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The upregulation or mutation of C-MYC has been observed in gastric, colon, breast, and lung tumors and in Burkitt's lymphoma. However, little is known about the role C-MYC plays in gastric adenocarcinoma. In the present study, we intended to investigate the influence of C-MYC on the growth, proliferation, apoptosis, invasion, and cell cycle of the gastric cancer cell line SGC7901 and the gastric cell line HFE145. C-MYC cDNA was subcloned into a constitutive vector PCDNA3.1 followed by transfection in normal gastric cell line HFE145 by using liposome. Then stable transfectants were selected and appraised. Specific inhibition of C-MYC was achieved using a vector-based siRNA system which was transfected in gastric cancer cell line SGC7901. The apoptosis and cell cycles of these clones were analyzed by using flow cytometric assay. The growth and proliferation were analyzed by cell growth curves and colony-forming assay, respectively. The invasion of these clones was analyzed by using cell migration assay. The C-MYC stable expression clones (HFE-Myc) and C-MYC RNAi cells (SGC-MR) were detected and compared with their control groups, respectively. HFE-Myc grew faster than HFE145 and HFE-PC (HFE145 transfected with PCDNA3.1 vector). SGC-MR1, 2 grew slower than SGC7901 and SGC-MS1, 2 (SGC7901 transfected with scrambled control duplexes). The cell counts of HFE-Myc in the third, fourth, fifth, sixth, and seventh days were significantly more than those of control groups (P < 0.05). Those of SGC-MR1, 2 in the fourth, fifth, sixth, and seventh days were significantly fewer than those of control groups (P < 0.05). Cell cycle analysis showed that proportions of HFE-Myc and SGC-MR cells in G0-G1 and G2-M were different significantly with their control groups, respectively (P < 0.05). The apoptosis rate of HFE-Myc was significantly higher than those of control groups (P < 0.05). Results of colony-forming assay showed that the colony formation rate of HFE-Myc was higher than those of control groups; otherwise, the rate of SGC-MR was lower than those of their control groups (P < 0.05). The results of cell migration assay showed that there were no significant differences between experimental groups and control groups (P > 0.05). In conclusion, C-MYC can promote the growth and proliferation of normal gastric cells, and knockdown of C-MYC can restrain the growth and proliferation of gastric cancer cells. It can induce cell apoptosis and help tumor cell maintain malignant phenotype. But it can have not a detectable influence on the ability of invasion of gastric cancer cells.	Which are the types of cancer that c-Myc is associated with?	The upregulation or mutation of C-MYC has been observed in gastric, colon, breast, and lung tumors and in Burkitt's lymphoma.
A 27-year-old man bearing an erythropoietic protoporphyria (EPP)-associated ferrochelatase (FECH) mutation was admitted to our hospital for general malaise and marked elevation of the serum levels of hepatobiliary enzymes and bilirubin. Initial treatment with plasma exchange did not reduce the blood protoporphyrin or serum liver enzyme levels, so phlebotomy was started. Surprisingly, weekly phlebotomy normalized the serum levels of liver enzymes, accompanied by a marked reduction in the blood protoporphyrin levels. The clinical course of this case strongly suggests that phlebotomy may be a suitable treatment option for EPP-related hepatopathy.	Which protein is mutated in Erythropoietic Protoporphyria?	an erythropoietic protoporphyria (EPP)-associated ferrochelatase (FECH) mutation
Microtubules are found in all eukaryotes and are built from alphabeta-tubulin heterodimers. The alpha-tubulins and beta-tubulins are among the most highly conserved eukaryotic proteins. Other members of the tubulin family have come to light recently and, like gamma-tubulin, appear to play roles in microtubule nucleation and assembly. Microtubule assembly is accompanied by hydrolysis of GTP associated with beta-tubulin so that microtubules consist principally of "GDP-tubulin" stabilized by a short "GTP cap." Microtubules are polar, cylindrical structures some 25 nm in diameter. Protofilaments made from tubulin heterodimers run lengthwise along the microtubule wall with the beta-tubulin subunit at the microtubule plus end. The crystallographic structures of tubulins are essential to understand in detail microtubule architecture and interactions with stabilizing and destabilizing drugs and proteins.	What is the typical outer diameter of microtubules (tubulin heterodimers)?	Microtubule assembly is accompanied by hydrolysis of GTP associated with beta-tubulin so that microtubules consist principally of "GDP-tubulin" stabilized by a short "GTP cap." Microtubules are polar, cylindrical structures some 25 nm in diameter.
E3 ubiquitin ligases are a large family of proteins that can be classified into three major structurally distinct types: N-end rule E3s, E3s containing the HECT (Homology to E6AP C-Terminus) domain, and E3s with the RING (Really Interesting New Gene) finger, including its derivatives, the U- Box and the PHD (Plant Homeo-Domain). E3 ubiquitin ligases exist as single polypeptide or multimeric complexes. Together with ubiquitin activating enzyme E1 and ubiquitin conjugating enzyme E2, E3 ubiquitin ligases catalyze the ubiquitination of a variety of protein substrates for targeted degradation via the 26S proteasome. E3 ubiqutin ligases, therefore, play an essential role in regulation of many biological processes. Furthermore, E3s are enzymes that determine the specificity of protein substrates; they represent a class of "drugable" targets for pharmaceutical intervention. In this review, I will mainly focus on E3 ubiquitin ligases as potential cancer targets and discuss three of the most promising E3s, Mdm2/Hdm2, IAPs, and SCF, for their target rationales, target validation, and critical issues associated with them. These E3 ligases or their components are overexpressed in many human cancers and their inhibition leads to growth suppression or apoptosis. In addition, I will evaluate two current methodologies available for the high throughput screening for small molecular weight chemical inhibitors of the E3 ubiquitin ligases. Although targeting E3 ubiquitin ligases is still in its infancy, speedy approval of the general proteasome inhibitor, Velcade (bortezomib) by the FDA for the treatment of relapsed and refractory multiple myeloma suggests the promise of specific E3 inhibitors in anti-cancer therapy. Emerging technologies, such as siRNA, will provide a better validation of many E3s. It is anticipated that E3 ubiquitin ligases will represent an important new target platform for future mechanism-driven drug discovery.	Which is the target of bortezomib used in cancer therapy?	Although targeting E3 ubiquitin ligases is still in its infancy, speedy approval of the general proteasome inhibitor, Velcade (bortezomib) by the FDA for the treatment of relapsed and refractory multiple myeloma suggests the promise of specific E3 inhibitors in anti-cancer therapy.
Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b (miR-29b) expression during iPSC generation and that miR-29b expression is required for OSKM- and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA methylation-related events during reprogramming.	Which transcription factors are known as the four (4) "Yamanaka factors" that have been used to create induced pluripotent stem cells (iPSCs)?	Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood.
ADAMTSL4 is the most important known causative gene in isolated EL. Mutations in ADAMTSL4 appear to cause earlier manifestation of EL and are associated with increased axial length as compared to FBN1. We suggest that ADAMTSL4 be screened in all patients with isolated EL and that physicians be vigilant for the more severe ocular phenotype associated with mutations in this gene.	Which mutated genes are associated with isolated ectopia lentis?	ADAMTSL4 is the most important known causative gene in isolated EL. Mutations in ADAMTSL4 appear to cause earlier manifestation of EL and are associated with increased axial length as compared to FBN1. We suggest that ADAMTSL4 be screened in all patients with isolated EL and that physicians be vigilant for the more severe ocular phenotype associated with mutations in this gene.
Granuloma annulare and necrobiosis lipoidica diabeticorum have rarely been reported in the same patient. We describe the unusual case of a woman with diabetes and a history of generalized granuloma annulare who noted leg ulcers that clinically represented ulcerated necrobiosis lipoidica diabeticorum and had histologic features of necrobiosis lipoidica diabeticorum and granuloma annulare. Her condition responded to treatment with antiplatelet agents.	Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?	We describe the unusual case of a woman with diabetes and a history of generalized granuloma annulare who noted leg ulcers that clinically represented ulcerated necrobiosis lipoidica diabeticorum and had histologic features of necrobiosis lipoidica diabeticorum and granuloma annulare.
Brucella abortus is a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. The mechanism of virulence of Brucella spp. is not fully understood yet. Furthermore, genes that allow Brucella to reach the intracellular niche and to interact with host cells need to be identified. Using the genomic survey sequence (GSS) approach, we identified the gene encoding an ATP-binding cassette (ABC) transporter of B. abortus strain S2308. The deduced amino acid sequence encoded by this gene exhibited 69 and 67% identity with the sequences of the ABC transporters encoded by the exsA genes of Rhizobium meliloti and Mesorhizobium loti, respectively. Additionally, B. abortus ExsA, like R. meliloti and M. loti ExsA, possesses ATP-binding motifs and the ABC signature domain features of a typical ABC transporter. Furthermore, ortholog group analysis placed B. abortus ExsA in ortholog group 6 of ABC transporters more likely to be involved in bacterial pathogenesis. In R. meliloti, ExsA is an exopolysaccharide transporter essential for alfalfa root nodule invasion and establishment of infection. To test the role of ExsA in Brucella pathogenesis, an exsA deletion mutant was constructed. Replacement of the wild-type exsA by recombination was demonstrated by Southern blot analysis of Brucella genomic DNA. Decreased survival in mice of the Brucella DeltaexsA mutant compared to the survival of parental strain S2308 demonstrated that ExsA is critical for full bacterial virulence. Additionally, the B. abortus exsA deletion mutant was used as a live vaccine. Challenge experiments revealed that the exsA mutant strain induced superior protective immunity in BALB/c mice compared to the protective immunity induced by strain S19 or RB51.	Is Brucella abortus the organism that causes brucillosis known to cause spontaneous abortions in humans?	Brucella abortus is a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans.
As part of an effort to diagnose the physiological status of Geobacter species during in situ bioremediation of uranium-contaminated groundwater, transcript levels for two genes potentially associated with oxidative stress, cydA and sodA, were quantified throughout a bioremediation field study in Rifle, CO, USA. Despite the accumulation of Fe(II) in the groundwater, which is inconsistent with the presence of dissolved oxygen, both genes were highly expressed during the bioremediation process. Therefore, the response to oxidative stress was further evaluated with Geobacter uraniireducens, an isolate from the Rifle site. When G. uraniireducens cultured with fumarate as the electron acceptor was exposed to 5% oxygen for 8 h, there was a significant increase in cydA and sodA transcripts as well as other genes associated with oxygen respiration or oxidative stress. Oxygen-exposed cells had lower transcript abundance for genes associated with anaerobic respiration, metabolism and motility. Short-term oxygen exposure had little impact on cydA transcript levels, as more than 1 h was required for increases to levels comparable to the subsurface. Abundance of cydA and sodA transcripts for the isolate G. sulfurreducens were always higher in cells cultured with Fe(III) compared with fumarate as an electron acceptor, even when fumarate-grown cells were exposed to oxygen, and Fe(III)-grown cells were grown anaerobically. These results suggest that the apparently high Geobacter cydA and sodA expression during bioremediation cannot necessarily be attributed to oxidative stress and demonstrate that diagnosis of the metabolic status of subsurface microorganisms through transcript analysis should be coupled with appropriate geochemical analyses.	List bacteria that may be useful in uranium bioremediation.	Geobacter uraniireducens
Entacapone (Comtess/Comtan) is Orion Pharma's original proprietary catechol-O-methyl transferase (COMT) inhibitor. Entacapone is able to slow down degradation of levodopa and improve the availability and efficacy of each levodopa dose, hence its use as a complement to levodopa/carbidopa in patients with Parkinson's disease. In order to simplify the daily dosing of these medications, Orion has developed an entacapone/levodopa/carbidopa combination tablet. Three tablet strengths are being developed so as to cover the most common clinical dosing needs. In September 2000, Orion signed a marketing and distribution agreement with Novartis for the combination tablet. Under the terms of the agreement, Orion has exclusive marketing rights for the product in Germany, the UK, Ireland, the Nordic and Baltic countries, and several Eastern European countries. Novartis has exclusive rights to the US and territories other than those markets for which Orion holds market exclusivity. Orion also has the option to co-promote the product in France, Spain and several other countries. In June 2003, the US FDA approved the entacapone/levodopa/carbidopa combination tablet (Stalevo) for the treatment of patients with idiopathic Parkinson's disease who experience signs and symptoms of end-of-dose 'wearing off'. Market launch of the product is expected toward the end of 2003 in the US. Also in June 2003, the Committee for Proprietary Medicinal Products of the European Agency for the Evaluation of Medicinal Products adopted a positive opinion of the combination tablet. In September 2002, Orion submitted an application for the approval of the combination product in the European Union. It is expected that the product will be marketed in the European Union in early 2004. Orion estimates that about two of three fluctuating Parkinson's disease patients will be able to be treated effectively with the triple combination tablet.	Which two catechol-O-methyl transferase (COMT) inhibitors can be used for treatment of Parkinson disease?	Entacapone (Comtess/Comtan) is Orion Pharma's original proprietary catechol-O-methyl transferase (COMT) inhibitor. Entacapone is able to slow down degradation of levodopa and improve the availability and efficacy of each levodopa dose, hence its use as a complement to levodopa/carbidopa in patients with Parkinson's disease.
Mouse PUMILIO1 (PUM1) and PUMILIO2 (PUM2) belong to the PUF (Pumilio/FBF) family, a highly conserved RNA binding protein family whose homologues play critical roles in embryonic development and germ line stem cell maintenance in invertebrates. However, their roles in mammalian embryonic development and stem cell maintenance remained largely uncharacterized. Here we report an essential requirement of the Pum gene family in early embryonic development. A loss of both Pum1 and Pum2 genes led to gastrulation failure, resulting in embryo lethality at E8.5. Pum-deficient blastocysts, however, appeared morphologically normal, from which embryonic stem cells (ESCs) could be established. Both mutant ESCs and embryos exhibited reduced growth and increased expression of endoderm markers Gata6 and Lama1, making defects in growth and differentiation the likely causes of gastrulation failure. Furthermore, ESC Gata6 transcripts could be pulled down via PUM1 immunoprecipitation and mutation of conserved PUM-binding element on 3'UTR (untranslated region) of Gata6 enhanced the expression of luciferase reporter, implicating PUM-mediated posttranscriptional regulation of Gata6 expression in stem cell development and cell lineage determination. Hence, like its invertebrate homologues, mouse PUM proteins are conserved posttranscriptional regulators essential for embryonic and stem cell development.	What is the function of the protein encoded by PUMILIO1?	Mouse PUMILIO1 (PUM1) and PUMILIO2 (PUM2) belong to the PUF (Pumilio/FBF) family, a highly conserved RNA binding protein family whose homologues play critical roles in embryonic development and germ line stem cell maintenance in invertebrates.
SETD1A, a lysine-methyltransferase, is a key schizophrenia susceptibility gene. Mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics accompanied by working memory deficits. We show that Setd1a binds both promoters and enhancers with a striking overlap between Setd1a and Mef2 on enhancers. Setd1a targets are highly expressed in pyramidal neurons and display a complex pattern of transcriptional up- and downregulations shaped by presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice. Our findings advance understanding of how SETD1A mutations predispose to schizophrenia (SCZ) and point to novel therapeutic interventions.	Do SETD1A mutations predispose to schizophrenia?	SETD1A, a lysine-methyltransferase, is a key schizophrenia susceptibility gene. Mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics accompanied by working memory deficits. We show that Setd1a binds both promoters and enhancers with a striking overlap between Setd1a and Mef2 on enhancers. Setd1a targets are highly expressed in pyramidal neurons and display a complex pattern of transcriptional up- and downregulations shaped by presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice. Our findings advance understanding of how SETD1A mutations predispose to schizophrenia (SCZ) and point to novel therapeutic interventions.
There are currently two Food and Drug Administration-approved classes of biologic agents that target tumor necrosis factor-alpha (TNF-alpha): anti-TNF monoclonal antibodies (mAbs) (adalimumab and infliximab), and soluble TNF receptors (etanercept). This study examined the ability of the TNF antagonists to: (1) bind various polymorphic variants of cell surface-expressed Fc receptors (FcgammaRs) and the complement component C1q, and (2) mediate Ab-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) killing of cells expressing membrane-bound TNF (mTNF) in vitro. Both mAbs and the soluble TNF receptor demonstrated low-level binding to the activating receptors FcgammaRI, FcgammaRIIa, and FcgammaRIIIa, and the inhibitory receptor FcgammaRIIb, in the absence of exogenous TNF. However, upon addition of TNF, the mAbs, but not etanercept, showed significantly increased binding, in particular to the FcgammaRII and FcgammaRIII receptors. Infliximab and adalimumab induced ADCC much more potently than etanercept. In the presence of TNF, both mAbs bound C1q in in vitro assays, but etanercept did not bind C1q under any conditions. Infliximab and adalimumab also induced CDC in cells expressing mTNF more potently than etanercept. Differences in the ability to bind ligand and mediate cell death may account for the differences in efficacy and safety of TNF antagonists.	What is the target of adalimumab?	There are currently two Food and Drug Administration-approved classes of biologic agents that target tumor necrosis factor-alpha (TNF-alpha): anti-TNF monoclonal antibodies (mAbs) (adalimumab and infliximab), and soluble TNF receptors (etanercept). This st
Minisatellites are repetitive sequences of DNA that are present throughout the genome. Although the origin and function of these minisatellites is still unknown, they found clinical applications as markers of many diseases, including cancer. Also, they are useful tools for DNA fingerprinting and linkage analysis. Kallikreins are serine proteases that appear to be involved in many diseases including brain disorders and malignancy. We have recently characterized the human kallikrein gene locus on chromosome 19q13.4, which includes 15 kallikrein genes. In this study, we examined the kallikrein locus ( approximately 300 Kb) for all known repeat elements. About 50% of this genomic area is occupied by different repeat elements. We also identified unique minisatellite elements that are restricted to chromosome 19q13. Ten clusters of these minisatellites are distributed along the locus on either DNA strand. The clusters are located in the promoters and enhancers of genes, in introns, and in untranslated regions of the mRNA. Analysis of these elements indicates that they are polymorphic, thus they can be useful in linkage analysis and DNA fingerprinting. Our preliminary results indicate also that the distribution of the different alleles of these minisatellites might be associated with malignancy.	How many tissue kallikrein genes are present in the human genome?	We have recently characterized the human kallikrein gene locus on chromosome 19q13.4, which includes 15 kallikrein genes.
Suicide is a major problem in Western society. However we have very little understanding of suicidal behaviour among individuals with autism spectrum disorders. The purpose of this review is to synthesise primary research on suicidal behaviour among adolescents and young adults with autism spectrum disorders in order to estimate prevalence and to identify and critically evaluate risk factors for suicidal behaviour in this population. Four primary research studies were identified for this review following a comprehensive literature search. The available research provides little empirical evidence for the processes underlying suicidal behaviour in adolescents and young adults with autism.	Is there any association between suicide and autism in adolescents, yes or no?	Suicide is a major problem in Western society. However we have very little understanding of suicidal behaviour among individuals with autism spectrum disorders.
Risdiplam (Evrysdi™) is an orally administered, survival motor neuron 2 (SMN2)-directed RNA splicing modifier being developed by Roche, PTC Therapeutics Inc and the SMA Foundation for the treatment of the spinal muscular atrophy. The small molecule is designed to treat spinal muscular atrophy caused by mutations in chromosome 5q leading to SMN protein deficiency. The drug boosts the ability of an alternative gene SMN2 to produce full-length and functional SMN protein. In August 2020, Evrysdi™ (risdiplam) received its first approval in the USA for the treatment of spinal muscular atrophy in patients 2 months of age and older. Risdiplam is in pre-registration for this indication in numerous countries worldwide, including the European Union, Brazil, Chile, China, Indonesia, Russia, South Korea and Taiwan. This article summarizes the milestones in the development of risdiplam leading to this first approval for spinal muscular atrophy.	Which disease is treated with Risdiplam?	Risdiplam (Evrysdi™) is an orally administered, survival motor neuron 2 (SMN2)-directed RNA splicing modifier being developed by Roche, PTC Therapeutics Inc and the SMA Foundation for the treatment of the spinal muscular atrophy. The
Interest in nonpharmaceutical supplements for treating major depressive disorder (MDD) has increased signiﬁcantly, both among patients and among clinicians during the past decades. Despite the large array of antidepressants (ADs) available, many patients continue to experience relatively modest response and remission rates, in addition to a burden of side effects that can hinder treatment compliance and acceptability. In this article, we review the literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds linked in the 1-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. Background information, efﬁcacy data, proposed mechanisms of action, and side effects are reviewed. Based on existing data, supplementation with SAMe, as well as with various formulations of folates, appears to be efficacious and well tolerated in reducing depressive symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate (L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD given its greater bioavailability in patients with a genetic polymorphism, and the lower risk of specific side effects associated with folic acid. Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium.	Is treatment resistant depression related to vitamin B9?	Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium.
Preeclampsia is a pregnancy-specific disorder, of which one of its major subtypes, the placental subtype is considered a response to an ischemic placental environment, impacting fetal growth and pregnancy outcome. Inflammatory immune responses have been linked to metabolic and inflammatory disorders as well as reproductive failures. In healthy pregnancy, immune regulatory mechanisms prevent excessive systemic inflammation. However, in preeclampsia, the regulation of immune responses is disrupted as a result of aberrant activation of innate immune cells and imbalanced differentiation of T-helper cell subsets creating a cytotoxic environment . Recognition events that facilitate immune interaction between maternal decidual T cells, NK cells, and cytotrophoblasts are considered an indirect cause of the incomplete remodeling of spiral arteries in preeclampsia. The mechanisms involved include the activation of immune cells and the subsequent secretion of cytokines and placental growth factors affecting trophoblast invasion, angiogenesis, and eventually placentation. In this review, we focus on the role of excessive systemic inflammation as the result of a dysregulated immune system in the development of preeclampsia. These include insufficient control of inflammation, failure of tolerance toward paternal antigens at the fetal-maternal interface, and subsequent over- or insufficient activation of immune mediators. It is also possible that external stimuli, such as bacterial endotoxin, may contribute to the excessive systemic inflammation in preeclampsia by stimulating the release of pro-inflammatory cytokines. In conclusion, a disrupted immune system might be a predisposing factor or result of placental oxidative stress or excessive inflammation in preeclampsia. Preeclampsia can thus be considered a hyperinflammatory state associated with defective regulation of the immune system proposed as a key element in the pathological events of the placental subtype of this disorder.	Is disruption of immune regulation mechanisms associated with adverse pregnancy outcomes, including preeclampsia (PE)?	ever, in preeclampsia, the regulation of immune responses is disrupted as a result of aberrant activation of innate immune cells and imbalanced differ
We show here that the in vivo methylation-based tagging technique DamID (DNA adenine methyltransferase identification) can be used for studies of DNA-protein interactions or chromatin profiling in plants. We have demonstrated the feasibility, reproducibility and sensitivity of the method in Arabidopsis thaliana, using the well-known yeast GAL4 transcription factor, for which DNA-binding sites (UAS(G)) were introduced into the plant genome. We monitored the methylation resulting from the activity of DNA adenine methyltransferase fused to the protein of interest, by combining digestion with methylation-sensitive restriction enzymes and quantitative PCR. We then used DamID to identify genomic targets of LHP1, a protein mostly associated with euchromatin. We showed that LHP1 was targeted to the promoter and transcribed regions of four genes: AG, AP3, FT and PI. Our data also demonstrate that LHP1, like its animal homologues, has a high binding affinity for A/T-rich regions, binding particularly strongly to the large regulatory introns of AG and PI. We identified three major characteristics of LHP1 binding, highlighting the similarities between plant LHP1 and animal HP1 proteins.	What is the basis of the DamID experimental protocol?	We show here that the in vivo methylation-based tagging technique DamID (DNA adenine methyltransferase identification) can be used for studies of DNA-protein interactions or chromatin profiling in plants
Novel genetic profiling tests of breast cancer tissue have been shown to be prognostic for overall survival and predictive of local and distant rates of recurrence in breast cancer patients. One of these tests, Oncotype DXtrade mark, is a diagnostic test comprised of a 21-gene assay applied to paraffin-embedded breast cancer tissue, which allows physicians to predict subgroups of hormone-receptor-positive, node-negative patients who may benefit from hormonal therapy alone or require adjuvant chemotherapy to attain the best survival outcome. The results of the assay are converted to a recurrence score (0-100) that has been found to be predictive of 10- and 15-year local and distant recurrence in node-negative, estrogen-receptor-positive breast cancer patients. Previous studies have shown that patients with high recurrence scores benefit from adjuvant chemotherapy, whereas patients with low recurrence scores do not. To evaluate the ability to guide treatment decisions in the group with a mid-range recurrence score, the North American Cooperative Groups developed the Trial Assessing IndiviuaLized Options for Treatment for breast cancer, a randomized trial of chemotherapy followed by hormonal therapy versus hormonal therapy alone on invasive disease-free survival-ductal carcinoma in situ (IDFS-DCIS) survival in women with node-negative, estrogen-receptor-positive breast cancer with a recurrence score of 11-25. The study was initiated in May 2006 and approximately 4500 patients will be randomized. This article describes the rationale, methodology, statistical ana-lysis and implications of the results on clinical practice.	What is the relationship between TailorX and Oncotype?	To evaluate the ability to guide treatment decisions in the group with a mid-range recurrence score, the North American Cooperative Groups developed the Trial Assessing IndiviuaLized Options for Treatment for breast cancer, a randomized trial of chemotherapy followed by hormonal therapy versus hormonal therapy alone on invasive disease-free survival-ductal carcinoma in situ (IDFS-DCIS) survival in women with node-negative, estrogen-receptor-positive breast cancer with a recurrence score of 11-25.
The perinuclear actin cap is an important cytoskeletal structure that regulates nuclear morphology and re-orientation during front-rear polarisation. The mechanisms regulating the actin cap are currently poorly understood. Here, we demonstrate that STEF/TIAM2, a Rac1 selective guanine nucleotide exchange factor, localises at the nuclear envelope, co-localising with the key perinuclear proteins Nesprin-2G and Non-muscle myosin IIB (NMMIIB), where it regulates perinuclear Rac1 activity. We show that STEF depletion reduces apical perinuclear actin cables (a phenotype rescued by targeting active Rac1 to the nuclear envelope), increases nuclear height and impairs nuclear re-orientation. STEF down-regulation also reduces perinuclear pMLC and decreases myosin-generated tension at the nuclear envelope, suggesting that STEF-mediated Rac1 activity regulates NMMIIB activity to promote stabilisation of the perinuclear actin cap. Finally, STEF depletion decreases nuclear stiffness and reduces expression of TAZ-regulated genes, indicating an alteration in mechanosensing pathways as a consequence of disruption of the actin cap.	What are the effects of STEF depletion?	We show that STEF depletion reduces apical perinuclear actin cables (a phenotype rescued by targeting active Rac1 to the nuclear envelope), increases nuclear height and impairs nuclear re-orientation.
CYLD is a tumour-suppressor gene that is mutated in a benign skin tumour syndrome called cylindromatosis. The CYLD gene product is a deubiquitinating enzyme that was shown to regulate cell proliferation, cell survival and inflammatory responses, mainly through inhibiting NF-kappaB signalling. Here we show that CYLD controls cell growth and division at the G(1)/S-phase as well as cytokinesis by associating with alpha-tubulin and microtubules through its CAP-Gly domains. Translocation of activated CYLD to the perinuclear region of the cell is achieved by an inhibitory interaction of CYLD with histone deacetylase-6 (HDAC6) leading to an increase in the levels of acetylated alpha-tubulin around the nucleus. This facilitates the interaction of CYLD with Bcl-3, leading to a significant delay in the G(1)-to-S-phase transition. Finally, CYLD also interacts with HDAC6 in the midbody where it regulates the rate of cytokinesis in a deubiquitinase-independent manner. Altogether these results identify a mechanism by which CYLD regulates cell proliferation at distinct cell-cycle phases.	Is the protein product of the cylindromatosis gene (CYLD) a deubiquitinating enzyme?	The CYLD gene product is a deubiquitinating enzyme that was shown to regulate cell proliferation, cell survival and inflammatory responses, mainly through inhibiting NF-kappaB signalling.
We describe a gene silencing method that employs a mechanism of action distinct from those of antisense and RNA interference. U1 Adaptors are bifunctional oligonucleotides with a 'target domain' complementary to a site in the target gene's terminal exon and a 'U1 domain' that binds to the U1 small nuclear RNA component of the U1 small nuclear ribonucleoprotein (U1 snRNP) splicing factor. Tethering of U1 snRNP to the target pre-mRNA inhibits poly(A)-tail addition, causing degradation of that RNA species in the nucleus. U1 Adaptors can inhibit both endogenous and reporter genes in a sequence-specific manner. Comparison of U1 Adaptors with small interfering RNA (siRNA) using a genome-wide microarray analysis indicates that U1 Adaptors have limited off-target effects and no detectable adverse effects on splicing. Further, targeting the same gene either with multiple U1 Adaptors or with a U1 Adaptor and siRNA strongly enhances gene silencing.	How could U1 small nuclear RNA be used in therapeutics?	U1 Adaptors are bifunctional oligonucleotides with a 'target domain' complementary to a site in the target gene's terminal exon and a 'U1 domain' that binds to the U1 small nuclear RNA component of the U1 small nuclear ribonucleoprotein (U1 snRNP) splicing factor
Chromosomal translocation that results in fusion of the genes encoding RNA-binding protein EWS and transcription factor FLI1 (EWS-FLI1) is pathognomonic for Ewing sarcoma. EWS-FLI1 alters gene expression through mechanisms that are not completely understood. We performed RNA sequencing (RNAseq) analysis on primary pediatric human mesenchymal progenitor cells (pMPCs) expressing EWS-FLI1 in order to identify gene targets of this oncoprotein. We determined that long noncoding RNA-277 (Ewing sarcoma-associated transcript 1 [EWSAT1]) is upregulated by EWS-FLI1 in pMPCs. Inhibition of EWSAT1 expression diminished the ability of Ewing sarcoma cell lines to proliferate and form colonies in soft agar, whereas EWSAT1 inhibition had no effect on other cell types tested. Expression of EWS-FLI1 and EWSAT1 repressed gene expression, and a substantial fraction of targets that were repressed by EWS-FLI1 were also repressed by EWSAT1. Analysis of RNAseq data from primary human Ewing sarcoma further supported a role for EWSAT1 in mediating gene repression. We identified heterogeneous nuclear ribonucleoprotein (HNRNPK) as an RNA-binding protein that interacts with EWSAT1 and found a marked overlap in HNRNPK-repressed genes and those repressed by EWS-FLI1 and EWSAT1, suggesting that HNRNPK participates in EWSAT1-mediated gene repression. Together, our data reveal that EWSAT1 is a downstream target of EWS-FLI1 that facilitates the development of Ewing sarcoma via the repression of target genes.	Which fusion protein is involved in the development of Ewing sarcoma?	Chromosomal translocation that results in fusion of the genes encoding RNA-binding protein EWS and transcription factor FLI1 (EWS-FLI1) is pathognomonic for Ewing sarcoma.
Hemophilic pseudotumor is a rare but well-known complication of hemophilia manifesting as recurrent hemorrhage and progressive enlargement of hematoma. A patient with severe hemophilia has 1% to 2% chance to develop pseudotumor. The chronic pressure of osseous hemorrhage usually results in bone destruction or resorption. Cranial hemophilic pseudotumors are extremely rare, with only 7 reported cases associated with mild or moderate factor VIII or IX deficiency. A 42-year-old man with a mild factor VIII deficiency developed a pseudotumor of the bilateral skull. Computed tomography and magnetic resonance imaging revealed an extra-axial lesion with bone destruction, and signal changes are consistent with chronic hemorrhage. With adequate factor-deficient replacement therapy, surgical removal was performed. Histologic examination disclosed old blood coagulum. No recurrence was observed in 3 years of follow-up. Cranial hemophilic pseudotumor is extremely rare, and with adequate factor-deficient replacement therapy, surgical management is a safe and effective way for cranial hemophilic pseudotumor treatment.	What is Hemophilic Pseudotumor?	Hemophilic pseudotumor is a rare but well-known complication of hemophilia manifesting as recurrent hemorrhage and progressive enlargement of hematoma.
Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high-throughput fragment-based docking of a diversity set of approximately 40,000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC(50)=2-5 microM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium- and high-throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.	Could plasmepsins be used as targets for developing anti-malaria drugs?	Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria.
Mutations in the structural protein dystrophin underlie muscular dystrophies characterized by progressive deterioration of muscle function. Dystrophin-deficient mdx mice are considered a model for Duchenne muscular dystrophy (DMD). Individuals with DMD are also susceptible to mood disorders, such as depression and anxiety. Therefore, the study objectives were to investigate the effects of the tricyclic antidepressant amitriptyline on mood, learning, central cytokine expression and skeletal muscle inflammation in mdx mice. Amitriptyline-induced effects (10 mg kg(-1) daily s.c. injections, 25 days) on the behaviour of mdx mice were investigated using the open field arena and tail suspension tests. The effects of chronic amitriptyline treatment on inflammatory markers were studied in the muscle and plasma of mdx mice, and mood-associated monoamine and cytokine concentrations were measured in the amygdala, hippocampus, prefrontal cortex, striatum, hypothalamus and midbrain. The mdx mice exhibited increased levels of anxiety and depressive-like behaviour compared with wild-type mice. Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus. Inflammation in mdx skeletal muscle tissue was also reduced following amitriptyline treatment as indicated by decreased immune cell infiltration of muscle and lower levels of the pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6 in the forelimb flexors. Interleukin-6 mRNA expression was remarkably reduced in the amygdala of mdx mice by chronic amitriptyline treatment. Positive effects of amitriptyline on mood, in addition to its anti-inflammatory effects in skeletal muscle, may make it an attractive therapeutic option for individuals with DMD.	What is the effect of amitriptyline in the mdx mouse model of Duchenne muscular dystrophy?	Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus.
The RESID Database is a comprehensive collection of annotations and structures for protein pre-, co- and post-translational modifications including amino-terminal, carboxyl-terminal and peptide chain cross-link modifications. The RESID Database includes: systematic and alternate names, atomic formulas and masses, enzyme activities generating the modifications, keywords, literature citations, Gene Ontology cross-references, Protein Information Resource (PIR) and SWISS-PROT protein sequence database feature table annotations, structure diagrams and molecular models. This database is freely accessible on the Internet through the European Bioinformatics Institute at http://srs.ebi.ac.uk/srs6bin/cgi-bin/wgetz?-page+LibInfo+-lib+RESID, through the National Cancer Institute - Frederick Advanced Biomedical Computing Center at http://www.ncifcrf.gov/RESID, or through the Protein Information Resource at http://pir.georgetown.edu/pirwww/dbinfo/resid.html.	What is the RESID database?	The RESID Database is a comprehensive collection of annotations and structures for protein pre-, co- and post-translational modifications including amino-terminal, carboxyl-terminal and peptide chain cross-link modifications.
Non-coding "ultraconserved" regions containing hundreds of consecutive bases of perfect sequence conservation across mammalian genomes can function as distant-acting enhancers. However, initial deletion studies in mice revealed that loss of such extraordinarily constrained sequences had no immediate impact on viability. Here, we show that ultraconserved enhancers are required for normal development. Focusing on some of the longest ultraconserved sites genome wide, located near the essential neuronal transcription factor Arx, we used genome editing to create an expanded series of knockout mice lacking individual or combinations of ultraconserved enhancers. Mice with single or pairwise deletions of ultraconserved enhancers were viable and fertile but in nearly all cases showed neurological or growth abnormalities, including substantial alterations of neuron populations and structural brain defects. Our results demonstrate the functional importance of ultraconserved enhancers and indicate that remarkably strong sequence conservation likely results from fitness deficits that appear subtle in a laboratory setting.	Are ultraconserved enhancers important for normal development?	Here, we show that ultraconserved enhancers are required for normal development.
A cohort of genes associated with embryonic stem (ES) cell behaviour, including NANOG, are expressed in a number of human cancers. They form an ES-like signature we first described in glioblastoma multiforme (GBM), a highly invasive and incurable brain tumour. We have also shown that HEDGEHOG-GLI (HH-GLI) signalling is required for GBM growth, stem cell expansion and the expression of this (ES)-like stemness signature. Here, we address the function of NANOG in human GBMs and its relationship with HH-GLI activity. We find that NANOG modulates gliomasphere clonogenicity, CD133(+) stem cell cell behavior and proliferation, and is regulated by HH-GLI signalling. However, GLI1 also requires NANOG activity forming a positive loop, which is negatively controlled by p53 and vice versa. NANOG is essential for GBM tumourigenicity in orthotopic xenografts and it is epistatic to HH-GLI activity. Our data establish NANOG as a novel HH-GLI mediator essential for GBMs. We propose that this function is conserved and that tumour growth and stem cell behaviour rely on the status of a functional GLI1-NANOG-p53 network.	Which cellular processes are regulated by Nanog?	We find that NANOG modulates gliomasphere clonogenicity, CD133(+) stem cell cell behavior and proliferation
With the advantages of high throughput, digital control, and highly accurate placement of cells and biomaterial scaffold to the desired 2D and 3D locations, bioprinting has great potential to develop promising approaches in translational medicine and organ replacement. The most recent advances in organ and tissue bioprinting based on the thermal inkjet printing technology are described in this review. Bioprinting has no or little side effect to the printed mammalian cells and it can conveniently combine with gene transfection or drug delivery to the ejected living systems during the precise placement for tissue construction. With layer-by-layer assembly, 3D tissues with complex structures can be printed using scanned CT or MRI images. Vascular or nerve systems can be enabled simultaneously during the organ construction with digital control. Therefore, bioprinting is the only solution to solve this critical issue in thick and complex tissues fabrication with vascular system. Collectively, bioprinting based on thermal inkjet has great potential and broad applications in tissue engineering and regenerative medicine. This review article introduces some important patents related to bioprinting of living systems and the applications of bioprinting in tissue engineering field.	For the constructions of which organs has 3D printing been tested?	Bioprinting has no or little side effect to the printed mammalian cells and it can conveniently combine with gene transfection or drug delivery to the ejected living systems during the precise placement for tissue construction.
Epithelial ovarian cancer (EOC) is one of the leading causes of cancer deaths in women worldwide. Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in sumoylation-mediated cellular pathways. Although sumoylation plays a key role in DNA repair and tumorgenesis, whether Ubc9 is involved in EOC progression remains unknown. In the present study, we constructed Ubc-9 expressed recombined plasmid pEGFP-N1-Ubc9. The mRNA levels of Ubc9 were confirmed in human ovarian cell lines before and after transfection with pEGFP-N1-Ubc9 or small interfering RNA (siRNA) targeted Ubc9 by real-time polymerase chain reaction (PCR). The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to observe the effect of Ubc9 on cell proliferation. The protein levels of Ubc9, and proliferation-related signals Akt and physphorylated Akt were determined by Western blot. Our results showed that proliferation of EOC cells increased significantly in Ubc9 overexpressing cells, but decreased in Ubc9 knockdown cells. The physphorylation of Akt showed similar trends. In addition, the inhibitor of PI3K/Akt signaling pathway, LY294002, dramatically inhibited the growth of Ubc9 overexpressing cells. Therefore, Ubc9 gene plays an important role in cell proliferation in EOC through PI3K/Akt signaling pathway.	What is the role of the UBC9 enzyme in the protein sumoylation pathway?	Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in sumoylation-mediated cellular pathways.
The transcription-repair coupling factor (TRCF, the product of the mfd gene) is a widely conserved bacterial protein that mediates transcription-coupled DNA repair. TRCF uses its ATP-dependent DNA translocase activity to remove transcription complexes stalled at sites of DNA damage, and stimulates repair by recruiting components of the nucleotide excision repair pathway to the site. A protein/protein interaction between TRCF and the β-subunit of RNA polymerase (RNAP) is essential for TRCF function. CarD (also called CdnL), an essential regulator of rRNA transcription in Mycobacterium tuberculosis, shares a homologous RNAP interacting domain with TRCF and also interacts with the RNAP β-subunit. We determined the 2.9-Å resolution X-ray crystal structure of the RNAP interacting domain of TRCF complexed with the RNAP-β1 domain, which harbors the TRCF interaction determinants. The structure reveals details of the TRCF/RNAP protein/protein interface, providing a basis for the design and interpretation of experiments probing TRCF, and by homology CarD, function and interactions with the RNAP.	Which proteins act as factors that promote transcription-coupled repair in bacteria?	The transcription-repair coupling factor (TRCF, the product of the mfd gene) is a widely conserved bacterial protein that mediates transcription-coupled DNA repair.
Several computational methods exist for the identification of transmembrane beta barrel proteins (TMBs) from sequence. Some of these methods also provide the transmembrane (TM) boundaries of the putative TMBs. The aim of this study is to (1) derive the propensities of the TM residues to be exposed to the lipid bilayer and (2) to predict the exposure status (i.e. exposed to the bilayer or hidden in protein structure) of TMB residues. Three novel propensity scales namely, BTMC, BTMI and HTMI were derived for the TMB residues at the hydrophobic core region of the outer membrane (OM), the lipid-water interface regions of the OM, and for the helical membrane proteins (HMPs) residues at the lipid-water interface regions of the inner membrane (IM), respectively. Separate propensity scales were derived for monomeric and functionally oligomeric TMBs. The derived propensities reflect differing physico-chemical properties of the respective membrane bilayer regions and were employed in a computational method for the prediction of the exposure status of TMB residues. Based on the these propensities, the conservation indices and the frequency profile of the residues, the transmembrane residues were classified into buried/exposed with an accuracy of 77.91% and 80.42% for the residues at the membrane core and the interface regions, respectively. The correlation of the derived scales with different physico-chemical properties obtained from the AAIndex database are also discussed. Knowledge about the residue propensities and burial status will be useful in annotating putative TMBs with unknown structure.	What are the computational methods for the prediction of beta-barrel transmembrane proteins?	Several computational methods exist for the identification of transmembrane beta barrel proteins (TMBs) from sequence. Some of these methods also provide the transmembrane (TM) boundaries of the putative TMBs. The aim of this study is to (1) derive the propensities of the TM residues to be exposed to the lipid bilayer and (2) to predict the exposure status (i.e. exposed to the bilayer or hidden in protein structure) of TMB residues.
cause sudden cardiac death?	Over 80% of SCD occurs in patients with organic heart disease. However, approximately 10-15% of SCD occurs in the presence of structurally normal heart and the majority of those patients are young. In this group of patients, changes in genes encoding cardiac ion channels produce modification of the function of the channel resulting in an electrophysiological substrate of VA and SCD. Collectively these disorders are referred to as Cardiac Ion Channelopathies. The 4 major syndromes in this group are: The Long QT Syndrome (LQTS), the Brugada Syndrome (BrS), the Short QT Syndrome (SQTS), and the Catecholaminergic Polymorphic VT (CPVT).	null
Gene looping, defined as the interaction of the promoter and the terminator regions of a gene during transcription, requires transcription factor IIB (TFIIB). We have earlier demonstrated association of TFIIB with the distal ends of a gene in an activator-dependent manner (El Kaderi, B., Medler, S., Raghunayakula, S., and Ansari, A. (2009) J. Biol. Chem. 284, 25015-25025). The presence of TFIIB at the 3' end of a gene required its interaction with cleavage factor 1 (CF1) 3' end processing complex subunit Rna15. Here, employing affinity chromatography and glycerol gradient centrifugation, we show that TFIIB associates with poly(A) polymerase and the entire CF1 complex in yeast cells. The factors required for general transcription such as TATA-binding protein, RNA polymerase II, and TFIIH are not a component of the TFIIB complex. This holo-TFIIB complex was resistant to MNase digestion. The complex was observed only in the looping-competent strains, but not in the looping-defective sua7-1 strain. The requirement of Rna15 in gene looping has been demonstrated earlier. Here we provide evidence that poly(A) polymerase (Pap1) as well as CF1 subunits Rna14 and Pcf11 are also required for loop formation of MET16 and INO1 genes. Accordingly, cross-linking of TFIIB to the 3' end of genes was abolished in the mutants of Pap1, Rna14, and Pcf11. We further show that in sua7-1 cells, where holo-TFIIB complex is not formed, the kinetics of activated transcription is altered. These results suggest that a complex of TFIIB, CF1 subunits, and Pap1 exists in yeast cells. Furthermore, TFIIB interaction with the CF1 complex and Pap1 is crucial for gene looping and transcriptional regulation.	Which protein mediates gene loop formation in the yeast S. cerevisiae?	We have earlier demonstrated association of TFIIB with the distal ends of a gene in an activator-dependent manner
Glaucoma is an ocular disease characterized by distinctive changes in the optic nerve head (ONH) and visual field. Glaucoma can strike without symptoms and causes blindness if it remains without treatment. Therefore, early disease detection is important so that treatment can be initiated and blindness prevented. In this context, important advances in technology for non-invasive imaging of the eye have been made providing quantitative tools to measure structural changes in ONH topography, an essential element for glaucoma detection and monitoring. 3D spectral domain optical coherence tomography (SD-OCT), an optical imaging technique, has been commonly used to discriminate glaucomatous from healthy subjects. In this paper, we present a new framework for detection of glaucoma progression using 3D SD-OCT images. In contrast to previous works that the retinal nerve fiber layer (RNFL) thickness measurement provided by commercially available spectral-domain optical coherence tomograph, we consider the whole 3D volume for change detection. To integrate a priori knowledge and in particular the spatial voxel dependency in the change detection map, we propose the use of the Markov Random Field to handle a such dependency. To accommodate the presence of false positive detection, the estimated change detection map is then used to classify a 3D SDOCT image into the "non-progressing" and "progressing" glaucoma classes, based on a fuzzy logic classifier. We compared the diagnostic performance of the proposed framework to existing methods of progression detection.	What is the 3D tomography imaging technique for diagnosis of eye disease?	3D spectral domain optical coherence tomography (SD-OCT), an optical imaging technique, has been commonly used to discriminate glaucomatous from healthy subjects.
Migalastat (Galafold™)-a small molecule drug developed by Amicus Therapeutics that restores the activity of specific mutant forms of α-galactosidase-has been approved for the treatment of Fabry disease in the EU in patients with amenable mutations. Fabry disease is a rare disorder that results in a deficiency or absence of α-galactosidase, leading to accumulation of globotriaosylceramide in the lysosomes of various cells. This article summarizes the milestones in the development of migalastat leading to this first approval in the EU for the long-term treatment of adults and adolescents aged ≥16 years with a confirmed diagnosis of Fabry disease.	Is Migalastat used for treatment of Fabry Disease?	Migalastat (Galafold™)-a small molecule drug developed by Amicus Therapeutics that restores the activity of specific mutant forms of α-galactosidase-has been approved for the treatment of Fabry disease in the EU in patients with amenable mutations.
The concept of (bacterio)phage therapy is simple; target the phage to the bacterial pathogen causing disease. As phages are natural killers of bacteria, one could expect this to be an easy task. However, when it comes to phage therapy within the gut, it might not be quite that simple. Already without exogenous intervention, a multitude of phage-bacterial interactions occur within the human gut, some of which might play a direct role in disease progression. In this perspective, we aim to summarise the current understanding of phages within our gut, moving from infancy, adulthood, and then into disease progression. We then highlight recent advances in phage-based interventions, both conventional phage therapy and the progressing field of whole virome transplant.	Do we find bacteriophages in the gut?	Already without exogenous intervention, a multitude of phage-bacterial interactions occur within the human gut, some of which might play a direct role in disease progression
The intermediate syndrome (IMS) following organophosphorus (OP) insecticide poisoning was first described in the mid-1980s. The syndrome described comprised characteristic symptoms and signs occurring after apparent recovery from the acute cholinergic syndrome. As the syndrome occurred after the acute cholinergic syndrome but before organophosphate-induced delayed polyneuropathy, the syndrome was called 'intermediate syndrome'. The IMS occurs in approximately 20% of patients following oral exposure to OP pesticides, with no clear association between the particular OP pesticide involved and the development of the syndrome. It usually becomes established 2-4 days after exposure when the symptoms and signs of the acute cholinergic syndrome (e.g. muscle fasciculations, muscarinic signs) are no longer obvious. The characteristic features of the IMS are weakness of the muscles of respiration (diaphragm, intercostal muscles and accessory muscles including neck muscles) and of proximal limb muscles. Accompanying features often include weakness of muscles innervated by some cranial nerves. It is now emerging that the degree and extent of muscle weakness may vary following the onset of the IMS. Thus, some patients may only have weakness of neck muscles whilst others may have weakness of neck muscles and proximal limb muscles. These patients may not require ventilatory care but close observation and monitoring of respiratory function is mandatory. Management is essentially that of rapidly developing respiratory distress and respiratory failure. Delays in instituting ventilatory care will result in death. Initiation of ventilatory care and maintenance of ventilatory care often requires minimal doses of non-depolarising muscle relaxants. The use of depolarising muscle relaxants such as suxamethonium is contraindicated in OP poisoning. The duration of ventilatory care required by patients may differ considerably and it is usual for patients to need ventilatory support for 7-15 days and even up to 21 days. Weaning from ventilatory care is best carried out in stages, with provision of continuous positive airway pressure prior to complete weaning. Continuous and close monitoring of respiratory function (arterial oxygen saturation, partial pressure of oxygen in arterial blood, partial pressure of carbon dioxide in arterial blood) and acid-base status are an absolute necessity. Prophylactic antibiotics are usually not required unless there has been evidence of aspiration of material into the lungs. Close monitoring of fluid and electrolyte balance is mandatory in view of the profuse offensive diarrhoea that most patients develop. Maintenance of nutrition, physiotherapy, prevention of bed sores and other routine measures to minimise discomfort during ventilatory care are necessary. Recovery from the intermediate syndrome is normally complete and without any sequelae. The usefulness of oximes during the IMS remains uncertain. In animal experiments, very early administration of oximes has prevented the occurrence of myopathy. There are reports from developed countries where administration of oximes at recommended doses and within 2 hours of ingestion of OP insecticide did not prevent the onset of the IMS. Controlled randomised clinical studies are necessary to evaluate the efficacy of oximes in combating the IMS. Electrophysiological studies following OP poisoning have revealed three characteristic phenomena: (i) repetitive firing following a single stimulus; (ii) gradual reduction in twitch height or compound muscle action potential followed by an increase with repetitive stimulation (the 'decrement-increment response'); and (iii) continued reduction in twitch height or compound muscle action potential with repetitive simulation ('decrementing response'). Of these, the decrementing response is the most frequent finding during the IMS, whilst repetitive firing is observed during the acute cholinergic syndrome. The distribution of the weakness in human cases of the IMS, in general, parallels the distribution of the myopathy observed in a number of studies in experimental animals. This has led to speculation that myopathy is involved in the causation of the IMS. However, while myopathy and the IMS have a common origin in acetylcholine accumulation, they are not causally related to one another.	Is pesticide exposure associated with polyneuropathy?	As the syndrome occurred after the acute cholinergic syndrome but before organophosphate-induced delayed polyneuropathy, the syndrome was called 'intermediate syndrome'.