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Fecal microbiota transplantation (FMT) is becoming a more widely used technology for treatment of recurrent Clostridum difficile infection (CDI). While previous treatments used fresh fecal slurries as a source of microbiota for FMT, we recently reported the successful use of standardized, partially purified and frozen fecal microbiota to treat CDI. Here we report that high-throughput 16S rRNA gene sequencing showed stable engraftment of gut microbiota following FMT using frozen fecal bacteria from a healthy donor. Similar bacterial taxa were found in post-transplantation samples obtained from the recipients and donor samples, but the relative abundance varied considerably between patients and time points. Post FMT samples from patients showed an increase in the abundance of Firmicutes and Bacteroidetes, representing 75-80% of the total sequence reads. Proteobacteria and Actinobacteria were less abundant (< 5%) than that found in patients prior to FMT. Post FMT samples from two patients were very similar to donor samples, with the Bacteroidetes phylum represented by a great abundance of members of the families Bacteroidaceae, Rikenellaceae and Porphyromonadaceae, and were largely comprised of Bacteroides, Alistipes and Parabacteroides genera. Members of the phylum Firmicutes were represented by Ruminococcaceae, Lachnospiraceae, Verrucomicrobiaceae and unclassified Clostridiales and members of the Firmicutes. One patient subsequently received antibiotics for an unrelated infection, resulting in an increase in the number of intestinal Proteobacteria, primarily Enterobacteriaceae. Our results demonstrate that frozen fecal microbiota from a healthy donor can be used to effectively treat recurrent CDI resulting in restoration of the structure of gut microbiota and clearing of Clostridum difficile.	Fecal transplantation is used to treat infection with what bacteria?	While previous treatments used fresh fecal slurries as a source of microbiota for FMT, we recently reported the successful use of standardized, partially purified and frozen fecal microbiota to treat CDI.
Biological expression language (BEL) is one of the most popular languages to represent the causal and correlative relationships among biological events. Automatically extracting and representing biomedical events using BEL can help biologists quickly survey and understand relevant literature. Recently, many researchers have shown interest in biomedical event extraction. However, the task is still a challenge for current systems because of the complexity of integrating different information extraction tasks such as named entity recognition (NER), named entity normalization (NEN) and relation extraction into a single system. In this study, we introduce our BelSmile system, which uses a semantic-role-labeling (SRL)-based approach to extract the NEs and events for BEL statements. BelSmile combines our previous NER, NEN and SRL systems. We evaluate BelSmile using the BioCreative V BEL task dataset. Our system achieved an F-score of 27.8%, ∼7% higher than the top BioCreative V system. The three main contributions of this study are (i) an effective pipeline approach to extract BEL statements, and (ii) a syntactic-based labeler to extract subject-verb-object tuples. We also implement a web-based version of BelSmile (iii) that is publicly available at iisrserv.csie.ncu.edu.tw/belsmile.	What is BEL(Biological Expression Language) used for?	Biological expression language (BEL) is one of the most popular languages to represent the causal and correlative relationships among biological events.
The hepatic stellate cell (HSC) is the predominant cell type responsible for excess collagen deposition during liver fibrosis. Both transforming growth factor-beta (TGF-beta), the most potent fibrogenic cytokine for HSCs, which classically activates Smad signaling, and p38 MAPK signaling have been shown to influence collagen gene expression; however, the relative contribution and mechanisms that these two signaling pathways have in regulating collagen gene expression have not been investigated. The aim of this study was to investigate the relative roles and mechanisms of both Smad and p38 MAPK signaling in alpha1(I) collagen gene expression in HSCs. Inhibiting either p38 MAPK or Smad signaling reduced alpha1(I) collagen mRNA expression in untreated or TGF-beta-treated HSCs, and when both signaling pathways were simultaneously inhibited, alpha1(I) collagen gene expression was essentially blocked. Both signaling pathways were found to independently and additively increase alpha1(I) collagen gene expression by transcriptional mechanisms. TGF-beta treatment increased alpha1(I) collagen mRNA half-life, mediated by increased stability of alpha1(I) collagen mRNA through p38 MAPK signaling but not through Smad signaling. In conclusion, both p38 MAPK and Smad signaling independently and additively regulate alpha1(I) collagen gene expression by transcriptional activation, whereas p38 MAPK and not Smad signaling increased alpha1(I) collagen mRNA stability.	Which cytokine molecule activates SMADs?	h transforming growth factor-beta (TGF-beta), the most potent fibrogenic cytokine for HSCs, which classically activates Smad signaling, and p38 MAPK signaling have been shown to influence collagen gene expression; however, the relative contribution and mechanisms that these two signaling pathways have in regulating collagen gene expression have not been investigated. The aim
RNA-guided endonucleases (RGENs), derived from the prokaryotic adaptive immune system known as CRISPR/Cas, enable targeted genome engineering in cells and organisms. RGENs are ribonucleoproteins that consist of guide RNA and Cas9, a protein component originated from Streptococcus pyogenes. These enzymes cleave chromosomal DNA, whose sequence is complementary, to guide RNA in a targeted manner, producing site-specific DNA double-strand breaks (DSBs), the repair of which gives rise to targeted genome modifications. Despite broad interest in RGEN-mediated genome editing, these nucleases are limited by off-target mutations and unwanted chromosomal translocations associated with off-target DNA cleavages. Here, we show that off-target effects of RGENs can be reduced below the detection limits of deep sequencing by choosing unique target sequences in the genome and modifying both guide RNA and Cas9. We found that both the composition and structure of guide RNA can affect RGEN activities in cells to reduce off-target effects. RGENs efficiently discriminated on-target sites from off-target sites that differ by two bases. Furthermore, exome sequencing analysis showed that no off-target mutations were induced by two RGENs in four clonal populations of mutant cells. In addition, paired Cas9 nickases, composed of D10A Cas9 and guide RNA, which generate two single-strand breaks (SSBs) or nicks on different DNA strands, were highly specific in human cells, avoiding off-target mutations without sacrificing genome-editing efficiency. Interestingly, paired nickases induced chromosomal deletions in a targeted manner without causing unwanted translocations. Our results highlight the importance of choosing unique target sequences and optimizing guide RNA and Cas9 to avoid or reduce RGEN-induced off-target mutations.	Which are the newly identified DNA nucleases that can be used to treat thalassemia?	RNA-guided endonucleases (RGENs), derived from the prokaryotic adaptive immune system known as CRISPR/Cas, enable targeted genome engineering in cells and organisms.
Autophagy is an important catabolic process with roles in cell survival and cell death. It sequesters cytosol and organelles within double-membrane autophagosomes that deliver their contents to lysosomes for degradation. Autophagosome biogenesis is coordinated by the autophagy-related protein 4 (Atg4) family of C54 endopeptidases (Atg4A-Atg4D). These enzymes prime and then later delipidate the autophagosome marker, Atg8. Here, we show that one family member, Atg4D, is cleaved by caspase-3 in vitro and in apoptotic cells. Atg4D is a poor priming and delipidation enzyme in vitro, but truncated DeltaN63 Atg4D displays increased activity against the Atg8 paralogue, gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAP-L1). In living cells, DeltaN63 Atg4D stimulates the delipidation of GABARAP-L1, whereas siRNA silencing of the gene expressing Atg4D abrogates GABARAP-L1 autophagosome formation and sensitises cells to starvation and staurosporine-induced cell death. Interestingly, Atg4D overexpression induces apoptosis, which is preceded by the caspase-independent recruitment of Atg4D to mitochondria and is facilitated by a putative C-terminal Bcl-2 homology 3 (BH3) domain. Atg4D also acquires affinity for damaged mitochondria in cells treated with hydrogen peroxide. These data suggest that Atg4D is an autophagy regulator that links mitochondrial dysfunction with apoptosis.	Which are the Atg8 homologs in human?	truncated DeltaN63 Atg4D displays increased activity against the Atg8 paralogue, gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAP-L1)
Iron disorders of genetic origin are mainly composed of iron overload diseases, the most frequent being HFE-related hemochromatosis. Hepcidin deficiency underlies iron overload in HFE-hemochromatosis as well as in several other genetic iron excess disorders, such as hemojuvelin or hepcidin-related hemochromatosis and transferrin receptor 2-related hemochromatosis. Deficiency of ferroportin, the only known cellular protein iron exporter, produces iron overload in the typical form of ferroportin disease. By contrast, genetically enhanced hepcidin production, as observed in matriptase-2 deficiency, generates iron-refractory iron deficiency anemia. Diagnosis of these iron storage disorders is usually established noninvasively through combined biochemical, imaging and genetic approaches. Moreover, improved knowledge of the molecular mechanisms accounting for the variations of iron stores opens the way of novel therapeutic approaches aiming to restore normal iron homeostasis. In this review, we will summarize recent findings about these various genetic entities that have been identified owing to an exemplary interplay between clinicians and basic scientists.	Which disorders are associated to mutated Hepcidin (HAMP)?	Hepcidin deficiency underlies iron overload in HFE-hemochromatosis as well as in several other genetic iron excess disorders, such as hemojuvelin or hepcidin-related hemochromatosis and transferrin receptor 2-related hemochromatosis.
Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain pre-exposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in future.	List phagosomal markers.	late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation.
Metabolite-sensing mRNAs, or "riboswitches," specifically interact with small ligands and direct expression of the genes involved in their metabolism. Riboswitches contain sensing "aptamer" modules, capable of ligand-induced structural changes, and downstream regions, harboring expression-controlling elements. We report the crystal structures of the add A-riboswitch and xpt G-riboswitch aptamer modules that distinguish between bound adenine and guanine with exquisite specificity and modulate expression of two different sets of genes. The riboswitches form tuning fork-like architectures, in which the prongs are held in parallel through hairpin loop interactions, and the internal bubble zippers up to form the purine binding pocket. The bound purines are held by hydrogen bonding interactions involving conserved nucleotides along their entire periphery. Recognition specificity is associated with Watson-Crick pairing of the encapsulated adenine and guanine ligands with uridine and cytosine, respectively.	What process involves metabolite-sensing mRNAs to control gene expression?	Metabolite-sensing mRNAs, or "riboswitches," specifically interact with small ligands and direct expression of the genes involved in their metabolism. Riboswitches contain sensing "aptamer" modules, capable of ligand-induced structural changes, and downstream regions, harboring expression-controlling elements.
DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.	Is DITPA a thyroid hormone analog utilized in experimental and clinical studies	DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure
Pupil size is determined by the interaction of the parasympathetic and the sympathetic nervous system. The parasympathetic system conducts the light reaction with its major center in the dorsal midbrain. The sympathetic nervous system acts either directly on the dilator muscle (peripherally) or centrally by inhibiting the Edinger-Westphal nucleus. Psychosensory reactions are transmitted via the sympathetic system. The afferent input of the light reflex system in humans is characteristically wired, allowing a detailed analysis of a lesion of the afferent input. Even in humans a subgroup of ganglion cells containing melansopsin plays an important role as a light sensor for the pupillary system. To diagnose normal pupillary function, pupils need to be isocoric and react bilaterally equally to light. Anisocoria indicates a problem of the efferent pupillary pathway. Pupillary disorders may involve the afferent pathways (relative afferent pupillary defect) or the efferent pathways. Physiological anisocoria is a harmless condition that has to be distinguished from Horner's syndrome. In this case pharmacological testing with cocaine eye-drops is helpful. Disorders of the parasympathetic system will impair the light response. They include dorsal midbrain syndrome, third-nerve palsy, and tonic pupil. Tonic pupils are mainly idiopathic and do not need imaging. Disorders of the iris, including application of cholinergic agents, need also to be considered in impaired pupillary light reaction.	What is the effect induced by sympathetic nervous system on pupil size?	Pupil size is determined by the interaction of the parasympathetic and the sympathetic nervous system
Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828 pharmacokinetics and pharmacodynamics were investigated using cell lines and tumor models, and the antitumor effect of oral INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, and 3 by INCB054828 (half maximal inhibitory concentration [IC50] 0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM). INCB054828 selectively inhibited growth of tumor cell lines with activation of FGFR signaling compared with cell lines lacking FGFR aberrations. The preclinical pharmacokinetic profile suggests target inhibition is achievable by INCB054828 in vivo with low oral doses. INCB054828 suppressed the growth of xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the combination of INCB054828 with cisplatin provided significant benefit over either single agent, with an acceptable tolerability. The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations.	What are the targets of pemigatinib?	Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials.
Clinical and health-related quality of life (HRQoL) information was analyzed to determine: (a) patient-reported signs, symptoms, and functioning, (b) HRQoL questionnaire psychometrics, and (c) treatment impact on HRQoL. Data from the Melanoma Subscale (MS) of the Functional Assessment of Cancer Therapy-Melanoma and the worst pain question from the Brief Pain Inventory (BPI) were taken from a clinical trial evaluating intetumumab alone or with dacarbazine in Stage IV metastatic melanoma. Descriptive statistics examined patient-reported disease burden at baseline. Correlations explored clinical endpoint and HRQoL associations. Psychometrics included Cronbach's α internal consistency and intraclass correlation coefficient (ICC). Treatment impact on HRQoL was evaluated through HRQoL maintenance and response analyses. Patients (n=127) had a mean age of 62 years, a mean±SD hemoglobin of 13.0±2.6 g/dl, and a mean±SD lactic dehydrogenase of 394±454 IU/l. Ninety-eight percent were Caucasian, 67% were men, and 64% had an Eastern Cooperative Oncology Group status of 0. Baseline BPI worst pain and MS scores (mean±SD) were 1.6±2.2 and 54.5±7.2, respectively. Top three patient-reported health decrements in the MS were appetite, fatigue, and limited physical activity. Observed HRQoL decrements were consistent with the literature. MS and BPI worst pain item demonstrated good psychometrics: Cronbach's α and ICC for the MS were 0.79 and 0.86, respectively; BPI ICC was 0.74. A trend for HRQoL response was observed 3 weeks postbaseline in the dacarbazine + 10 mg/kg intetumumab arm compared with dacarbazine + placebo: 22 versus 10%, respectively, for the MS; 23 versus 5% for the BPI. Further research on the HRQoL benefit of intetumumab in larger studies appears warranted.	Intetumumab has been tested in clinical trials for treatment of which cancers?	Data from the Melanoma Subscale (MS) of the Functional Assessment of Cancer Therapy-Melanoma and the worst pain question from the Brief Pain Inventory (BPI) were taken from a clinical trial evaluating intetumumab alone or with dacarbazine in Stage IV metastatic melanoma.
Biochemical studies to date have not been able to identify the linker histone H1 protein in the budding yeast Saccharomyces cerevisiae. Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain. To determine whether Hho1p can assume the shape of an H1 protein, homology model building experiments were performed using the structure of chicken histone H5 globular domain as the basis for comparison. A statistically significant match between each of the two globular domains of Hho1p and the chicken histone H5 structure was obtained, and probability values indicate that there is a less than 1 in 100 chance that such a match would be the result of a random event. These findings support the proposal that Hho1p acts as an "H1 dimer" and could be responsible for the decreased linker DNA length observed between nucleosomal core particles.	Does a linker histone exist in the yeast genome?	Biochemical studies to date have not been able to identify the linker histone H1 protein in the budding yeast Saccharomyces cerevisiae. Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain.
Telomerase catalyzes telomeric DNA synthesis, an essential process to maintain the length of telomere for continuous cell proliferation and genomic stability. Telomerase is activated in gametes, stem cells, and most tumor cells, and its activity is tightly controlled by a catalytic human telomerase reverse transcriptase (hTERT) subunit and a collection of associated proteins. In the present work, normal human testis tissue was used for the first time to identify proteins involved in the telomerase regulation under normal physiological conditions. Immunoprecipitation was performed using total protein lysates from the normal testis tissue and the proteins of interest were identified by microfluidic high-performance liquid chromatography and tandem mass spectrometry (HPLC-Chip-MS/MS). The regulatory role of PCDH10 in telomerase activity was confirmed by a telomeric repeat amplification protocol (TRAP) assay, and the biological functions of it were characterized by in vitro proliferation, migration, and invasion assays. A new in vivo hTERT interacting protein, protocadherin 10 (PCDH10), was identified. Overexpression of PCDH10 in pancreatic cancer cells impaired telomere elongation by inhibiting telomerase activity while having no obvious effect on hTERT expression at mRNA and protein levels. As a result of this critical function in telomerase regulation, PCDH10 was found to inhibit cell proliferation, migration, and invasion, suggesting a tumor suppressive role of this protein. Our data suggested that PCDH10 played a critical role in cancer cell growth, by negatively regulating telomerase activity, implicating a potential value in future therapeutic development against cancer.	What is the aim of the TRAP assay?	The regulatory role of PCDH10 in telomerase activity was confirmed by a telomeric repeat amplification protocol (TRAP) assay, and the biological functions of it were characterized by in vitro proliferation, migration, and invasion assays.
The outer membrane proteins (OMPs) are beta-barrel membrane proteins that performed lots of biology functions. The discriminating OMPs from other non-OMPs is a very important task for understanding some biochemical process. In this study, a method that combines increment of diversity with modified Mahalanobis Discriminant, called IDQD, is presented to predict 208 OMPs, 206 transmembrane helical proteins (TMHPs) and 673 globular proteins (GPs) by using Chou's pseudo amino acid compositions as parameters. The overall accuracy of jackknife cross-validation is 93.2% and 96.1%, respectively, for three datasets (OMPs, TMHPs and GPs) and two datasets (OMPs and non-OMPs). These predicted results suggest that the method can be effectively applied to discriminate OMPs, TMHPs and GPs. And it also indicates that the pseudo amino acid composition can better reflect the core feature of membrane proteins than the classical amino acid composition.	What are the computational methods for the prediction of beta-barrel transmembrane proteins?	In this study, a method that combines increment of diversity with modified Mahalanobis Discriminant, called IDQD, is presented to predict 208 OMPs, 206 transmembrane helical proteins (TMHPs) and 673 globular proteins (GPs) by using Chou's pseudo amino acid compositions as parameters.
Adult PD of bone is the second commonest metabolic bone condition after osteoporosis. The condition is characterized by increased bone cell activity, with bone-resorbing osteoclasts often larger and containing more nuclei than normal, and osteoblasts producing increased amounts of disorganized bone. This leads to expanded bone of poor quality possessing both sclerotic and lytic areas. PD of bone has a strong genetic element, with a family history being noted in 10-20% of cases. A number of genetic defects have been found to be associated with the condition. The most common disease-associated variants identified affect the SQSTM1 gene, providing insights into disease aetiology, with the clinical value of knowledge of SQSTM1 mutation status currently under active investigation. The diagnosis may be suggested by an isolated raised total ALP without other identifiable causes. This can be confirmed on plain X-rays and the extent determined by isotope bone scan. The mainstays of treatment are the bisphosphonates, especially i.v. zoledronate, which results in long-term suppression of bone turnover. ALP is the usual means of monitoring the condition, although more specific bone turnover markers can be helpful, especially in coincident liver disease. Patients should be followed up to monitor for biochemical relapse or development of complications, which may require medical or surgical intervention.	What is Paget's Disease?	Adult PD of bone is the second commonest metabolic bone condition after osteoporosis. The condition is characterized by increased bone cell activity, with bone-resorbing osteoclasts often larger and containing more nuclei than normal, and osteoblasts producing increased amounts of disorganized bone. This leads to expanded bone of poor quality possessing both sclerotic and lytic areas
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, affecting up to 10 million people worldwide. Current treatment primarily involves symptom management with dopaminergic replacement therapy. Levodopa remains the most effective oral treatment, although long-term use is associated with complications such as wearing off, dyskinesias, and on-off fluctuations. Non-dopaminergic medications that improve PD symptoms and motor fluctuations are in demand. Adenosine A2A receptors are abundantly expressed within the basal ganglia and offer a unique target to modify abnormal striatal signaling associated with PD. Preclinical animal models have shown the ability of adenosine A2A receptor antagonists to improve PD motor symptoms, reduce motor fluctuations and dyskinesia, as well as protect against toxin-induced neuronal degeneration. Both istradefylline and preladenant have demonstrated moderate efficacy in reducing off time in PD patients with motor fluctuations. The safety and efficacy of this class of compounds continues to be defined and future studies should focus on non-motor symptoms, dyskinesias, and neuroprotection.	List adenosine A2A receptor antagonists that are used for Parkinson's disease treatment.	Both istradefylline and preladenant have demonstrated moderate efficacy in reducing off time in PD patients with motor fluctuations.
Embryonic stem (ES) cells have a unique regulatory circuitry, largely controlled by the transcription factors Oct4, Sox2, and Nanog, which generates a gene expression program necessary for pluripotency and self-renewal. How external signals connect to this regulatory circuitry to influence ES cell fate is not known. We report here that a terminal component of the canonical Wnt pathway in ES cells, the transcription factor T-cell factor-3 (Tcf3), co-occupies promoters throughout the genome in association with the pluripotency regulators Oct4 and Nanog. Thus, Tcf3 is an integral component of the core regulatory circuitry of ES cells, which includes an autoregulatory loop involving the pluripotency regulators. Both Tcf3 depletion and Wnt pathway activation cause increased expression of Oct4, Nanog, and other pluripotency factors and produce ES cells that are refractory to differentiation. Our results suggest that the Wnt pathway, through Tcf3, brings developmental signals directly to the core regulatory circuitry of ES cells to influence the balance between pluripotency and differentiation.	What is the role of Tcf3 in the maintenance of pluripotency?	Our results suggest that the Wnt pathway, through Tcf3, brings developmental signals directly to the core regulatory circuitry of ES cells to influence the balance between pluripotency and differentiation.
In comparison with midazolam, clonidine 4 microg kg-1 reduced sevoflurane-induced emergence agitation without increasing postoperative side-effects.	Can clonidine be used to reduce agitation in children.	In comparison with midazolam, clonidine 4 microg kg-1 reduced sevoflurane-induced emergence agitation without increasing postoperative side-effects.
In the past few years research in the underlying pathogenic mechanisms of acute myeloid leukaemia (AML) has led to remarkable advances in our understanding of the disease. Cytogenetic and molecular aberrations are the most important factors in determining response to chemotherapy as well as long-term outcome, but beyond prognostication are potential therapeutic targets. Our increased understanding of the pathogenesis of AML facilitated by next-generation sequencing has spurred the development of new compounds in the treatment of AML, particularly the creation of small molecules that target the disease on a molecular level. Many of the hopeful predictions outlined in our AML review of 2018 are now therapeutic realities: gemtuzumab ozogamicin, venetoclax, FLT3 inhibitors (midostaurin, gilteritinib), IDH inhibitors (ivosidenib, enasidenib), CPX-351, glasdegib, oral decitabine, and oral azacitidine. Others may soon be (quizartinib, APR246 magrolimab, menin inhibitors). The wealth of positive data allows reconsideration of what might soon be new standards of care in younger and older patients with AML. In this review we give an overview of recently approved therapies in AML and address present and future research directions.	What is the mechanisms of action of Gilteritinib?	Many of the hopeful predictions outlined in our AML review of 2018 are now therapeutic realities: gemtuzumab ozogamicin, venetoclax, FLT3 inhibitors (midostaurin, gilteritinib), IDH inhibitors (ivosidenib, enasidenib), CPX-351, glasdegib, oral decitabine, and oral azacitidine. Others may soon be (quizartinib, APR246 magrolimab, menin inhibitors).
Catechol-O-methyl transferase (COMT) inhibitors block the peripheral metabolism of levodopa, increase its plasma half-life, and enhance its brain availability. Two COMT inhibitors, tolcapone and entacapone, have recently been made available as adjunctive agents to levodopa. In PD patients with motor fluctuations, they have been shown to increase "on" time and reduce "off" time. In patients with more advanced disease, they provide similar benefits, but patients tend to experience less overall benefit and a greater likelihood of developing dopaminergic adverse events. Accordingly, closer monitoring is required. In stable patients who have not yet developed motor complications, there are preliminary data suggesting that they experience improvements in motor function and in activities of daily living. Finally, there are theoretical reasons to consider administering a COMT inhibitor to patients from the onset of levodopa therapy in order to reduce the likelihood that motor complications will develop. COMT inhibitors are easy to administer, do not require titration, and are generally well tolerated particularly in patients with relatively mild disease. Adverse events are primarily dopaminergic and can usually be controlled by levodopa dose adjustments. COMT inhibitors have thus proven to be a useful addition to the therapeutic armamentarium of PD.	Which two catechol-O-methyl transferase (COMT) inhibitors can be used for treatment of Parkinson disease?	Two COMT inhibitors, tolcapone and entacapone, have recently been made available as adjunctive agents to levodopa
CTCF is a transcription factor and a candidate tumor suppressor that contains a DNA-binding domain composed of 11 zinc fingers. We reported previously that CTCF is differentially regulated during differentiation of human myeloid leukemia cells. In this study we aimed to investigate the role of CTCF in myeloid cell differentiation. A human cell line, K562, that can be chemically induced to differentiate into various hematopoietic lineages was chosen as a model system for this study. Several K562 cell lines with constitutive and conditional expression of CTCF have been generated. By using these model systems we demonstrated that: (i) ectopic expression of CTCF in K562 cells led to growth retardation and promotion of differentiation into the erythroid lineage; (ii) CTCF knock-down significantly inhibited differentiation of K562 cells into erythroid lineage; (iii) differentiation of K562 into the megakaryocytic lineage was not significantly affected; and (iv) down-regulation of MYC has been identified as one of the mechanisms by which CTCF promotes erythroid differentiation. Taken together our results demonstrate that CTCF is involved in the control of myeloid cell growth and differentiation.	What is caused by the ectopic expression of CTCF?	By using these model systems we demonstrated that: (i) ectopic expression of CTCF in K562 cells led to growth retardation and promotion of differentiation into the erythroid lineage; (ii) CTCF knock-down significantly inhibited differentiation of K562 cells into erythroid lineage; (iii) differentiation of K562 into the megakaryocytic lineage was not significantly affected; and (iv) down-regulation of MYC has been identified as one of the mechanisms by which CTCF promotes erythroid differentiation.
POEMS syndrome is a rare conglomeration of disorders associated with plasma cell dyscrasia. The acronym POEMS is derived from main features of the syndrome namely 'polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin lesions'. Other clinical features include presence of sclerotic bone lesions, Castleman's disease, papilledema, pleural effusion, edema, ascites, erythrocytosis and thrombocytosis. Myeloma is the most common plasma cell dyscrasia associated with POEMS syndrome. Renal involvement is rare and renal biopsy is characterized by glomerular involvement with membranoproliferative glomerulonephritis and endothelial injury. We report a case of a 67-year-old male who presented with clinical features satisfying the diagnostic criteria of POEMS syndrome and had rapidly progressive renal failure. Renal biopsy showed extensive interstitial infiltration by plasma cells and concomitant presence of classic polyarteritis nodosa. Although association with small-vessel vasculitis has been reported in patients with POEMS syndrome, to the best of our knowledge, this is the first report of POEMS syndrome associated with medium-sized vessel vasculitis.	List main clinical features of the POEMS syndrome.	The acronym POEMS is derived from main features of the syndrome namely 'polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin lesions'.
Interleukin-5 is a Th2 homodimeric cytokine involved in the differentiation, maturation, migration, development, survival, trafficking and effector function of blood and local tissue eosinophils, in addition to basophils and mast cells. The IL-5 receptor (IL-5R) consists of an IL-5-specific α subunit that interacts in conformationally dynamic ways with the receptor's βc subunit, an aggregate of domains it shares with binding sites of IL-3 and granulocyte-macrophage colony-stimulating factor. IL-5 and IL-5R drive allergic and inflammatory immune responses characterizing numerous diseases, such as asthma, atopic dermatitis, chronic obstructive pulmonary disease, eosinophilic gastrointestinal diseases, hyper-eosinophilic syndrome, Churg-Strauss syndrome and eosinophilic nasal polyposis. Although corticosteroid therapy is the primary treatment for these diseases, a substantial number of patients exhibit incomplete responses and suffer side-effects. Two monoclonal antibodies have been designed to neutralize IL-5 (mepolizumab and reslizumab). Both antibodies have demonstrated the ability to reduce blood and tissue eosinophil counts. One additional monoclonal antibody, benralizumab (MEDI-563), has been developed to target IL-5R and attenuate eosinophilia through antibody-dependent cellular cytotoxicity. All three monoclonal antibodies are being clinically evaluated. Antisense oligonucleotide technology targeting the common βc IL-5R subunit is also being used therapeutically to inhibit IL-5-mediated effects (TPI ASM8). Small interfering RNA technology has also been used therapeutically to inhibit the expression of IL-5 in animal models. This review summarizes the structural interactions between IL-5 and IL-5R and the functional consequences of such interactions, and describes the pre-clinical and clinical evidence supporting IL-5R as a therapeutic target.	Which molecule is targeted by a monoclonal antibody Mepolizumab?	Two monoclonal antibodies have been designed to neutralize IL-5 (mepolizumab and reslizumab).
Emery Dreifuss muscular dystrophy (EDMD) is an uncommon hereditary myopathy characterized by 3 symptoms: slow progressive muscular atrophy, muscular contractures and cardiac disease which affect prognosis. We report a 22 year-old patient with EDMD which shows the typical features of the associated dilated cardiomyopathy, ventricular arrhythmia, atrio-ventricular block, atrial standstill then atrial paralysis.	What is Emery-Dreifuss Muscular Dystrophy (EDMD)?	Emery Dreifuss muscular dystrophy (EDMD) is an uncommon hereditary myopathy characterized by 3 symptoms: slow progressive muscular atrophy, muscular contractures and cardiac disease which affect prognosis.
Lactotransferrin (LTF) has been shown to regulate tumorogenesis. However, little is known about the role of LTF in regulating the development of human nasopharyngeal carcinoma (NPC). The aim of our study was to investigate whether LTF could regulate the development of NPC by characterizing the pattern of LTF expression in human NPC tissues using cDNA and tissue microarrays. Loss of LTF expression was observed in a significantly higher frequency of NPC tissues compared to that in nontumor nasopharyngeal epithelial tissues. While 61.25% of NPC tissues at the T1/T2 stage were positive for LTF expression, only 40.82% of NPC at the T3/T4 stage were stained by anti-LTF. Similarly, 41.58% of NPC with local lymph node metastasis displayed LTF expression, a value significantly lower than the 46.36% in primary tumors (p < 0.05). These findings suggest that LTF may negatively regulate the development and metastasis of NPC in vivo. Furthermore, overexpression of or treatment with LTF inhibited the proliferation of NPC cells and promoted cell cycle arrest at the G(0)/G(1) phase in vitro. While LTF treatment downregulated expression of cyclin D1 and phosphorylation of retinoblastoma protein (Rb), expression of p21 and p27 in 5-8F NPC cells was enhanced. Moreover, LTF treatment modulated the mitogen-activated protein kinase (MAPK) pathway, but did not affect p53 and STAT3 expression in 5-8F NPC cells. Thus LTF is likely to be a candidate tumor suppressor and downregulates the development of NPC by inhibiting NPC proliferation through induction of cell cycle arrest and modulation of the MAPK signaling pathway. Therefore, our findings provide new insights in understanding the mechanism(s) underlying the action of LTF in regulating the development of human NPC.	Is lactotransferrin a tumour suppressor?	LTF is likely to be a candidate tumor suppressor and downregulates the development of NPC by inhibiting NPC proliferation through induction of cell cycle arrest and modulation of the MAPK signaling pathway.
Spinocerebellar ataxia type 3 is caused by a polyglutamine expansion in the ataxin-3 protein, resulting in gain of toxic function of the mutant protein. The expanded glutamine stretch in the protein is the result of a CAG triplet repeat expansion in the penultimate exon of the ATXN3 gene. Several gene silencing approaches to reduce mutant ataxin-3 toxicity in this disease aim to lower ataxin-3 protein levels, but since this protein is involved in deubiquitination and proteasomal protein degradation, its long-term silencing might not be desirable. Here, we propose a novel protein modification approach to reduce mutant ataxin-3 toxicity by removing the toxic polyglutamine repeat from the ataxin-3 protein through antisense oligonucleotide-mediated exon skipping while maintaining important wild type functions of the protein. In vitro studies showed that exon skipping did not negatively impact the ubiquitin binding capacity of ataxin-3. Our in vivo studies showed no toxic properties of the novel truncated ataxin-3 protein. These results suggest that exon skipping may be a novel therapeutic approach to reduce polyglutamine-induced toxicity in spinocerebellar ataxia type 3.	Which is the treatment strategy followed in spinocerebellar ataxia type 3 for CAG removal?	we propose a novel protein modification approach to reduce mutant ataxin-3 toxicity by removing the toxic polyglutamine repeat from the ataxin-3 protein through antisense oligonucleotide-mediated exon skipping while maintaining important wild type functions of the protein
The ergot alkaloids studied do exert selective effects on monoamine receptor systems. Lisuride acts as a very potent stimulator of adenylate cyclase in cortical brain regions, and may function as a mixed agonist-antagonist at high concentrations. It is most likely that in cortex, lisuride effects both dopamine and serotonin receptors, but predominantly serotonin receptors coupled to adenylate cyclase. The antagonist molindone exhibits selectivity for cortical serotonin-stimulated cyclase versus dopamine-stimulated cyclase and may prove useful for further elucidating the sites of lisuride action. LSD interacts with serotonin-stimulated cortical adenylate cyclase at higher concentrations than are needed for lisuride stimulation but, nevertheless, at lower concentrations than for serotonin itself (2-4). Bromocriptine, lergotrile and ergonovine may also act as agonists in stimulating adenylate cyclase, but with considerably less potency, and with differences in regional specificity for this stimulation, from lisuride and LSD. Each of these ergots may act as a mixed agonist-antagonist at high concentrations. With respect to the regions studied, antagonist effects on cyclase appear to be more prominent in striatum than in the cortical regions. The greater specificity of lisuride for serotonergic cortical receptors should make this compound useful in further studies of this system.	What is the action of molindone?	The antagonist molindone exhibits selectivity for cortical serotonin-stimulated cyclase versus dopamine-stimulated cyclase and may prove useful for further elucidating the sites of lisuride action.
Ca(+)/calmodulin-dependent protein kinase II (CaM kinase II) has been implicated in the regulation of smooth muscle contractility. The goals of this study were to determine: 1) to what extent CaM kinase II is activated by contractile stimuli in intact arterial smooth muscle, and 2) the effect of a CaM kinase II inhibitor (KN-93) on CaM kinase II activation, phosphorylation of myosin regulatory light chains (MLC(20)), and force. Both histamine (1 microM) and KCl depolarization activated CaM kinase II with a time course preceding maximal force development, and suprabasal CaM kinase II activation was sustained during tonic contractions. CaM kinase II activation was inhibited by KN-93 pretreatment (IC(50) approximately 1 microM). KN-93 inhibited histamine-induced tonic force maintenance, whereas early force development and MLC(20) phosphorylation responses during the entire time course were unaffected. Both force development and maintenance in response to KCl were inhibited by KN-93. Rapid increases in KCl-induced MLC(20) phosphorylation were also inhibited by KN-93, whereas steady-state MLC(20) phosphorylation responses were unaffected. In contrast, phorbol 12,13-dibutyrate (PDBu) did not activate CaM kinase II and PDBu-stimulated force development was unaffected by KN-93. Thus KN-93 appears to target a step(s) essential for force maintenance in response to physiological stimuli, suggesting a role for CaM kinase II in regulating tonic contractile responses in arterial smooth muscle. Pharmacological activation of protein kinase C bypasses the KN-93 sensitive step.	Which kinase is inhibited by the small molecule KN-93?	CaM kinase II activation was inhibited by KN-93 pretreatment (IC(50) approximately 1 microM)
Long interspersed nuclear element 1 is an autonomous non-long terminal repeat retrotransposon that comprises ∼17% of the human genome. Its spontaneous retrotransposition and the accumulation of heritable L1 insertions can potentially result in genome instability and sporadic disorders. Moloney leukemia virus 10 homolog (MOV10), a putative RNA helicase, has been implicated in inhibiting L1 replication, although its underlying mechanism of action remains obscure. Moreover, the physiological relevance of MOV10-mediated L1 regulation in human disease has not yet been examined. Using a proteomic approach, we identified RNASEH2 as a binding partner of MOV10. We show that MOV10 interacts with RNASEH2, and their interplay is crucial for restricting L1 retrotransposition. RNASEH2 and MOV10 co-localize in the nucleus, and RNASEH2 binds to L1 RNAs in a MOV10-dependent manner. Small hairpin RNA-mediated depletion of either RNASEH2A or MOV10 results in an accumulation of L1-specific RNA-DNA hybrids, suggesting they contribute to prevent formation of vital L1 heteroduplexes during retrotransposition. Furthermore, we show that RNASEH2-MOV10-mediated L1 restriction downregulates expression of the rheumatoid arthritis-associated inflammatory cytokines and matrix-degrading proteinases in synovial cells, implicating a potential causal relationship between them and disease development in terms of disease predisposition.	Does the interaction of MOV10 and RNASEH2 promote L1 retrotransposition?	Furthermore, we show that RNASEH2-MOV10-mediated L1 restriction downregulates expression of the rheumatoid arthritis-associated inflammatory cytokines and matrix-degrading proteinases in synovial cells, implicating a potential causal relationship between them and disease development in terms of disease predisposition.
Emery-Dreifuss muscular dystrophy (EMD) is characterised by (1) early contractures of the Achilles tendons, elbows, and postcervical muscles, (2) slowly progressive muscle wasting and weakness with a predominantly humeroperoneal distribution in the early stages, and (3) cardiomyopathy with conduction defects and risk of sudden death. Inheritance is usually X linked recessive but can be autosomal dominant. Family linkage studies have mapped X linked EMD to the distal long arm of the X chromosome but precise genetic localisation has been hampered by the rarity of this condition. We report three new families with X linked Emery-Dreifuss muscular dystrophy studied with DNA markers from Xq27-qter and three previously published families typed for additional markers. No recombination was observed with the red/green cone pigment locus, RGCP (lod score, Z = 2.46), the factor VIII coagulant gene locus, F8C (Z = 6.39), or with DXS115 (Z = 4.94). Two recombinants were observed which mapped EMD distal to DXS15 (DX13) and DXS52 (St14) respectively. Multipoint linkage analysis gave odds exceeding 200:1 for EMD being distal to these markers. A multipoint analysis incorporating published data gave the map cen-DXS304-9cM-DXS15-3cM-DXS52-2 cM-(RGCP,EMD)-3cM-F8C-2cM-DXS115 with odds of 120:1 in favour of a location for EMD between DXS52 and F8C as compared to the next best position distal to F8C.	What is the inheritance pattern of Emery-Dreifuss muscular dystrophy?	Emery-Dreifuss muscular dystrophy (EMD) is characterised by (1) early contractures of the Achilles tendons, elbows, and postcervical muscles, (2) slowly progressive muscle wasting and weakness with a predominantly humeroperoneal distribution in the early stages, and (3) cardiomyopathy with conduction defects and risk of sudden death. Inheritance is usually X linked recessive but can be autosomal dominant.
Chronic ischemia or pressure overload decreases thyroid hormone (TH) signaling and activates the fetal gene program in the heart. While these features are of physiologic importance in the developing heart, their respective roles in the postnatal heart are debated. Administration of TH can prevent the changes of the fetal gene program and rebuild the heart after an "index event" such as ischemia. TH affects cardiac remodeling by limiting reperfusion injury, and, at later states, by inducing distinct changes in cardiac chamber geometry in a time-dependent manner. Furthermore, administration of TH can convert pathologic to physiologic hypertrophy. These effects are the result of favorable cellular remodeling. While preliminary clinical studies provide encouraging results, the potential and efficacy of TH in the treatment of heart disease still await evaluation in large clinical trials.	Does thyroid hormone affect cardiac remodeling?	TH affects cardiac remodeling by limiting reperfusion injury, and, at later states, by inducing distinct changes in cardiac chamber geometry in a time-dependent manner.
The bacterial mismatch-specific uracil-DNA glycosylase (MUG) and eukaryotic thymine-DNA glycosylase (TDG) enzymes form a homologous family of DNA glycosylases that initiate base-excision repair of G:U/T mismatches. Despite low sequence homology, the MUG/TDG enzymes are structurally related to the uracil-DNA glycosylase enzymes, but have a very different mechanism for substrate recognition. We have now determined the crystal structure of the Escherichia coli MUG enzyme complexed with an oligonucleotide containing a non-hydrolysable deoxyuridine analogue mismatched with guanine, providing the first structure of an intact substrate-nucleotide productively bound to a hydrolytic DNA glycosylase. The structure of this complex explains the preference for G:U over G:T mispairs, and reveals an essentially non-specific pyrimidine-binding pocket that allows MUG/TDG enzymes to excise the alkylated base, 3, N(4)-ethenocytosine. Together with structures for the free enzyme and for an abasic-DNA product complex, the MUG-substrate analogue complex reveals the conformational changes accompanying the catalytic cycle of substrate binding, base excision and product release.	What is the role of mismatched uracil glycosylase (Mug) in DNA repair?	The bacterial mismatch-specific uracil-DNA glycosylase (MUG) and eukaryotic thymine-DNA glycosylase (TDG) enzymes form a homologous family of DNA glycosylases that initiate base-excision repair of G:U/T mismatches
Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5' incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.	What is the cause of the disease Xeroderma Pigmentosum?	ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5' incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum,
In May 2014, tablets containing both trifluridine and tipiracil hydrochloride (Lonsurf® tablets) were launched in Japan ahead of other countries, for the treatment of advanced/relapsed unresectable colorectal cancer. The benefits of these tablets in terms of a new therapeutic option have been demonstrated. However, the manufacturer has requested healthcare professionals to help develop safety measures for the appropriate and safe use of the tablets. In this study, we evaluated the efficacy and safety of the tablets in 16 patients who received the tablets at our hospital. Among the 4 evaluable patients, none achieved a complete or partial response. One patient (25.0%) had stable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines outlined in the General Rules of the Study of Colorectal Cancer (The 8th Edition). Lonsurf® is considered to be a third-line (or later) treatment. Among the 16 cases studied, Lonsurf® was used as a third-, fourth-, and fifth-line treatment in 9, 6, and 1 cases, respectively. Therefore, Grade 3 or worse toxicities were a potential concern. Despite a high incidence of Grade 3 or worse neutropenia (7 of the 16 patients [43.8%]), none of the patients were hospitalized due to neutropenia or other treatment-related adverse events. Pharmacists have made 126 proposals to physicians regarding the use of Lonsurf®, 121 (96.0%) of which have been adopted. All of the adverse reactions experienced by our patients were resolved after supportive therapy.	Which drugs are included in the Lonsurf combination pill?	In May 2014, tablets containing both trifluridine and tipiracil hydrochloride (Lonsurf® tablets) were launched in Japan ahead of other countries, for the treatment of advanced/relapsed unresectable colorectal cancer
Background Neuropathic pain (NP) is a common condition accompanied by nerve injury. To date, there is no definite treatment approved for this disorder. In addition, many drugs that are used for NP cause adverse reactions. Luteolin is a naturally occurring flavonoid with diverse pharmacological properties such as anti-inflammatory, antioxidant and anticancer. We sought to investigate luteolin effects on chronic, acute and neuropathic pain as well as its potential to increase morphine anti-nociceptive effects in mice. Methods Albino mice (20-25 g) were randomly divided into 14 groups (n=7) including morphine 1 mg/kg body weight +luteolin (5 mg/kg body weight), morphine (9 mg/kg body weight, i.p.), luteolin (2.5, 5 and 10 mg/kg body weight), imipramine 40 mg/kg body weight and normal saline (NS) (0.9 %) as vehicle and subjected to hot plate test. Formalin test was done in the following groups: NS, diclofenac sodium (10 mg/kg body weight, i.p.), morphine (9 mg/kg body weight, i.p.) and luteolin (2.5, 5 and 10 mg/kg body weight). Results Administration of luteolin single dose (5 and 10 mg/kg body weight) significantly reduced neuropathic pain ( p<0.05$\rm{p}<0.05$) in comparison to negative control. Anti-nociceptive effects of luteolin were comparable to imipramine as the standard positive control ( p<0.001$\rm{p}<0.001$). Co-administration of luteolin and morphine potentiated morphine 1 mg/kg body weight painkilling effects ( p<0.001$\rm{p}<0.001$). Conclusions Our results showed that luteolin alone reduces neuropathic pain. Furthermore, when co-administered with morphine 1 mg/kg body weight, luteolin potentiates morphine effects. Therefore, luteolin-morphine co-administration might be a valuable alternative for the conventional treatment.	What is Luteolin?	Luteolin is a naturally occurring flavonoid with diverse pharmacological properties such as anti-inflammatory, antioxidant and anticancer.
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α-subunit of the voltage-gated Ca2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.	List characteristics of Developmental and Epileptic Encephalopathies (DEEs).	Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression.
A case of Couvelaire uterus with placenta accreta found during scheduled repeat low transverse Cesarean section will be discussed within this article. First described in the 1900s, Couvelaire syndrome, also known as uteroplacental apoplexy, is a rare form of nonfatal placenta abruption complication. The case involves a 30-year-old gravida 3 para 2 otherwise healthy female with an uncomplicated pregnancy and two previous cesarean deliveries without complication. She received routine prenatal care. During her pregnancy, she did not experience any symptoms such as vaginal bleeding or abdominal pain. After delivering a healthy female, there were several unsuccessful attempts to remove the placenta from the uterus. Upon inspection, the uterus was found have dark purple patches with ecchymosis and indurations, diagnostic of Couvelaire uterus. Furthermore, there was high clinical suspicion for placenta accreta as the 30-minute mark approached without placenta detachment. A telephonic emergency review with the wet desk radiologist of the 18-week ultrasound revealed high suspicion for placenta accreta. A Cesarean hysterectomy was performed for prevention of significant hemorrhage. This case report may be the first documented association of Couvelaire uterus with placenta accreta. Providers should be vigilant in monitoring for antenatal bleeding, timing of placenta separation, and postpartum hemorrhage.	What is Couvelaire Uterus?	A case of Couvelaire uterus with placenta accreta found during scheduled repeat low transverse Cesarean section will be discussed within this article. First described in the 1900s, Couvelaire syndrome, also known as uteroplacental apoplexy, is a rare form of nonfatal placenta abruption complication.
Notch signaling is an evolutionarily conserved mechanism, used to regulate cell fate decisions. Four Notch receptors have been identified in man (Notch-1 to -4). In this study, semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were used to examine the expression pattern of Notch receptor genes in whole adult human liver and isolated liver cell preparations. All 4 receptors were expressed in the adult liver, with no significant differences in the levels of Notch-1, -2, and -4 messenger RNA (mRNA) between normal and diseased liver. However, Notch-3 expression appeared to be increased in diseased tissue. The distribution of Notch-1 and -4 in normal tissue was similar, with Notch-1 also detectable at low levels in the sinusoidal endothelium. Notch-2 expression was more widely distributed, and detectable in hepatocytes, medium-sized bile ducts, and the sinusoidal endothelium. Notch-3 expression was seen on hepatocytes, with weaker expression detectable in portal veins, hepatic arteries, and the sinusoids. In normal liver tissue Notch-1, -2, and -3 were found to be coexpressed on bile duct epithelium; however, with the exception of Notch-3 in primary sclerosing cholangitis (PSC) livers, expression was absent on proliferating ductules in all disease states examined. Interestingly, the expression of Notch-2 and -3 was associated with numerous small vessels within the portal tract septa of diseased tissue. The absence of Notch receptor expression on proliferating bile ductules and its presence on neovessels suggests that Notch signaling may be important for normal bile duct formation and the aberrant neovascularization seen in diseased liver tissue.	Which are the different isoforms of the mammalian Notch receptor?	All 4 receptors were expressed in the adult liver, with no significant differences in the levels of Notch-1, -2, and -4 messenger RNA (mRNA) between normal and diseased liver. However, Notch-3 expression appeared to be increased in diseased tissue.
Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)]. This review examines the clinical experience from the MDS-001 and MDS-003 clinical trials that led to this approval, the results of biological correlates supporting the targets of drug action, and the results from a non-del(5q) multicenter study (MDS-002). Lenalidomide treatment resulted in both erythroid and cytogenetic responses in the majority of patients with del(5q), accompanied by reductions in inflammatory cytokine generation and marrow microvessel density and improvement in primitive hematopoietic progenitor recovery. Central pathology review showed that resolution of cytologic dysplasia was common in patients with del(5q) but was infrequent in erythroid-responding patients without the chromosome 5 deletion. These findings indicate that lenalidomide promotes erythropoiesis in lower-risk MDS, with two apparently distinct mechanisms of action: suppression of the ineffective del(5q) clone and promotion of effective erythropoiesis in non-del(5q) MDS progenitors. These studies identified lenalidomide as a highly active erythropoietic- and cytogenetic-remitting agent in lower-risk MDS patients who otherwise would not be expected to benefit from recombinant erythropoietin therapy. The most common adverse reactions include dose-dependent neutropenia and thrombocytopenia that are more pronounced in patients with del(5q) in whom early suppression of the clone is expected.	Has Revlimid been approved by the US Food and Drug Administration?	Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)]