infectious peritonitis (FIP).
Atrial fibrillation is the most common arrhythmia worldwide with increasing frequency noted with age. Hyperthyroidism is a well-known cause of atrial fibrillation with a 16%-60% prevalence of atrial fibrillation in patients with known hyperthyroidism Ross et al. (2016). While hyperthyroidism as a causative factor of atrial fibrillation is well established, this literature review aims to answer several questions on this topic including: 1. The relationship of atrial fibrillation to hyperthyroidism 2. Atrial fibrillation as a predictor of hyperthyroidism 3. The pathophysiology of thyrotoxic atrial fibrillation 4. Subclinical hyperthyroidism and the relationship with atrial fibrillation 5. Cardioversion and Catheter ablation of hyperthyroid patients with atrial fibrillation 6. Thrombotic risk of hyperthyroid patients with atrial fibrillation 7. Management of Thyrotoxic Atrial fibrillation 8. Pharmacological rhythm control in patients with hyperthyroidism and atrial fibrillation 9. Treatment of Hyperthyroidism to prevent atrial fibrillation 10. Clinical Implications of Hyperthyroidism and Atrial Fibrillation.	Please list 10 conditions which play a role in causing atrial fibrillation.	Atrial fibrillation is the most common arrhythmia worldwide with increasing frequency noted with age. Hyperthyroidism is a well-known cause of atrial fibrillation with a 16%-60% prevalence of atrial fibrillation in patients with known hyperthyroidism
miR-1 levels are greatly reduced in human AF, possibly contributing to up-regulation of Kir2.1 subunits, leading to increased I(K1). Because up-regulation of inward-rectifier currents is important for AF maintenance, these results provide potential new insights into molecular mechanisms of AF with potential therapeutic implications.	Is micro RNA 1 (miR-1) implicated in cardiac arrhythmias?	miR-1 levels are greatly reduced in human AF, possibly contributing to up-regulation of Kir2.1 subunits, leading to increased I(K1). Because up-regulation of inward-rectifier currents is important for AF maintenance, these results provide potential new insights into molecular mechanisms of AF with potential therapeutic implications.
Nearly 30 years have elapsed since Rowe and Weller and their colleagues discovered human cytomegalovirus (CMV). Because of its complex structure, long replicative cycle, low yield in vitro, and highly species-specific cell-substrate requirement, the cellular and molecular biologic analyses of human CMV have been slow, but recombinant DNA and monoclonal antibody technologies are bringing about rapid changes. Because of the long period of latency and wide range of disease presentations, epidemiologic and medical insights have also come slowly. However, the clinical events that occur during iatrogenic immunosuppression (transplantation and cancer therapy) and as a result of immunocompromise due to human immunodeficiency virus infection are currently promoting our understanding of the epidemiology of CMV disease and the definition of its clinical spectrum. Rapid diagnostic methods, antiviral drugs, and vaccines for CMV are becoming available. We may not yet understand completely the impact of this agent on the nonimmunosuppressed or aspects of its pathogenesis: e.g., the immune functions controlling recrudescence and the possibility of increased disease severity in those with no detectable immune defect. With the availability of new approaches, other issues should be clarified, such as the functions of host and virus involved in the mechanism of persistence.	Can you define iatrogenic disease?	However, the clinical events that occur during iatrogenic immunosuppression (transplantation and cancer therapy) and as a result of immunocompromise due to human immunodeficiency virus infection are currently promoting our understanding of the epidemiology of CMV disease and the definition of its clinical spectrum
The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the β branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 Å resolution. The structure reveals how suvorexant adopts a π-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous π-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.	What molecule is targeted by suvorexant?	The human OX2 receptor (OX2R) belongs to the β branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant.
Cohesin regulates sister chromatid cohesion during the mitotic cell cycle with Nipped-B-Like (NIPBL) facilitating its loading and unloading. In addition to this canonical role, cohesin has also been demonstrated to play a critical role in regulation of gene expression in nondividing cells. Heterozygous mutations in the cohesin regulator NIPBL or cohesin structural components SMC1A and SMC3 result in the multisystem developmental disorder Cornelia de Lange Syndrome (CdLS). Genome-wide assessment of transcription in 16 mutant cell lines from severely affected CdLS probands has identified a unique profile of dysregulated gene expression that was validated in an additional 101 samples and correlates with phenotypic severity. This profile could serve as a diagnostic and classification tool. Cohesin binding analysis demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of a boundary/insulator interacting protein. However, the binding sites are enriched within the promoter regions of the dysregulated genes and are significantly decreased in CdLS proband, indicating an alternative role of cohesin as a transcription factor.	What is the function of the NIPBL factor in genome conformation?	Cohesin regulates sister chromatid cohesion during the mitotic cell cycle with Nipped-B-Like (NIPBL) facilitating its loading and unloading
Are its level found to increase or to decrease?	The ability of Frzb/secreted Frizzled-related protein 3 (sFRP3) to inhibit Wnt signaling and the localization of Frzb/sFRP3 on chromosome 2q to a region frequently deleted in cancers have led some investigators to hypothesize that Frzb/sFRP3 is a tumor suppressor gene.	null
Does an activated oncogene that initiates tumor growth need to remain activated to maintain the cancer phenotype? This question has been answered affirmatively by experiments in which doxycycline-regulated oncogene activation induces growth of large tumors that regress completely upon oncogene inactivation--a phenomenon called oncogene addiction. We assemble here the evidence that oncogene addiction is angiogenesis-dependent. Although activated oncogenes increase tumor cell proliferation and decrease their apoptosis, these activities are not sufficient to expand tumor mass beyond a microscopic size. Oncogenes must also induce tumor angiogenesis for expansion of tumor mass. We propose experiments to validate the "endothelial centric" hypothesis of oncogene addiction.	Which phenomenon is described as oncogene addiction?	Does an activated oncogene that initiates tumor growth need to remain activated to maintain the cancer phenotype? This question has been answered affirmatively by experiments in which doxycycline-regulated oncogene activation induces growth of large tumors that regress completely upon oncogene inactivation--a phenomenon called oncogene addiction.
The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform for the further study of PLA2G6-associated neurodegeneration.	Which gene is mutated in the Karak syndrome?	Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome
Phospholamban (PLN) is a key regulator of Ca(2+) homeostasis and contractility in the heart. Its regulatory effects are mediated through its interaction with the sarcoplasmic reticulum Ca(2+)-ATPase, (SERCA2a), resulting in alterations of its Ca(2+)-affinity. To identify additional proteins that may interact with PLN, we used the yeast-two-hybrid system to screen an adult human cardiac cDNA library. HS-1 associated protein X-1 (HAX-1) was identified as a PLN-binding partner. The minimal binding regions were mapped to amino acid residues 203-245 for HAX-1 and residues 16-22 for PLN. The interaction between the two proteins was confirmed using GST-HAX-1, bound to the glutathione-matrix, which specifically adsorbed native PLN from human or mouse cardiac homogenates, while in reciprocal binding studies, recombinant His-HAX-1 bound GST-PLN. Kinetic studies using surface plasmon resonance yielded a K(D) of approximately 1 muM as the binding affinity for the PLN/HAX-1 complex. Phosphorylation of PLN by cAMP-dependent protein kinase reduced binding to HAX-1, while increasing concentrations of Ca(2+) diminished the PLN/HAX-1 interaction in a dose-dependent manner. HAX-1 concentrated to mitochondria, but upon transient co-transfection of HEK 293 cells with PLN, HAX-1 redistributed and co-localized with PLN at the endoplasmic reticulum. Analysis of the anti-apoptotic function of HAX-1 revealed that the presence of PLN enhanced the HAX-1 protective effects from hypoxia/reoxygenation-induced cell death. These findings suggest a possible link between the Ca(2+) handling by the sarcoplasmic reticulum and cell survival mediated by the PLN/HAX-1 interaction.	Which protein has been found to interact with phospholamban (PLN) and is also an anti-apoptotic protein?	Analysis of the anti-apoptotic function of HAX-1 revealed that the presence of PLN enhanced the HAX-1 protective effects from hypoxia/reoxygenation-induced cell death. These findings suggest a possible link between the Ca(2+) handling by the sarcoplasmic reticulum and cell survival mediated by the PLN/HAX-1 interaction.
Lysozymes are an ancient group of antimicrobial enzymes of the innate immune system. Here we provide a comparative analysis of the evolution and function of lysozymes during early development in fish, the most speciose vertebrate group. In fishes, lineage and species-specific evolution of both C-type (chicken or conventional) and G-type (goose type) genes occurred. Phylogenetic analysis revealed that the teleost lysozyme G-type members group with the tetrapod homologues but the teleost C-type form three different clusters with the tetrapods. Most of the teleost C-type cluster with tetrapod Lyz but there are some that group with the mammalian Lyzl1/2 and LALBA. This suggests that early in gnathostome evolution these genes already existed and that lyzl1/2 and lalba genes are present in fish and tetrapods. Gene synteny analysis to confirm sequence orthologies failed to identify conserved genome regions between teleosts and other vertebrates lysozyme gene regions suggesting that in the ancestral bony fish genome lyz, lyzl1/2, lalba and lyg precursor genes were transposed to different chromosome regions. The homologue of the mammalian lactalbumin (LALBA) gene was identified for the first time in teleosts and was expressed in skin and during egg and larval development. Lysozyme activity was detected in teleost eggs and varied between species and in the gilthead sea bream lyg and lalba transcript abundance differed in eggs and larvae from different brood stock suggesting differences exist in maternal innate immune protection.	What is the function of lysozyme?	Lysozymes are an ancient group of antimicrobial enzymes of the innate immune system.
Phylogenetic reconstruction using molecular data is often subject to homoplasy, leading to inaccurate conclusions about phylogenetic relationships among operational taxonomic units. Compared with other molecular markers, single-nucleotide polymorphisms (SNPs) exhibit extremely low mutation rates, making them rare in recently emerged pathogens, but they are less prone to homoplasy and thus extremely valuable for phylogenetic analyses. Despite their phylogenetic potential, ascertainment bias occurs when SNP characters are discovered through biased taxonomic sampling; by using whole-genome comparisons of five diverse strains of Bacillus anthracis to facilitate SNP discovery, we show that only polymorphisms lying along the evolutionary pathway between reference strains will be observed. We illustrate this in theoretical and simulated data sets in which complex phylogenetic topologies are reduced to linear evolutionary models. Using a set of 990 SNP markers, we also show how divergent branches in our topologies collapse to single points but provide accurate information on internodal distances and points of origin for ancestral clades. These data allowed us to determine the ancestral root of B. anthracis, showing that it lies closer to a newly described "C" branch than to either of two previously described "A" or "B" branches. In addition, subclade rooting of the C branch revealed unequal evolutionary rates that seem to be correlated with ecological parameters and strain attributes. Our use of nonhomoplastic whole-genome SNP characters allows branch points and clade membership to be estimated with great precision, providing greater insight into epidemiological, ecological, and forensic questions.	How homoplasy affects phylogenetic reconstruction?	Phylogenetic reconstruction using molecular data is often subject to homoplasy, leading to inaccurate conclusions about phylogenetic relationships among operational taxonomic units.
A histological analysis was conducted in 138 female breast cancer patients, and the results were classified in accordance with "Histological Typing of Breast Tumours" (WHO, Geneva 1981). Since about half of these tumors showed more than one histological type of carcinoma, a simplified classification system with four groups was adopted. When patients were categorized according to the number and degree of kinship of their relatives with breast cancer, no specific association with the histological types was found. Familial tumors also encompassed a wide spectrum of histopathologic diagnoses. This suggests the absence of a histological marker in familial breast cancer. Pedigrees of all the patients were then analyzed, special emphasis being placed on relatives suffering from the same and other malignancies. It was found that 13.8% of the probands had at least one first-degree relative with breast cancer and that, compared with the tumor spectra in the male and female population, there was a significantly higher number of esophageal carcinomas in the fathers, of stomach cancers in the uncles and grandfathers, of brain tumors in the mothers, and of sarcomas in the brothers. An accumulation of the same tumors, especially stomach cancer and tumors related to the SBLA syndrome, was observed in families of index patients with tubular or medullary breast cancer. The SBLA syndrome is a complex familial cancer syndrome characterized by a proclivity to Sarcomas, Breast cancers, brain tumors, Lung and laryngeal cancers, leukemia, and Adrenocortical carcinomas.	List the cancers that are associated with SBLA syndrome.	The SBLA syndrome is a complex familial cancer syndrome characterized by a proclivity to Sarcomas, Breast cancers, brain tumors, Lung and laryngeal cancers, leukemia, and Adrenocortical carcinomas.
Intramural hematoma of the aorta is a condition increasingly observed in clinical practice. Uncertainty exists whether such lesions represent a different pathology or simply the precursors of classic dissecting aneurysm. The patient was a 76-year-old woman with intramural hematoma of the ascending aorta. Clinical course, progression of the lesion to type A aortic dissection, and surgical treatment are described. Although natural history of intramural hematoma of the ascending aorta is not clearly elucidated, the case presented confirms that the evolution toward intimal flap formation is possible and that we cannot foresee the stabilization of these lesions. We stress that intramural hematoma of the ascending aorta has to be managed as an aortic type A dissection and that aggressive treatment is advisable.	What is the most frequent evolution (next stage) when Aortic intramural hematoma (IMH) is not treated?	Intramural hematoma of the aorta is a condition increasingly observed in clinical practice. Uncertainty exists whether such lesions represent a different pathology or simply the precursors of classic dissecting aneurysm
The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.	Inhibition of which enzyme is mechanism of action of alisertib?	We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo.
The 3'-ends of both prokaryotic and eukaryotic mRNA are polyadenylated, but the poly(A) tracts of prokaryotic mRNA are generally shorter, ranging from 15 to 60 adenylate residues and associated with only 2-60% of the molecules of a given mRNA species. The sites of polyadenylation of bacterial mRNA are diverse and include the 3'-ends of primary transcripts, the sites of endonucleolytic processing in the 3' untranslated and intercistronic regions, and sites within the coding regions of mRNA degradation products. The diversity of polyadenylation sites suggests that mRNA polyadenylation in prokaryotes is a relatively indiscriminate process that can occur at all mRNA's 3'-ends and does not require specific consensus sequences as in eukaryotes. Two poly(A) polymerases have been identified in Escherichia coli. They are encoded by unlinked genes, neither of which is essential for growth, suggesting significant functional overlap. Polyadenylation promotes the degradation of a regulatory RNA that inhibits the replication of bacterial plasmids and may play a similar role in the degradation of mRNA. However, under certain conditions, poly(A) tracts may lead to mRNA stabilization. Their ability to bind S1 ribosomal protein suggests that poly(A) tracts may also play a role in mRNA translation.	Is polyadenylation a process that stabilizes a protein by adding a string of Adenosine residues to the end of the molecule?	The diversity of polyadenylation sites suggests that mRNA polyadenylation in prokaryotes is a relatively indiscriminate process that can occur at all mRNA's 3'-ends and does not require specific consensus sequences as in eukaryotes.
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder that results from functional and ultrastructural abnormalities of motile cilia. Patients with PCD have diverse clinical phenotypes that include chronic upper and lower respiratory tract infections, situs inversus, heterotaxy with or without congenital heart disease, and male infertility, among others. In this report, the carrier frequencies for eleven mutations in eight PCD-associated genes (DNAI1, DNAI2, DNAH5, DNAH11, CCDC114, CCDC40, CCDC65, and C21orf59) that had been found in individuals of Ashkenazi Jewish descent were investigated in order to advise on including them in existing clinical mutation panels for this population. Results showed relatively high carrier frequencies for the DNAH5 c.7502G>C mutation (0.58%), the DNAI2 c.1304G>A mutation (0.50%), and the C21orf59 c.735C>G mutation (0.48%), as well as lower frequencies for mutations in DNAI1, CCDC65, CCDC114, and DNAH11 (0.10-0.29%). These results suggest that several of these genes should be considered for inclusion in carrier screening panels in the Ashkenazi Jewish population.	Which is the molecular function of the protein CCDC40?	Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder that results from functional and ultrastructural abnormalities of motile cilia.
Microneedling with dermaroller is a new treatment modality for the treatment of scars, especially acne scars, stretch marks, wrinkles, and for facial rejuvenation. It is a simple and relatively cheap modality that also can be used for transdermal drug delivery.	What are the applications of a Dermaroller ?	Microneedling with dermaroller is a new treatment modality for the treatment of scars, especially acne scars, stretch marks, wrinkles, and for facial rejuvenation. It is a simple and relatively cheap modality that also can be used for transdermal drug delivery.
Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting has, however, proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA replication initiation machinery and mitotic engine proteins in human tissues is now leading to the identification of novel biomarkers for cancer detection and prognostication, and is providing target validation for cell cycle-directed therapies.	What are negative cell-cycle regulators that can cause cancer when mutated called?	Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation.
Shapiro syndrome is a rare entity, comprising a triad of recurrent hypothermia, hyperhidrosis and congenital agenesis of the corpus callosum. Fewer than 50 cases have been described, almost invariably in patients presenting in childhood or early adulthood. We present a case of an 80 year old woman presenting with recurrent bouts of shivering, sweating and profound malaise, who sought medical attention because the frequency and severity of attacks worsened in her later years. MRI Brain demonstrated agenesis of the corpus callosum; a rigorous work-up excluded other causes for her symptomatology. The intricate interplay of neuronal networks involved in thermoregulation remains to be fully elucidated and as such, little is known about the pathophysiological mechanisms underlying the clinical manifestations of Shapiro syndrome. We present novel data from FDG-PET imaging of our patient, demonstrating hypermetabolism in a number of brainstem and cerebellar regions during the symptomatic phase. These findings imply that aberrant thermoregulation in Shapiro syndrome involves a number of structures remote from the callosal region. We also present neuropsychometric findings in our patient, of which there have been no reports to date. We postulate that the ageing brain may be more susceptible to the paroxysmal neurochemical fluxes implicated in the syndrome.	List common features of Shapiro syndrome	Shapiro syndrome is a rare entity, comprising a triad of recurrent hypothermia, hyperhidrosis and congenital agenesis of the corpus callosum.
: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with an increased risk of recurrence and cancer-related death. Unlike hormone receptor-positive or HER2-positive breast cancers, there are limited targeted therapies available to treat TNBC and cytotoxic chemotherapy remains the mainstay of treatment. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate targeting Trop-2 expressing cells and selectively delivering SN-38, an active metabolite of irinotecan. : This review covers the mechanism of action, safety and efficacy of sacituzumab govitecan in patients with previously treated, metastatic TNBC. Additionally, efficacy data in other epithelial malignancies is included based on a PubMed search for 'sacituzumab govitecan' and 'clinical trial'. : Sacituzumab govitecan has promising anti-cancer activity in patients with metastatic TNBC previously treated with at least two prior lines of systemic therapy based on a single arm Phase I/II clinical trial. A confirmatory Phase III randomized clinical trial is ongoing. Sacituzumab govitecan has a manageable side effect profile, with the most common adverse events being nausea, neutropenia, and diarrhea. The activity of sacituzumab govitecan likely extends beyond TNBC with promising early efficacy data in many other epithelial cancers, including hormone receptor-positive breast cancer.	Is sacituzumab govitecan effective for breast cancer?	The activity of sacituzumab govitecan likely extends beyond TNBC with promising early efficacy data in many other epithelial cancers, including hormone receptor-positive breast cancer.
Activating mutations in NOTCH1 consitute the most prominent genetic abnormality in T-cell acute lymphoblastic leukemia (T-ALL). However, most T-ALL cell lines with NOTCH1 mutations are resistant to treatment with γ-secretase inhibitors (GSIs). The spotlight is now shifting to the phosphatidylinositide 3-kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome ten (PTEN)/AKT/mammalian target of rapamycin (mTOR) pathway as another key potential target. These two signaling routes are deregulated in many types of cancer. In this review we discuss these two pathways with respect to their signaling mechanisms, functions during T-cell development, and their mutual roles in the development of T-ALL.	Are Notch mutations related to T-cell Acute Lymphoblastic Leukemia (T-ALL)?	Activating mutations in NOTCH1 consitute the most prominent genetic abnormality in T-cell acute lymphoblastic leukemia (T-ALL).
Worldwide over 12 million people were diagnosed with cancer (excluding non-melanoma skin cancer) and 8 million individuals died from cancer in 2008. Recent data indicate that 75-90% of patients with advanced stage diseases or metastatic cancer will experience significant cancer pain. Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a marked affinity to metastasize to bone. Once tumors metastasize to bone, they are a major cause of morbidity and mortality as the tumor induces significant skeletal remodeling, fractures, pain and anemia; all of which reduce the functional status, quality of life and survival of the patient. Currently, the factors that drive cancer pain are poorly understood, however, several recently introduced models of bone cancer pain that mirror the human condition, are providing insight into the mechanisms that drive bone cancer pain and guiding the development of novel therapies to treat the cancer pain. Several of these therapies have recently been approved by the FDA to treat bone cancer pain (bisphosphonates, denosumab) and others are currently being evaluated in human clinical trials (tanezumab). These new mechanism-based therapies are enlarging the repertoire of modalities available to treat bone cancer pain and improving the quality of life and functional status of patients with bone cancer.	Has Denosumab (Prolia) been approved by FDA?	Several of these therapies have recently been approved by the FDA to treat bone cancer pain (bisphosphonates, denosumab) and others are currently being evaluated in human clinical trials (tanezumab).