Miracle-dz/UniFAR-FTUs huggingface dataset:
VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects

Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Communication with other cell types is a vital prerequisite for the normal functions of the immune system, while disturbances in this communication support the development and progression of neoplastic disease. Integrins such as the integrin very late antigen-4 (VLA-4; CD49d/CD29) control the localization of healthy as well as malignant B cells within the tissue, and thus determine the patterns of organ infiltration. Malignant B cells retain some key characteristics of their normal counterparts, with B cell receptor (BCR) signaling and integrin-mediated adhesion being essential mediators of tumor cell homing, survival and proliferation. It is thus not surprising that targeting the BCR pathway using small molecule inhibitors has proved highly effective in the treatment of B cell malignancies. Attenuation of BCR-dependent lymphoma–microenvironment interactions was, in this regard, described as a main mechanism critically contributing to the efficacy of these agents. Here, we review the contribution of VLA-4 to normal B cell differentiation on the one hand, and to the pathophysiology of B cell malignancies on the other hand. We describe its impact as a prognostic marker, its interplay with BCR signaling and its predictive role for novel BCR-targeting therapies, in chronic lymphocytic leukemia and beyond.
Mycobacterium abscessus infection leads to enhanced production of type 1 interferon and NLRP3 inflammasome activation in murine macrophages via mitochondrial oxidative stress

Mycobacterium abscessus (MAB) is a rapidly growing mycobacterium (RGM), and infections with this pathogen have been increasing worldwide. Recently, we reported that rough type (MAB-R) but not smooth type (MAB-S) strains enhanced type 1 interferon (IFN-I) secretion via bacterial phagosome escape, contributing to increased virulence. Here, we sought to investigate the role of mitochondrial oxidative stress in bacterial survival, IFN-I secretion and NLRP3 inflammasome activation in MAB-infected murine macrophages. We found that live but not heat-killed (HK) MAB-R strains increased mitochondrial ROS (mtROS) and increased release of oxidized mitochondrial DNA (mtDNA) into the cytosol of murine macrophages compared to the effects of live MAB-S strains, resulting in enhanced NLRP3 inflammasome-mediated IL-1β and cGAS-STING-dependent IFN-I production. Treatment of the infected macrophages with mtROS-modulating agents such as mito-TEMPO or cyclosporin A reduced cytosolic oxidized mtDNA, which inhibited the MAB-R strain-induced production of IL-1β and IFN-I. The reduced cytosolic oxidized mtDNA also inhibited intracellular growth of MAB-R strains via cytosolic escape following phagosomal rupture and via IFN-I-mediated cell-to-cell spreading. Moreover, our data showed that mtROS-dependent IFN-I production inhibited IL-1β production, further contributing to MAB-R intracellular survival in murine macrophages. In conclusion, our data indicated that MAB-R strains enhanced IFN-I and IL-1β production by inducing mtROS as a pathogen-associated molecular pattern (PAMP). These events also enhance bacterial survival in macrophages and dampen inflammation, which contribute to the pathogenesis of MAB-R strains.
Everyday Thoughts in Time: Experience Sampling Studies of Mental Time Travel

Time is among the most important yet mysterious aspects of experience. We investigated everyday mental time travel, especially into the future. Two community samples, contacted at random points for 3 (Study 1; 6,686 reports) and 14 days (Study 2; 2,361 reports), reported on their most recent thought. Both studies found that thoughts about the present were frequent, thoughts about the future also were common, whereas thoughts about the past were rare. Thoughts about the present were on average highly happy and pleasant but low in meaningfulness. Pragmatic prospection (thoughts preparing for action) was evident in thoughts about planning and goals. Thoughts with no time aspect were lower in sociality and experiential richness. Thoughts about the past were relatively unpleasant and involuntary. Subjective experiences of thinking about past and future often were similar—while both differed from present focus, consistent with views that memory and prospection use similar mental structures.
Stem phototropism towards blue and ultraviolet light.

Positive phototropism is the process through which plants orient their organs towards a directional light source. While the blue light receptors phototropins (phot) play a major role in phototropism towards blue (B) and ultraviolet (UV) radiation, recent research showed that the UVB light receptor UVR8 also triggers phototropism towards UVB. In addition, new details of the molecular mechanisms underlying the activity of these receptors and interaction with other environmental signals have emerged in the past years. In this review we summarize the current knowledge about hypocotyledoneous and inflorescence stem growth reorientation towards B and UVB, with focus on the molecular mechanisms. This article is protected by copyright. All rights reserved.
Cardioprotective and Prognostic Effects of Remote Ischemic Preconditioning in Patients Undergoing Coronary Artery Bypass Surgery: A Single-Center Randomized, Double-Blind Trial

During the past 3 decades, several experimental studies have shown that ischemic conditioning reduces myocardial damage by modifying ischemia-reperfusion injury. A recent study in the Lancet indicates that remote ischemic preconditioning translates into clinical benefit in patients undergoing coronary artery bypass surgery. The implications of the study extend to patients undergoing elective and acute coronary angioplasty and beyond.
Dietary Fiber, Gut Microbiota, and Metabolic Regulation—Current Status in Human Randomized Trials

New knowledge about the gut microbiota and its interaction with the host’s metabolic regulation has emerged during the last few decades. Several factors may affect the composition of the gut microbiota, including dietary fiber. Dietary fiber is not hydrolyzed by human digestive enzymes, but it is acted upon by gut microbes, and metabolites like short-chain fatty acids are produced. The short-chain fatty acids may be absorbed into the circulation and affect metabolic regulation in the host or be a substrate for other microbes. Some studies have shown improved insulin sensitivity, weight regulation, and reduced inflammation with increases in gut-derived short-chain fatty acids, all of which may reduce the risk of developing metabolic diseases. To what extent a dietary intervention with fiber may affect the human gut microbiota and hence metabolic regulation, is however, currently not well described. The aim of the present review is to summarize recent research on human randomized, controlled intervention studies investigating the effect of dietary fiber on gut microbiota and metabolic regulation. Metabolic regulation is discussed with respect to markers relating to glycemic regulation and lipid metabolism. Taken together, the papers on which the current review is based, suggest that dietary fiber has the potential to change the gut microbiota and alter metabolic regulation. However, due to the heterogeneity of the studies, a firm conclusion describing the causal relationship between gut microbiota and metabolic regulation remains elusive.
Current Explorations of Nutrition and the Gut Microbiome: A Comprehensive Evaluation of the Review Literature.

CONTEXT The ability to measure the gut microbiome led to a surge in understanding and knowledge of its role in health and disease. The diet is a source of, fuel for, and influencer of composition of the microbiome. OBJECTIVE To assess the understanding of the interactions between nutrition and the gut microbiome in healthy adults. DATA SOURCES PubMed and Google Scholar searches were conducted in March and August 2018 limited to: English, 2010-2018, healthy adults, reviews. DATA EXTRACTION A total of 86 articles were independently screened for duplicates and relevance, based on pre-identified inclusion criteria. DATA ANALYSIS Research has focused on dietary fiber-microbiota fuel. The benefits of fiber center on Short Chain Fatty Acids, which are required by colonocytes, improve absorption, and reduce intestinal transit time. Contrastingly, protein promotes microbial protein metabolism and potentially harmful by-products that can stagnate in the gut. The microbiota utilize and produce micronutrients; the bidirectional relationship between micronutrition and the gut microbiome is emerging. CONCLUSIONS Nutrition has profound effects on microbial composition, in-turn, affecting wide-ranging metabolic, hormonal, and neurological processes. There is no consensus on what defines a "healthy" gut microbiome. Future research must consider individual responses to diet.
A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia.

BACKGROUND Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).
[Diagnosis and treatment of early esophageal squamous cell carcinoma and precancerous lesions].

我国是食管癌发病率和死亡率最高的国家之一，病理类型上我国以鳞癌为主。 提高早诊早治意识，识别高危人群并进行筛查，规范早期食管鳞状细胞癌及癌前病变诊断与治疗，并对治疗后患者进行高效随访，对提高食管鳞状细胞癌患者的生存率，降低其病死率至关重要。
Discovery of potential species-specific green insecticides targeting lepidopteran ryanodine receptor.

Ryanodine receptors (RyRs) are homo-tetrameric intracellular calcium (Ca2+) release channels responsible for excitation-contraction coupling of muscle cells. Diamide insecticides specifically act on RyRs of Lepidoptera and Coleoptera pests, and are safe for non-targeted organisms, generating big worldwide sales. Despite their popularity, several devastating agricultural pests have been reported to be resistant to them due to mutations in a small transmembrane region of their RyRs, hinting a binding pocket nearby. A potential solution to overcome resistance is to develop new insecticides targeting different binding sites in pest RyRs. Based on a high-resolution crystal structure of diamondback moth (DBM) RyR N-terminal domain (NTD) determined by our group, we carried out extensive structure-based insecticide screening targeting the inter-subunit interface. We identified eight lead compounds that selectively target the open conformation of DBM RyR, which are predicted to act as channel activators similar to diamide insecticides. Binding mode analysis shows selective binding to a hydrophobic pocket of DBM NTD-A but not to the pocket of its mammalian counterpart. We tested three available compounds on the HEK293 cell lines stably expressing DBM or mammalian RyR, one of which shows good potency and selectivity against DBM RyR. The insecticidal effect of the compound was also confirmed using fruit flies. The detailed binding mode, toxicity, ADME, and reactivity of the compound were predicted by bioinformatic methods. Together, our study lays a foundation for developing a new class of selective RyR-targeting insecticides to control both wild type and resistant pests.
Plaque Fluoride Levels as a Predictor of Caries Development in Early Childhood with High Sugar Exposure – A Preliminary Study

Objective This longitudinal study aimed to investigate if the plaque fluoride (PF) concentration can predict the early childhood caries onset. Design: As part of a larger study, 188 preschoolers were clinically evaluated for early childhood caries diagnosis, at baseline and after 1-year follow-up. After that, the final sample comprised: 1. children who had already caries at baseline (decayed, missing or filled surfaces, as well as white chalky white spot lesions adjacent to gingival margins) and developed at least one more cavitation after one year (n=16), and 2. children who never had or developed any caries lesions, including active white spots lesions (n=15). Before the clinical examinations, dental plaque was collected. PF concentration was determined with an ion-specific electrode. A chart was used to estimate the mean daily sugar exposure. The results were statistically analyzed by Spearman correlation and logistic regression analyses (α=0.05). Results After one year, a positive significant correlation between caries development and liquid sucrose, total sugar and total sucrose consumption increments was found (p<0.05). Moreover, the solid sugar, solid sucrose and total sugar exposure at baseline were positively correlated with the presence of dental plaque at follow-up (p<0.05). To top it all, children with PF concentrations ≤0.1 μg/mg at baseline were 10 times more likely to develop caries. Conclusion In conclusion, this study demonstrated for the first time in vivo that low PF concentration is a predictor of caries development in primary teeth.
Extensive Profiling of Polyphenols from Two Trollius Species Using a Combination of Untargeted and Targeted Approaches

Various species of globeflowers, belonging to the genus Trollius, have been extensively used in traditional Chinese medicine due to their anti-inflammatory, antimicrobial, and antiviral properties, which are mainly attributed to their high polyphenol content. Differences in polyphenol composition, and abundances, will lead to varying treatment efficacies of globeflowers. Herein, we employ a combination of targeted and untargeted mass spectrometry (MS) approaches to characterize and quantify a comprehensive array of polyphenols, mainly including flavonoids and phenolic acids in two globeflower species commonly used in Chinese medicine, Trollius chinensis Bunge and Trollius ledebouri Reichb. In addition, free radical scavenging activity was investigated to evaluate the association between polyphenol composition and antioxidation capacity. Liquid chromatography (LC)-based separation and multiple-reaction-monitoring (MRM) transitions were optimized using a library of 78 polyphenol reference compounds to achieve absolute quantification on triple quadrupoles MS (QqQ). The analytical method was further expanded via high-resolution MS to provide relative quantitation of an additional 104 endogenous polyphenols in globeflowers not included in our reference library. Our results revealed stark differences in polyphenol content between T. chinensis and T. ledebouri, emphasizing the need for systematic characterization of polyphenol composition to ensure treatment efficacy and consistency in standardizing the use of globeflowers in Chinese medicine.
Removal of Aβ Oligomers from the Blood: A Potential Therapeutic System for Alzheimer’s Disease

Purpose Amyloid-β protein (Aβ) is one of the causative proteins of Alzheimer’s disease. We have been developing extracorporeal blood Aβ-removal systems as a method for enhancing Aβ clearance from the brain. We reported previously that medical adsorbents and hemodialyzers removed Aβ monomers from peripheral blood, which was associated with influx of Aβ monomers from the brain into the bloodstream. Our intent here was to develop a method to promote clearance of Aβ oligomers and to provide an estimate of the molecular size of intact Aβ oligomers in plasma. Methods Two hollow-fiber devices with different pore sizes (Membranes A and B) were evaluated as removers of Aβ oligomers with human plasma in vitro. The concomitant removal of Aβ oligomers and monomers was investigated by using Membrane B and hexadecyl alkylated cellulose beads or polysulfone hemodialyzers. Double-filtration plasmapheresis with Membrane A was investigated as an approach for the removal of plasma Aβ oligomers in humans. Results Aβ oligomers were effectively removed by both Membranes A and B. The increase of Aβ oligomers in plasma was observed just after the removal of plasma Aβ oligomers in humans. The intact molecular size of major Aβ oligomers in the plasma was estimated to be larger than albumin at approximately 60 kDa or more. Additionally, the concomitant removal of Aβ monomers and oligomers evoked dissociation of larger Aβ oligomers into smaller ones and monomers. Conclusion Aβ oligomers were cleared from plasma both in vitro and in human subjects by using hollow-fiber membranes with large pores, indicating that their intact sizes were mostly larger than 60 kDa. Aβ oligomers in peripheral circulation were increased after some clearances in human. Further investigation will determine whether the Aβ oligomers detected in circulation after clearance were via influx from the brain.
Flow cytometric analysis of fine needle aspirates is affected by tumor subtype, but not by anatomic location nor technique

Current clinical practices are shifting towards utilizing less invasive biopsy techniques, including fine needle aspiration (FNA) and needle core biopsies. If a patient has a suspected hematologic malignancy, a portion of the FNA sample is typically submitted for flow cytometry (FC) analysis, providing valuable immunophenotypic data.
Emotional and non-emotional facets of impulsivity in eating disorders: From anorexia nervosa to bulimic spectrum disorders.

OBJECTIVE Impulsivity and difficulties in regulating emotions are considered to be transdiagnostic characteristics of patients with eating disorders (EDs). The study aimed to investigate trait impulsivity and inhibitory components of impulsivity, related or unrelated to emotions in patients with EDs. METHOD A total of 17 patients with anorexia nervosa (AN), 16 patients with bulimic-spectrum EDs (BSD) and 20 healthy control (HC) participants completed an impulsivity scale (UPPS-P) before performing an emotional inhibitory control task during electroencephalography (EEG) acquisition. RESULTS Higher trait impulsivity in EDs than HC (with higher scores among BSD patients) was observed. However, no differences in behavioural measures or neural indexes [event-related potential (ERP)] of emotional and non-emotional inhibitory control were observed between patients and HC. CONCLUSION The present results highlighted negative urgency, an impulsive personality trait related to emotions, as a common feature of AN and BSD. Lack of perseverance, a trait which is less related to emotions, specifically characterises patients with BSD. On the other hand, behavioural and ERP data did not show altered inhibitory control in EDs, for either general or emotional-related response inhibition.
Caregiver oral health literacy: relationship with socioeconomic factors, oral health behaviors and perceived child dental status.

OBJECTIVE To assess associations between caregiver oral health literacy (OHL) and socioeconomic factors, child and caregiver's oral health behaviors and perceptions of oral health status. BASIC RESEARCH DESIGN Cross-sectional study. CLINICAL SETTING University pediatric dentistry clinic. PARTICIPANTS 205 pairs of caregivers and children aged 6 to 12-years undergoing dental treatment. METHOD A questionnaire was sent to caregivers enquiring about socioeconomic factors, oral health behaviors, perceptions of own and child oral health. The clinical dental status of the children was recorded with the DMFT/dmft index. MAIN OUTCOME MEASURE OHL was measured by the Brazilian version of the Rapid Estimate of Adult Literacy in Dentistry (BREALD-30). Descriptive analysis, unadjusted and adjusted logistic regression, odds ratio and confidence interval were calculated considering a significance level of 5%. RESULTS The frequency of poor OHL was 21%. In adjusted analysis caregivers with 8 years or less of schooling had a 3.72 (95% CI 1.74-7.95) times greater chance of have poor OHL. Caregivers who perceived their child to have poor oral health were 2.70 (95% CI 1.10-6.63) times more likely to have poor OHL. CONCLUSIONS Poor oral health literacy was more common among caregivers with less schooling and a poor perception of their child's oral health. OHL was unrelated to monthly family income, child dental health status, perception of own oral health or child or caregiver oral health behaviors.
Low consumption two-terminal artificial synapse based on transfer-free single-crystal MoS2 memristor

Both synaptic emulators and brain-like calculation demand an energy-efficient and bio-realistic device where two-dimensional materials have been proven as a promising competitor. Lateral memristors based on transfer-free single-crystal MoS2 with single layer grown by chemical vapor deposition (CVD) were fabricated. Here the MoS2 memristor successfully emulates typical biological synaptic behaviors including excitatory/inhibitory post-synaptic current (EPSC/IPSC), spike timing-dependent plasticity (STDP), spike rate-dependent plasticity (SRDP) and long-term plasticity (LTP). Moreover, an interesting multi-state LTP and a low consumption of 1.8 pJ after LTP process are achieved which is attributed to the high resistance of transfer-free single-crystal monolayer MoS2, representing a low value among previous MoS2 devices. The migration of Sulfur vacancies lead the conductance modulation by changing the Schottky barrier instead of forming a filament. Our work demonstrates that MoS2 memristors can more flexibly satisfy the demands of complex artificial synaptic/neuron applications.
CJEM Debate Series: #TPA should be the initial treatment in eligible patients presenting with an acute ischemic stroke.

CJEM the to hear differing perspectives on topics pertin-ent to the practice of emergency medicine. The debaters have been allocated opposing arguments on topics where there is some controversy or perhaps scienti ﬁ c equipoise. We treatment of the debate of tPA in ischemic on unhealthy coun-terpart is an integral part of critical thinking. The state of evidence as it exists in 2019 is that tPA delivered in a timely manner improves outcomes from acute ischemic stroke, but only in patients or surrogates who understand and agree to the risks involved.