Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural basis for murine norovirus engagement of bile acids and the CD300lf receptor

Significance The mechanisms of norovirus capsid interactions with host receptors and the mechanisms by which soluble cofactors augment norovirus infection are not understood. We recently identified CD300lf as a cell surface receptor for murine norovirus (MNoV) and observed that a small molecule cofactor was critical for efficient binding of virus to CD300lf. Herein we identify the bile acid GCDCA as a cofactor enhancing MNoV infection and provide a biophysical characterization of the capsid–receptor and capsid–cofactor interactions, thereby providing a structure-based understanding of how noroviruses initiate cellular infection. This work has important implications for the design of norovirus therapeutics. Murine norovirus (MNoV) is closely related to human norovirus (HNoV), an infectious agent responsible for acute gastroenteritis worldwide. Here we report the X-ray crystal structure of the dimeric MNoV VP1 protruding (P) domain in complex with its cellular receptor CD300lf. CD300lf binds the P domain with a 2:2 stoichiometry, engaging a cleft between the AB and DE loops of the P2 subdomain at a site that overlaps the epitopes of neutralizing antibodies. We also identify that bile acids are cofactors enhancing MNoV cell-binding and infectivity. Structures of CD300lf–P domain in complex with glycochenodeoxycholic acid (GCDCA) and lithocholic acid (LCA) reveal two bile acid binding sites at the P domain dimer interface distant from receptor binding sites. The structural determinants for receptor and bile acid binding are supported by numerous biophysical assays utilizing interface residue mutations. We find that the monomeric affinity of CD300lf for the P domain is low and is divalent cation dependent. We have also determined the crystal structure of CD300lf in complex with phosphocholine, revealing that MNoV engages its receptor in a manner mimicking host ligands including similar metal coordination. Docking of the cocomplex structures onto a cryo-EM–derived model of MNoV suggests that each virion can make multiple CD300lf engagements, and thus, infection may be driven by the avidity of cell surface clustered CD300lf. These studies identify multiple potential modulators of norovirus infection that may act to regulate the interaction between the viral capsid P domain and its cognate cellular receptor.
Prevalence and behavioural associations of unintentional injuries among Chinese college students: a 50-University population-based study

Objective To assess the prevalence, demographic characteristics and behavioural correlates of unintentional injuries among Chinese college students. Methods A cross-sectional multistage survey sampling process was conducted among 11 770 undergraduates from 50 universities in China. Students were asked to report different types of unintentional injuries that required medical attention from a doctor over the past year. The χ² test and multiple logistic regression analysis were used to identify factors associated with these injuries. Results The overall unintentional injury prevalence was 47.9% (95% CI 47.6% to 48.2%). Most injuries occurred at sport venues (24.0%), following by home/dormitory injuries (20.5%) and traffic injuries (13.0%). Some behavioural factors exhibiting significant associations with overall unintentional injuries were: sleeping less than 7 hours (OR=1.32, 95% CI 1.27 to 1.37), smoking (OR=1.28, 95% CI 1.23 to 1.32), alcohol consumption (OR=1.74, 95% CI 1.69 to 1.78) and heavy internet use (OR=1.60, 95% CI 1.52 to 1.67). Male students were more likely to be involved in traffic and sport injuries than female students. Students majoring in non-medical fields had a higher risk of sport and home injuries than students majoring in medical fields. Those who drank alcohol, slept less than 7 hours or who reported heavy internet use were more likely to experience all types of injuries than students who did not participate in these behaviours. Finally, students who smoked had a higher likelihood of traffic and sport injuries than non-smoking students. Conclusions A substantial number of college students reported injuries in the past year, and several key behavioural factors were associated with injuries. These findings could be beneficial for the design, implementation and assessment of injury intervention programme with college students. Based on these findings, policy implications for unintentional injury prevention and control were also considered.
Dimmable integrated CMOS LED driver based on a resonant DC/DC hybrid‐switched capacitor converter

This paper presents a 7.7‐mm2 on‐chip LED driver based on a DC/DC resonant hybrid‐switched capacitor converter operating in the MHz range with and without output capacitor. The converter operation allows continuously dimming the LED while keeping control on both peak and average current. Also, it features no flickering even in the absence of output capacitor and for light dimmed down to 10% of the nominal value. The capacitors and switches of the LED driver are integrated on a single IC die fabricated in a low‐cost 5 V 0.18‐μm bulk CMOS technology. This LED driver uses a small (0.7 mm2) inductor of 100 nH, which is 10 times smaller value than prior art integrated inductive LED drivers, still showing a competitive peak efficiency of 93% and achieving a power density of 0.26 W/mm2 (0.34 W/mm3).
From bench to bedside: Fecal calprotectin in inflammatory bowel diseases clinical setting

Fecal calprotectin (FC) has emerged as one of the most useful tools for clinical management of inflammatory bowel diseases (IBD). Many different methods of assessment have been developed and different cut-offs have been suggested for different clinical settings. We carried out a comprehensive literature review of the most relevant FC-related topics: the role of FC in discriminating between IBD and irritable bowel syndrome (IBS) and its use in managing IBD patients In patients with intestinal symptoms, due to the high negative predictive value a normal FC level reliably rules out active IBD. In IBD patients a correlation with both mucosal healing and histology was found, and there is increasing evidence that FC assessment can be helpful in monitoring disease activity and response to therapy as well as in predicting relapse, post-operative recurrence or pouchitis. Recently, its use in the context of a treat-to-target approach led to a better outcome than clinically-based therapy adjustment in patients with early Crohn’s disease. In conclusion, FC measurement represents a cheap, safe and reliable test, easy to perform and with a good reproducibility. The main concerns are still related to the choice of the optimal cut-off, both for differentiating IBD from IBS, and for the management of IBD patients.
Increases in plasma corin levels following experimental myocardial infarction reflect the severity of ischemic injury

Following acute myocardial infarction, clinical studies show alterations in the blood levels of corin, a cardiac-selective activator of the natriuretic peptides pro-atrial natriuretic peptide (pro-ANP) and pro-B-type natriuretic peptide (pro-BNP). However, the temporal changes in circulating and cardiac corin levels and their relationships to the severity of myocardial infarction have not been studied. The main objective of this study was to examine the relationship between cardiac and circulating corin levels and their association with cardiac systolic function and infarct size during the early phase of acute myocardial infarction (<72 h) in a translationally relevant induced coronary ligation mouse model. This acute phase timeline was chosen to correlate with the clinical practice within which blood samples are collected from myocardial infarction patients. Heart and plasma samples were examined at 3, 24, and 72 hours post acute myocardial infarction. Plasma corin levels were examined by enzyme-linked immunosorbent assay, transcripts of cardiac corin, pro-ANP and pro-BNP by quantitative real-time polymerase chain reaction, cardiac corin expression by immunohistology, infarct size by histology and heart function by echocardiography. Plasma corin levels were significantly increased at 3 (P<0.05), 24 (P<0.001), and 72 hours (P<0.01) post-acute myocardial infarction. In contrast, cardiac corin transcript levels dropped by 5% (P>0.05), 69% (P<0.001) and 65% (P<0.001) and immunoreactive cardiac corin protein levels dropped by 30% (P<0.05), 76% (P<0.001) and 75% (P<0.001), while cardiac pro-ANP and pro-BNP transcript levels showed an opposite pattern. Plasma corin levels were negatively correlated with immunoreactive cardiac corin (P<0.01), ejection fraction (P<0.05) and fractional shortening (P<0.05), but positively correlated with infarct size (P<0.01). In conclusion, acute myocardial infarction induces rapid increases in plasma corin and decreases in cardiac corin levels. In the early phase of acute myocardial infarction, plasma corin levels are inversely correlated with heart function and may reflect the severity of myocardial damage.
PDEδ inhibition impedes the proliferation and survival of human colorectal cancer cell lines harboring oncogenic KRas

Novelty and Impact The ‘undruggable’ KRas is a prevalent oncogene in CRC with poor prognosis. In hPDAC cells pharmacological targeting of PDEδ affects oncogenic KRas signaling, but it remained unclear whether this approach is transferable to other cancer cells. Here, we show that genetic and pharmacologic PDEδ inhibition also impedes the proliferation of oncogenic, but not wild-type KRas bearing CRC cells indicating that PDEδ inhibition is a specific tool for targeting growth of oncogenic KRas bearing CRC. Abstract Ras proteins, most notably KRas, are prevalent oncogenes in human cancer. Plasma membrane localization and thereby signaling of KRas is regulated by the prenyl-binding protein PDEδ. Recently, we have reported the specific anti-proliferative effects of PDEδ inhibition in KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, we investigated the proliferative dependence on the solubilizing activity of PDEδ of human colorectal cancer (CRC) cell lines with or without oncogenic KRas mutations. Our results show that genetic and pharmacologic interference with PDEδ specifically inhibits proliferation and survival of CRC cell lines harboring oncogenic KRas mutations whereas isogenic cell lines in which the KRas oncogene has been removed, or cell lines with oncogenic BRaf mutations or EGFR overexpression are not dependent on PDEδ. Pharmacological PDEδ inhibition is therefore a possible new avenue to target oncogenic KRas bearing CRC.
Development and validation of an ensemble classifier for real-time recognition of cow behavior patterns from accelerometer data and location data

Behaviors are important indicators for assessing the health and well-being of dairy cows. The aim of this study is to develop and validate an ensemble classifier for automatically measuring and distinguishing several behavior patterns of dairy cows from accelerometer data and location data. The ensemble classifier consists of two parts, our new Multi-BP-AdaBoost algorithm and a data fusion method based on D-S evidence theory. We identify seven behavior patterns: feeding, lying, standing, lying down, standing up, normal walking, and active walking. Accuracy, sensitivity, and precision were used to validate classification performance. The Multi-BP-AdaBoost algorithm performed well when identifying lying (92% accuracy, 93% sensitivity, 82% precision), lying down (99%, 82%, 86%), standing up (99%, 74%, 85%), normal walking (97%, 92%, 86%), and active walking (99%, 94%, 89%). Its results were poor for feeding (80%, 52%, 55%) and standing (80%, 46%, 58%), which are difficult to differentiate using a leg-mounted sensor. Position data made it possible to differentiate feeding and standing. The D-S evidence fusion method for combining accelerometer data and location data in classification was used to fuse two pieces of basic behavior-related evidence into a single estimation model. With this addition, the sensitivity and precision of the two difficult behaviors increased by approximately 20 percentage points. In conclusion, the classification results indicate that the ensemble classifier effectively recognizes various behavior patterns in dairy cows. However, further work is needed to study the robustness of the feature and model by increasing the number of cows enrolled in the trial.
Mortality and adverse events with brand and generic clopidogrel in the Food and Drug Administration Adverse Event Reporting System (FAERS).

Background and Aim Clopidogrel is commonly used even after expiring patents. The brand clopidogel (BC) was dealt by single company, while numerous manufacturers produce generic clopidogrel (GC). There are no convincing data to compare the safety of different formulations. Therefore, the data yielded from international, uniform, government-mandated registries may be useful. Methods and Results We assessed primary causative adverse events (PCAE) after BC and GC in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The outcomes were divided into death, cardiac, thrombotic/embolic, hemorrhagic, and rash/dermal complications. These primary endpoints were then examined by proportional risk ratios (PRR) and Chi-square ((χ2). Among total FAERS (n = 9,466,679) reports, overall BC (n = 88,863) cases were more common than after GC (n = 36,559). When triaged by PCAE role, BC (n = 18,328) was also more abundant than GC (n = 3,987). The reported death rates were more than doubled after BC (18.4% vs. 7.0%; PRR=0.38; 95%CI:0.32-0.43; χ2=369.7;p<0.0001) for total FAERS, and consistent for late 2010-2017 (17.6% vs. 7.0% PRR=0.40; 95%CI:0.37-0.45; χ2=286.2;p<0.004) PCAE cases. In contrast, GC trended to co-report more cardiac (14.6% vs.13.3%; PRR=1.12; 95%CI:1.0-1.25; χ2=3.5;p<0.06). The hemorrhagic (40.9% vs. 32.3%; PRR=1.45; 95%CI:1.33-1.57; χ2=75.8;p<0.0001), and rash/dermal (5.4% vs.4.6%; PRR=1.20; 95%CI:1.0-1.44; χ2=3.75;p<0.05) events were also more common for GC. Thrombotic/embolic events were reported equally (at 7.0%) after each formulation. Conclusion The PCAE profiles differ with BC and GC in FAERS. While deaths reports were higher, the rates of cardiac, hemorrhagic, and skin complications were less common for BC. Despite expected reporting bias, this may indicate that the manufacturers of GC are reluctant to report deaths to the FDA. However, the overall adverse event profile suggests potentially better safety of BC over GC formulations.
Folate deficiency and utilization of folic acid fortified flour among pregnant women attending antenatal clinic at Pumwani Maternity Hospital, Kenya, 2015

Introduction in 2012, the Government of Kenya amended the Food, Drug and Chemical Substances Act to make the fortification of maize and wheat flour with folic acid mandatory. We assessed folate deficiency, awareness and use of folic acid fortified flour among pregnant women receiving antenatal care (ANC) at a clinic at Pumwani Maternity Hospital, Kenya, 2015. Methods we conducted a cross-sectional survey at Pumwani Maternity Hospital between October and November 2014. We enrolled pregnant women who received ANC and interviewed them using a semi-structured questionnaire after obtaining informed consent. Blood samples were collected from all study participants and serum folate level was analyzed by electrochemiluminescence immunoassay. Folate deficiency was defined as serum folate of < 10nmols/L and borderline folate deficiency was defined as serum folate of between 10nmols/L and 15nmols/L. Results among the 247 study participants, two (1%) had folate deficiency. One hundred and seventy-nine (73.4%) had heard about folic acid, but only 56 (23%) had heard about folic acid fortified flour. Overall, 198 (80%) study participants consumed fortified brands of maize flour and 205 (84%) consumed fortified brands of wheat flour; only four (2%) and two (1%) of study participants consumed specific brands of maize and wheat flour respectively because they were fortified. Conclusion the prevalence of folate deficiency was low and this may have been because of the availability of fortification programs. Although there was limited knowledge of fortified flour, utilization was high. The Kenyan Ministry of Health should enforce implementation of the legislation on maize flour and wheat flour fortification by all milling industries.
Nesting ecology of hawksbill turtles, Eretmochelys imbricata, in an extreme environmental setting

Relatively few details of hawksbill turtle (Eretmochelys imbricata) nesting ecology exist within the Arabian Gulf. Moreover, little is known about how their nesting dynamics compare to nesting populations throughout the rest of the world. Due to the extreme environmental setting, nesting ecology of hawksbills in the Arabian Gulf is of significant interest to researchers and conservationists. The current research reports on a long-term tagging and monitoring program undertaken at Fuwairit beach, Qatar. To investigate nesting behavior, site surveys and tagging were employed from 2010 to 2016. Presence of nests and clutch sizes were confirmed by excavation. Over the entire study period, nesting hawksbills had a mean curved carapace length of 70.8 cm (SD±2.8). A total 187 nests were confirmed, which contained a mean 78.9 eggs per clutch (SD±17.1), over an annual nesting season that lasted an average of 52.2 days (SD±6.3) from the start of April to the start of June. Meta-analysis with other global regions showed these characteristics to be significantly reduced when compared to nesting hawksbills from other populations. Meteorological data analysis showed air temperatures in the Arabian Gulf to increase on average 13.2°C (SD±0.26) from start to the end of nesting annually, which is significantly greater than other global nesting regions. Their smaller body size and reduced fecundity coupled with the extreme change in ambient air temperatures support the hypothesis that hawksbills in the region are more at risk than the already critically endangered hawksbill populations elsewhere in the world.
New corneal assessment index from the relational thickness and other OCULUS values (CAIRO Index)

Purpose The aim of this study was to find indices for keratoconus (KC) detection with higher sensitivity and specificity than the currently available ones with the rotating Scheimpflug imaging (Oculyzer I, Pentacam) software. Patients and methods Data of 103 normal and 73 KC eyes imaged by Oculyzer I, including slit-lamp examination, refraction, Scheimpflug images, and follow-up data were collected. Logistic regression was done to find new indices with higher area under receiver operating characteristic curves using the currently available ones. Results The Corneal Assessment Index from Relational thickness and other OCULUS Values 9 (CAIRO 9) index, deduced from the Ambrosio relational thickness-maximum and the anterior elevation at thinnest point from 9 mm best-fit sphere, and the CAIRO 8, deduced from Ambrosio relational thickness-maximum and anterior elevation at thinnest point from 8 mm best-fit sphere, have a very high area under receiver operating characteristic curves for KC detection (0.997 and 0.995, respectively). Conclusion New corneal assessment index is deduced with better sensitivity and specificity for KC detection.
Clinicopathological Stratification and Long-term Follow-up of Patients with Periampullary Carcinomas

Background: Periampullary carcinomas generally confer a poor outcome. Choosing the most effective treatment regimen for each sub-entity proves challenging and is usually based on experience from pancreatic adenocarcinoma (PDAC). Patients and Methods: The long-term follow-up is presented of 472 patients with periampullary tumors [PDAC, distal cholangiocarcinoma (dCC) and ampullary carcinomas (AC)] who underwent radical resection considering clinical characteristics, paraclinical findings and histopathological features in order to define factors of prognostic relevance. Results: Patients with PDACs presented with larger tumor sizes, more frequent R1 resection, higher rate of nodal and perineural invasion, higher tumor stage according to the classification of tumors of the Union Internationale contre le Cancer when compared to those with dCCs and ACs. In a multivariate analysis, age >65 years, postoperative complications and higher grading of the tumor proved to be independent prognostic factors for survival. Conclusion: Patients suffering from PDAC have the worst prognosis and greatest benefit from radical resection of all patients with periampullary tumors. More detailed studies are warranted to better distinguish between the different entities.
Mechanisms of template handling and pseudoknot folding in human telomerase and their manipulation to expand the sequence repertoire of processive repeat synthesis

Abstract Telomerase adds telomeric repeats to chromosome ends by processive copying of a template within the telomerase RNA bound to telomerase reverse transcriptase. Telomerase RNAs have single-stranded regions that separate the template from a 5′ stem and 3′ pseudoknot, and mammals gained additional stem P2a.1 separating the template from the pseudoknot. Using human telomerase, we show that the length of template 3′-flanking single-stranded RNA is a determinant of repeat addition processivity whereas template 5′-flanking single-stranded RNA and P2a.1 are critical for activity but not processivity. In comparison, requirements for the template sequence itself are confounding: different substitutions of the same position have strikingly different consequences, from improved processivity and activity to complete inactivation. We discovered that some altered-template sequences stabilize an alternative RNA conformation that precludes the pseudoknot by base-pairing of one pseudoknot strand to the template 3′ end. Using mutations to reduce over-stability of the alternative conformation, we restore high activity and processivity to otherwise inactive altered-template telomerase ribonucleoproteins. In cells, over-stabilization or destabilization of the alternative state severely inhibited biogenesis of active telomerase. Our findings delineate roles for human telomerase RNA template-flanking regions, establish a biologically relevant pseudoknot-alternative RNA conformation, and expand the repertoire of human telomerase repeat synthesis.
Enzyme immunoassay may be inadequate for measuring salivary testosterone in older men

Abstract Several correlations have been reported between men’s testosterone (T) and other characteristics. Stalwart findings are a decline in T during the day, decline with obesity, and decline with advancing age. Here seven previously reported correlations are tested among older American men in the National Social Life, Health and Aging Project (NSHAP), their salivary T measured by enzyme immunoassays (EIA). Few significant correlations are found, with most tests producing weak or null results. These findings, overall, suggest that T does not “work” much among older men. However, a threat to this conclusion is raised by Welker et al. namely that EIA of salivary T may contain large errors, invalidating the tests. To check this possibility, these correlations from the literature were tested among older British men whose salivary T was measured by liquid chromatography-tandem mass spectroscopy (LC-MS/MS), a technique noted for its specificity. Not all could be tested, but the relationships of T with age, obesity, and health are significant among British men, indicating that T remains active in older men, and throwing doubt on the adequacy of EIA for measuring salivary T.