Miracle-dz/UniFAR-FTUs huggingface dataset:
Semi-parametric Bayesian regression for subgroup analysis in clinical trials

ABSTRACT Determining whether there are differential treatment effects in subgroups of trial participants remains an important topic in clinical trials as precision medicine becomes ever more relevant. Any assessment of differential treatment effect is predicated on being able to estimate the treatment response accurately while satisfying constraints of balancing the risk of overlooking an important subgroup with the potential to make a decision based on a false discovery. While regression models, such as marginal interaction model, have been widely used to improve accuracy of subgroup parameter estimates by leveraging the relationship between treatment and covariate, there is still a possibility that it can lead to excessively conservative or anti-conservative results. Conceivably, this can be due to the use of the normal distribution as a default prior, which forces outlying subjects to have their means over-shrunk towards the population mean, and the data from such subjects may be excessively influential in estimation of both the overall mean response and the mean response for each subgroup, or a model mis-specification. To address this issue, we investigate the use of nonparametric Bayes, particularly Dirichlet process priors, to create semi-parametric models. These models represent uncertainty in the prior distribution for the overall response while accommodating heterogeneity among individual subgroups. They also account for the effect and variation due to the unaccounted terms. As a result, the models do not force estimates to excessively shrink but still retain the attractiveness of improved precision given by the narrower credible intervals. This is illustrated in extensive simulations investigating bias, mean squared error, coverage probability and credible interval widths. We applied the method on a simulated data based closely on the results of a cystic fibrosis Phase 2 trial.
Botryosphaeriaceae Species Associated with Avocado Branch Cankers in California.

Members of the family Botryosphaeriaceae cause branch cankers and dieback on California avocado trees. More intensive pruning, a practice associated with high-density planting that is becoming more common in the California avocado industry, may increase the occurrence of branch canker. This study was undertaken to identify and characterize the Botryosphaeriaceae spp. involved in the branch canker disease complex in order to develop future management strategies. From 2008 to 2009, branch cankers were sampled from four or five trees from each of eight avocado groves in five California counties. Six Botryosphaeriaceae spp. were identified based on morphology as well as phylogenetic analysis of the internal transcribed spacer region (ITS1-5.8S-ITS2) and a partial sequence of the β-tubulin gene. These six species included Neofusicoccum australe, N. luteum, N. parvum, an unknown Neofusicoccum sp. , Fusicoccum aesculi, and Dothiorella iberica. Members of the Botryosphaeriaceae were isolated from all avocado-growing regions sampled in California; however, incidence and distribution of species varied. This report is the first description of the isolation of D. iberica from avocado branch cankers in California.
Enhancement of Exercise Performance by 48 Hours, and 15-Day Supplementation with Mangiferin and Luteolin in Men

The natural polyphenols mangiferin and luteolin have free radical-scavenging properties, induce the antioxidant gene program and down-regulate the expression of superoxide-producing enzymes. However, the effects of these two polyphenols on exercise capacity remains mostly unknown. To determine whether a combination of luteolin (peanut husk extract containing 95% luteolin, PHE) and mangiferin (mango leave extract (MLE), Zynamite®) at low (PHE: 50 mg/day; and 140 mg/day of MLE containing 100 mg of mangiferin; L) and high doses (PHE: 100 mg/day; MLE: 420 mg/day; H) may enhance exercise performance, twelve physically active men performed incremental exercise to exhaustion, followed by sprint and endurance exercise after 48 h (acute effects) and 15 days of supplementation (prolonged effects) with polyphenols or placebo, following a double-blind crossover design. During sprint exercise, mangiferin + luteolin supplementation enhanced exercise performance, facilitated muscle oxygen extraction, and improved brain oxygenation, without increasing the VO2. Compared to placebo, mangiferin + luteolin increased muscle O2 extraction during post-exercise ischemia, and improved sprint performance after ischemia-reperfusion likely by increasing glycolytic energy production, as reflected by higher blood lactate concentrations after the sprints. Similar responses were elicited by the two doses tested. In conclusion, acute and prolonged supplementation with mangiferin combined with luteolin enhances performance, muscle O2 extraction, and brain oxygenation during sprint exercise, at high and low doses.
Evaluating CAR‐T Cell Therapy in a Hypoxic 3D Tumor Model

Despite its revolutionary success in hematological malignancies, chimeric antigen receptor T (CAR‐T) cell therapy faces disappointing clinical results in solid tumors. The poor efficacy has been partially attributed to the lack of understanding in how CAR‐T cells function in a solid tumor microenvironment. Hypoxia plays a critical role in cancer progression and immune editing, which potentially results in solid tumors escaping immunosurveillance and CAR‐T cell‐mediated cytotoxicity. Mechanistic studies of CAR‐T cell biology in a physiological environment has been limited by the complexity of tumor‐immune interactions in clinical and animal models, as well as by a lack of reliable in vitro models. A microdevice platform that recapitulates a 3D tumor section with a gradient of oxygen and integrates fluidic channels surrounding the tumor for CAR‐T cell delivery is engineered. The design allows for the evaluation of CAR‐T cell cytotoxicity and infiltration in the heterogeneous oxygen landscape of in vivo solid tumors at a previously unachievable scale in vitro.
Programmable RNA detection with a fluorescent RNA aptamer using optimized three-way junction formation

RNAs play essential roles in various cellular processes and can be used as biomarkers. Hence, it is important to detect endogenous RNA for understanding diverse cellular functions and diagnosing diseases. To construct a low-cost and easy-to-use RNA detection probe, a chemically unmodified RNA aptamer that binds to a pro-fluorophore to increase its fluorescence is desirable. Here, we focused on Broccoli, a superior variant of Spinach, which is a well-known fluorescent RNA aptamer that binds to DFHBI-1T and emits green fluorescence. We experimentally characterized Broccoli and predicted that it forms a G-quadruplex–based DFHBI-1T recognition region sandwiched between two stems. Based on this, we designed a Broccoli-based RNA detection probe (BRD probe) composed of a sequence of destabilized Broccoli fused with complementary sequences against target RNA. The resulting probe with its target RNA formed a stable three-way junction, named the MT2 three-way junction, which contributed to efficient refolding of the Broccoli structure and allowed for programmable RNA detection with high signal-to-noise ratio and sensitivity. Interestingly, the MT2 three-way junction also could be applied to probe construction of a truncated form of Spinach (Baby Spinach). The BRD and Baby Spinach–based RNA detection probes (BSRD probe) exhibited up to 48- and 140-fold fluorescence enhancements in the presence of their target RNAs and detected small amounts of target RNA that were as low as 160 and 5 nM, respectively. Thus, we experimentally characterized the higher order structure of Broccoli and developed structure-switching aptamer probes for highly sensitive, programmable, RNA detection using an MT2 three-way junction.
Factors Associated with Increased Adoption of a Research Data Warehouse

The increased demand of clinical data for the conduct of clinical and translational research incentivized repurposing of the University of Arkansas for Medical Sciences' enterprise data warehouse (EDW) to meet researchers' data needs. The EDW was renamed the Arkansas Clinical Data Repository (AR-CDR), underwent content enhancements, and deployed a self-service cohort estimation tool in late of 2016. In an effort to increase adoption of the AR-CDR, a team of physician informaticist and information technology professionals conducted various informational sessions across the UAMS campus to increase awareness of the AR-CDR and the informatics capabilities. The restructuring of the data warehouse resulted in four-fold utilization increase of the AR-CDR data services in 2017. To assess acceptance rates of the AR-CDR and quantify outcomes of services provided, Everett Rogers' diffusion of innovation (DOI) framework was applied, and a survey was distributed. Results show the factors that had impact on increased adoption were: presence of physician informaticist to mediate interactions between researchers and analysts, data quality, communication with and engagement of researchers, and the AR-CDR's team responsiveness and customer service mindset.
Isolation by instability: Historical climate change shapes population structure and genomic divergence of treefrogs in the Neotropical Cerrado savanna

Although the impact of Pleistocene glacial cycles on the diversification of the tropical biota was once dismissed, increasing evidence suggests that Pleistocene climatic fluctuations greatly affected the distribution and population divergence of tropical organisms. Landscape genomic analyses coupled with paleoclimatic distribution models provide a powerful way to understand the consequences of past climate changes on the present‐day tropical biota. Using genome‐wide SNP data and mitochondrial DNA, combined with projections of the species distribution across the late Quaternary until the present, we evaluate the effect of paleoclimatic shifts on the genetic structure and population differentiation of Hypsiboas lundii, a treefrog endemic to the South American Cerrado savanna. Our results show a recent and strong genetic divergence in H. lundii across the Cerrado landscape, yielding four genetic clusters that do not seem congruent with any current physical barrier to gene flow. Isolation by distance (IBD) explains some of the population differentiation, but we also find strong support for past climate changes promoting range shifts and structuring populations even in the presence of IBD. Post‐Pleistocene population persistence in four main areas of historical stable climate in the Cerrado seems to have played a major role establishing the present genetic structure of this treefrog. This pattern is consistent with a model of reduced gene flow in areas with high climatic instability promoting isolation of populations, defined here as “isolation by instability,” highlighting the effects of Pleistocene climatic fluctuations structuring populations in tropical savannas.
The mitochondrial genome of Ixobrychus flavicollis (Ardeidae: Ixobrychus)

Abstract Ixobrychus flavicollis is the largest bittern in Ixobrychus which has very wide geographical range. In our results, the complete mitochondrial genome of I. flavicollis is 17,016 bp in length. Thirteen protein-coding genes, two rRNA genes, twenty-two tRNA genes and one non-coding region (D-loop) are present in this mitochondrial genome. No special arrangement when compared with other typical mitochondrial of vertebrates. The percentage of A and T (56.7%) was slightly higher than G and C.
2D selenium allotropes from first principles and swarm intelligence

Combining the particle-swarm optimization method with first-principles calculations, we explore a new category of two-dimensional (2D) monolayers composed of solely the element selenium. Three stable structures are screened from outputs of crystal search computations, namely T-Se (1T-MoS2-like), C-Se (tiled 1D helical chain), and S-Se (square structure). Phonon calculations, as well as formation energy calculations have been performed to confirm the stability of the three phases. The electronic structure calculations show that both T-Se and C-Se are indirect-band-gap semiconductors, with gap values of 1.11 eV and 2.64 eV respectively when using the hybrid HSE06 functional. In particular, C-Se has a centrosymmetry-breaking structure which provides a spontaneous in-plane ferroelectric polarization of about 2.68 × 10−10 C m−1 per layer. Interestingly, S-Se has a Dirac cone that can open up a band gap of 0.11 eV if spin–orbit coupling is included. The tilted Dirac cone of S-Se shows anisotropic band dispersion as characterized with different Fermi velocities of 1.26 × 106 and 0.24 × 106 m s−1 around the Dirac point. Our works enrich the family of 2D materials of selenium allotropes and show that their versatile properties could give rise to potential application in various fields.
Cytoplasm and Beyond: Dynamic Innate Immune Sensing of Influenza A Virus by RIG-I

Innate immune sensing of influenza A virus (IAV) requires retinoic acid-inducible gene I (RIG-I), a fundamental cytoplasmic RNA sensor. How RIG-I’s cytoplasmic localization reconciles with the nuclear replication nature of IAV is poorly understood. ABSTRACT Innate immune sensing of influenza A virus (IAV) requires retinoic acid-inducible gene I (RIG-I), a fundamental cytoplasmic RNA sensor. How RIG-I’s cytoplasmic localization reconciles with the nuclear replication nature of IAV is poorly understood. Recent findings provide advanced insights into the spatiotemporal RIG-I sensing of IAV and highlight the contribution of various RNA ligands to RIG-I activation. Understanding a compartment-specific RIG-I-sensing paradigm would facilitate the identification of the full spectrum of physiological RIG-I ligands produced during IAV infection.
Measles cases in Europe tripled from 2017 to 2018

More than 80 000 people in 47 of 53 European countries contracted measles in 2018, with 72 deaths, the World Health Organization has said.1 In countries reporting hospitalisation data 61% of patients with measles were admitted to hospital.2 The total number of people infected with the virus in 2018 was the highest this decade,1 three times the total reported in 2017 (23 927 cases) and 15 times the record low recorded in 2016 (5273 cases). 3 Despite more children in the WHO European region being vaccinated against the disease than ever before, progress on vaccination is uneven between and within countries. This leaves clusters of susceptible people unprotected, particularly …
Use of a combination strategy to improve neuroprotection and neuroregeneration in a rat model of acute spinal cord injury

Spinal cord injury is a very common pathological event that has devastating functional consequences in patients. In recent years, several research groups are trying to find an effective therapy that could be applied in clinical practice. In this study, we analyzed the combination of different strategies as a potential therapy for spinal cord injury. Immunization with neural derived peptides (INDP), inhibition of glial scar formation (dipyridyl: DPY), as well as the use of biocompatible matrix (fibrin glue: FG) impregnated with bone marrow mesenchymal stem cells (MSCs) were combined and then its beneficial effects were evaluated in the induction of neuroprotection and neuroregeneration after acute SCI. Sprague-Dawley female rats were subjected to a moderate spinal cord injury and then randomly allocated into five groups: 1) phosphate buffered saline; 2) DPY; 3) INDP + DPY; 4) DPY+ FG; 5) INDP + DPY + FG + MSCs. In all rats, intervention was performed 72 hours after spinal cord injury. Locomotor and sensibility recovery was assessed in all rats. At 60 days after treatment, histological examinations of the spinal cord (hematoxylin-eosin and Bielschowsky staining) were performed. Our results showed that the combination therapy (DPY+ INDP + FG + MSCs) was the best strategy to promote motor and sensibility recovery. In addition, significant increases in tissue preservation and axonal density were observed in the combination therapy group. Findings from this study suggest that the combination theapy (DPY+ INDP + FG + MSCs) exhibits potential effects on the protection and regeneration of neural tissue after acute spinal cord injury. All procedures were approved by the Animal Bioethics and Welfare Committee (approval No. 178544; CSNBTBIBAJ 090812960) on August 15, 2016.
In vivo validity of proximal caries detection in primary teeth, with histological validation.

BACKGROUND Detection and diagnosis of proximal caries in primary molars are challenging. AIM The aim of this in vivo study was to assess the validity and reproducibility of four methods of proximal caries detection in primary molar teeth. DESIGN Eighty-two children (5-10 years) were recruited. Initially, 1030 proximal surfaces were examined using meticulous visual examination (ICDAS) (VE1), bitewing radiographs (RE), and a laser fluorescence pen device (LF1). Temporary tooth separation (TTS) was achieved for 447 surfaces, and these were re-examined visually (VE2) and using the LF pen (LF2). Three hundred and fifty-six teeth (542 surfaces) were subsequently extracted and provided histological validation. RESULTS At D1 (enamel and dentine caries) diagnostic threshold, the sensitivity of VE1, RE, VE2, LF1, and LF2 examination was 0.52, 0.14, 0.75, 0.58, and 0.60 and the specificity values were 0.89, 0.97, 0.88, 0.85, and 0.77, respectively. At D3 (dentine caries) threshold, the sensitivity values were 0.42, 0.71, 0.49, 0.63, and 0.65, respectively, whereas specificity was 0.93 for VE1 and VE2, and 0.98, 0.87, and 0.88 for RE, LF1, and LF2 examinations, respectively. ROC analysis showed radiographic examination to be superior at D3 . CONCLUSION Meticulous caries diagnosis (ICDAS) should be supported by radiographs for detection of dentinal proximal caries in primary molars.
Biomarkers in tumors of the central nervous system – a review

Until recently, diagnostics of brain tumors were almost solely based on morphology and immunohistochemical stainings for relatively unspecific lineage markers. Although certain molecular markers have been known for longer than a decade (combined loss of chromosome 1p and 19q in oligodendrogliomas), molecular biomarkers were not included in the WHO scheme until 2016. Now, the classification of diffuse gliomas rests on an integration of morphology and molecular results. Also, for many other central nervous system tumor entities, specific diagnostic, prognostic and predictive biomarkers have been detected and continue to emerge. Previously, we considered brain tumors with similar histology to represent a single disease entity. We now realize that histologically identical tumors might show alterations in different molecular pathways, and often represent separate diseases with different natural history and response to treatment. Hence, knowledge about specific biomarkers is of great importance for individualized treatment and follow‐up. In this paper we review the biomarkers that we currently use in the diagnostic work‐up of brain tumors.
Loss of R-Spondin1 and Foxl2 Amplifies Female-to-Male Sex Reversal in XX Mice

In vertebrates, 2 main genetic pathways have been shown to regulate ovarian development. Indeed, a loss of function mutations in Rspo1 and Foxl2 promote partial female-to-male sex reversal. In mice, it has been shown that the secreted protein RSPO1 is involved in ovarian differentiation and the transcription factor FOXL2 is required for follicular formation. Here, we analysed the potential interactions between these 2 genetic pathways and have shown that while Rspo1 expression seems to be independent of Foxl2 up-regulation, Foxl2 expression partly depends of Rspo1 signalisation. This suggests that different Foxl2-positive somatic cell lineages exist within the ovaries. In addition, a combination of both mutated genes in XX Foxl2–/–/Rspo1–/– gonads promotes sex reversal, detectable at earlier stages than in XX Rspo1–/– mutants. Ectopic development of the steroidogenic lineage is more pronounced in XX Foxl2–/–/Rspo1–/– gonads than in XX Rspo1–/– embryos, suggesting that Foxl2 is involved in preventing ectopic steroidogenesis in foetal ovaries.
Genetic and environmental effects on body mass index from infancy to the onset of adulthood: an individual-based pooled analysis of 45 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) study.

BACKGROUND Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking. OBJECTIVES We analyzed the genetic and environmental contributions to BMI variation from infancy to early adulthood and the ways they differ by sex and geographic regions representing high (North America and Australia), moderate (Europe), and low levels (East Asia) of obesogenic environments. DESIGN Data were available for 87,782 complete twin pairs from 0.5 to 19.5 y of age from 45 cohorts. Analyses were based on 383,092 BMI measurements. Variation in BMI was decomposed into genetic and environmental components through genetic structural equation modeling. RESULTS The variance of BMI increased from 5 y of age along with increasing mean BMI. The proportion of BMI variation explained by additive genetic factors was lowest at 4 y of age in boys (a(2) = 0.42) and girls (a(2) = 0.41) and then generally increased to 0.75 in both sexes at 19 y of age. This was because of a stronger influence of environmental factors shared by co-twins in midchildhood. After 15 y of age, the effect of shared environment was not observed. The sex-specific expression of genetic factors was seen in infancy but was most prominent at 13 y of age and older. The variance of BMI was highest in North America and Australia and lowest in East Asia, but the relative proportion of genetic variation to total variation remained roughly similar across different regions. CONCLUSIONS Environmental factors shared by co-twins affect BMI in childhood, but little evidence for their contribution was found in late adolescence. Our results suggest that genetic factors play a major role in the variation of BMI in adolescence among populations of different ethnicities exposed to different environmental factors related to obesity.
Perivascular spaces and their associations with risk factors, clinical disorders and neuroimaging features: A systematic review and meta-analysis

Background Perivascular spaces, visible on brain magnetic resonance imaging, are thought to be associated with small vessel disease, neuroinflammation, and to be important for cerebral hemodynamics and interstitial fluid drainage. Aims To benchmark current knowledge on perivascular spaces associations with risk factors, neurological disorders, and neuroimaging lesions, using systematic review and meta-analysis. Summary of review We searched three databases for perivascular spaces publications, calculated odds ratios with 95% confidence interval and performed meta-analyses to assess adjusted associations with perivascular spaces. We identified 116 relevant studies (n = 36,108) but only 23 (n = 12,725) were meta-analyzable. Perivascular spaces assessment, imaging and clinical definitions varied. Perivascular spaces were associated (n; OR, 95%CI, p) with ageing (8395; 1.47, 1.28–1.69, p = 0.00001), hypertension (7872; 1.67, 1.20–2.31, p = 0.002), lacunes (4894; 3.56, 1.39–9.14, p = 0.008), microbleeds (5015; 2.26, 1.04–4.90, p = 0.04) but not WMH (4974; 1.54, 0.71–3.32, p = 0.27), stroke or cognitive impairment. There was between-study heterogeneity. Lack of appropriate data on other brain disorders and demographic features such as ethnicity precluded analysis. Conclusions Despite many studies, more are required to determine potential pathophysiological perivascular spaces involvement in cerebrovascular, neurodegenerative and neuroinflammatory disorders.