Miracle-dz/UniFAR-FTUs huggingface dataset:
QBiC-Pred: quantitative predictions of transcription factor binding changes due to sequence variants

Abstract Non-coding genetic variants/mutations can play functional roles in the cell by disrupting regulatory interactions between transcription factors (TFs) and their genomic target sites. For most human TFs, a myriad of DNA-binding models are available and could be used to predict the effects of DNA mutations on TF binding. However, information on the quality of these models is scarce, making it hard to evaluate the statistical significance of predicted binding changes. Here, we present QBiC-Pred, a web server for predicting quantitative TF binding changes due to nucleotide variants. QBiC-Pred uses regression models of TF binding specificity trained on high-throughput in vitro data. The training is done using ordinary least squares (OLS), and we leverage distributional results associated with OLS estimation to compute, for each predicted change in TF binding, a P-value reflecting our confidence in the predicted effect. We show that OLS models are accurate in predicting the effects of mutations on TF binding in vitro and in vivo, outperforming widely-used PWM models as well as recently developed deep learning models of specificity. QBiC-Pred takes as input mutation datasets in several formats, and it allows post-processing of the results through a user-friendly web interface. QBiC-Pred is freely available at http://qbic.genome. duke.edu.
Change in diffusion weighted MRI during liver cancer radiotherapy: Preliminary observations

Purpose. To evaluate diffusion weighted magnetic resonance imaging (DWI) in liver and liver cancers during and following conformal radiotherapy (RT). To determine the feasibility of using changes in apparent diffusion coefficients (ADC) as a potential surrogate for tumour control or normal tissue injury. Materials and methods. Patients on a six-fraction conformal liver RT protocol underwent DW-MRI at the time of treatment planning, during RT (week one and two) and one month following RT. Diffusion weighted MR images were acquired in exhale breath hold, using b-values of 0 and 600. Regions of interest (ROIs) corresponding to maximal tumour dose, high-dose peri-tumour liver, irradiated normal liver, non-irradiated liver, and spleen were analyzed on ADC maps. Results. Eleven patients (four hepatocellular carcinoma, five liver metastases, two cholangiocarcinoma) were evaluated. The baseline median tumour ADC of 1.56×10−3mm2/sec increased to 1.89×10-3mm2/sec at RT week one, to1.91x10-3mm2/sec during week two and to 2.01×10-3mm2/sec at one month following treatment (p < 0.0001). Early increases in mean ADC were correlated with higher dose and sustained tumour response, whereas RECIST and volume changes on T2 images were not. Peri-tumour mean ADC also increased, from 1.40×10−3mm2/sec (baseline) to 1.55×10−3mm2/sec (RT week 2) and 1.64 × 10−3mm2/sec (follow-up). Small ADC changes were seen in the irradiated liver, and no significant changes were seen in the un-irradiated liver. Conclusions. Changes in tumour ADC were seen during RT. Larger increases were correlated with higher doses and increased likelihood of response.
Examination of a dual-process model predicting riding with drinking drivers.

BACKGROUND Nearly 1 in 5 of the fatalities in alcohol-related crashes are passengers. Few studies have utilized theory to examine modifiable psychosocial predictors of individuals' tendencies to be a passenger in a vehicle operated by a driver who has consumed alcohol. This study used a prospective design to test a dual-process model featuring reasoned and reactive psychological influences and psychosocial constructs as predictors of riding with drinking drivers (RWDD) in a sample of individuals aged 18 to 21. METHODS College students (N = 508) completed web-based questionnaires assessing RWDD, psychosocial constructs (attitudes, expectancies, and norms), and reasoned and reactive influences (intentions and willingness) at baseline (the middle of the spring semester) and again 1 and 6 months later. Regression was used to analyze reasoned and reactive influences as proximal predictors of RWDD at the 6-month follow-up. Subsequent analyses examined the relationship between the psychosocial constructs as distal predictors of RWDD and the mediation effects of reasoned and reactive influences. RESULTS Both reasoned and reactive influences predicted RWDD, while only the reactive influence had a significant unique effect. Reactive influences significantly mediated the effects of peer norms, attitudes, and drinking influences on RWDD. Nearly all effects were constant across gender except parental norms (significant for females). CONCLUSIONS Findings highlight that the important precursors of RWDD were reactive influences, attitudes, and peer and parent norms. These findings suggest several intervention methods, specifically normative feedback interventions, parent-based interventions, and brief motivational interviewing, may be particularly beneficial in reducing RWDD.
The Arabidopsis defensin gene AtPDF2.5 mediates cadmium tolerance and accumulation.

Although excess cadmium (Cd) accumulation is harmful to plants, the molecular mechanisms underlying Cd detoxification and accumulation in Arabidopsis thaliana remain largely undetermined. In this study, we demonstrated that the A. thaliana PLANT DEFENSIN 2 gene AtPDF2.5 is involved in Cd tolerance and accumulation. In vitro Cd-binding assays revealed that AtPDF2.5 has Cd-chelating activity. Site-directed mutagenesis of AtPDF2.5 identified eight cysteine residues that were essential for mediating Cd tolerance and chelation. Histochemical analysis demonstrated that AtPDF2.5 was mainly expressed in root xylem vascular bundles, and that AtPDF2.5 was significantly induced by Cd. Subcellular localization analysis revealed that AtPDF2.5 was localized to the cell wall. The overexpression of AtPDF2.5 significantly enhanced Cd tolerance and accumulation in A. thaliana and its heterologous overexpression in rice increased Cd accumulation; however, the functional disruption of AtPDF2.5 decreased Cd tolerance and accumulation. Physiological analysis suggested that AtPDF2.5 promoted Cd efflux from the protoplast and its subsequent accumulation in the cell wall. These data suggest that AtPDF2.5 promotes cytoplasmic Cd efflux via chelation, thereby enhancing Cd detoxification and apoplastic accumulation.
Clostridioides difficile in transplant patients: early diagnosis, treatment, and prevention.

PURPOSE OF REVIEW Clostridioides difficile infection is common in solid organ transplant and hematopoietic stem-cell transplant recipients and is associated with significant morbidity and mortality. These populations are also underrepresented in clinical trials, making optimal management difficult. Because of this, management of these populations follows national guideline recommendations. This review aims to summarize the recent relevant literature pertaining to the clinical management of C. difficile infection in transplant patients, with a particular focus on diagnosis, treatment, and prevention. RECENT FINDINGS Early diagnosis of C. difficile colonization may mitigate both horizontal and vertical transmission (progression from colonization to colitis) of infection. Once diagnosed, recent literature suggests antibiotic treatment should align with that recommended by national guidelines. Fecal microbiota transplant is an emerging therapy for recurrent C. difficile infection, and recent data have demonstrated safety and efficacy. Prevention strategies including antimicrobial stewardship, probiotic administration, antibiotic administration, and bezlotoxumab may be beneficial in transplant populations, but more data are needed to confirm recent findings. SUMMARY Studies evaluating C. difficile infection in transplant patients are only recently starting to emerge. Further research is needed to identify optimal treatment and prevention strategies, and to examine novel strategies such as microbiome manipulation.
Restoration of Cellular Proliferation and Characteristics of Human Tenocytes by Vitamin D

Vitamin D (Vit D) increases calcium absorption in the intestine after binding to the Vit D receptor (VDR). The VDR has also been identified in muscle cells. Vit D supplementation resulted in improved muscle strength. However, there is a paucity of studies of the role of Vit D on tenocytes. We investigated the effects of Vit D on damaged tenocytes. Human tenocytes were treated with dexamethasone (Dex) to induce cell injury. Expression of the tenocyte‐related markers tenomodulin (Tnmd), tenascin C (Tnc), scleraxis (Scx), mohawk (Mkx), and collagen (Col) 1 and 3 were measured. Then, tenocytes were cotreated with Vit D. 1‐α‐Hydroxylase and VDR were explored in tenocytes. With 10 μM Dex, the growth of tenocytes was significantly inhibited, and the gene expression of Tnmd, Tnc, Scx, Mkx, Col 1 and 3 also decreased. When tenocytes were cotreated with Vit D, cell proliferation recovered in a dose‐dependent manner, and the expression of TNMD and Col 1 improved. When studying the mechanisms of the effects of Vit D on tenocytes, reactive oxygen species produced by Dex decreased with Vit D, and the phosphorylation of extracellular signal–regulated kinase and p38 was stimulated by Vit D cotreatment. 1‐α‐Hydroxylase and VDR were found in tenocytes, indicating that the cells have the ability to use an inactive form of Vit D and interact with it. Vit D is known to perform diverse actions and its protective effects on tenocytes suggest its beneficial role in tendon in addition to muscle and bone. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2241–2248, 2019
A Simplified Crossing Fiber Model in Diffusion Weighted Imaging

Diffusion MRI (dMRI) is a vital source of imaging data for identifying anatomical connections in the living human brain that form the substrate for information transfer between brain regions. dMRI can thus play a central role toward our understanding of brain function. The quantitative modeling and analysis of dMRI data deduces the features of neural fibers at the voxel level, such as direction and density. The modeling methods that have been developed range from deterministic to probabilistic approaches. Currently, the Ball-and-Stick model serves as a widely implemented probabilistic approach in the tractography toolbox of the popular FSL software package and FreeSurfer/TRACULA software package. However, estimation of the features of neural fibers is complex under the scenario of two crossing neural fibers, which occurs in a sizeable proportion of voxels within the brain. A Bayesian non-linear regression is adopted, comprised of a mixture of multiple non-linear components. Such models can pose a difficult statistical estimation problem computationally. To make the approach of Ball-and-Stick model more feasible and accurate, we propose a simplified version of Ball-and-Stick model that reduces parameter space dimensionality. This simplified model is vastly more efficient in the terms of computation time required in estimating parameters pertaining to two crossing neural fibers through Bayesian simulation approaches. Moreover, the performance of this new model is comparable or better in terms of bias and estimation variance as compared to existing models.
Native Surface Oxides Featured Liquid Metals for Printable Self-Powered Photoelectrochemical Device

Constructing high-performance photo-electrodes by patterning the photo-active semiconducting components with desirable texture and architecture is one of the most promising approaches to achieve the practical and scale-up application of photo-electric or photoelectrochemical (PEC) devices. However, it is a still big challenge to efficiently and effectively handle nano-structural semiconducting materials into intergraded circuit devices, displaying good electric-contact and stability. Here, a facile manufacture strategy for fabricating native metal-oxides based photo-electrodes by directly printing Ga-based liquid metals is explored. The PEC device, functionalized by the native Ga-oxide functional layer, exhibits self-powered photo-detection behaviors and presents fast photo-electric responsibility in response to the simulated Sunlight illumination. This printable PEC device shows good potential for high sensitive self-powered photo-detector and provides a flexible and versatile approach for the design and fabrication of novel electrode structures.
Identification of Breast Cancer Stem Cell Related Genes Using Functional Cellular Assays Combined With Single-Cell RNA Sequencing in MDA-MB-231 Cells

Breast cancer tumors display different cellular phenotypes. A growing body of evidence points toward a population of cancer stem cells (CSCs) that is important for metastasis and treatment resistance, although the characteristics of these cells are incomplete. We used mammosphere formation assay and label-retention assay as functional cellular approaches to enrich for cells with different degree of CSC properties in the breast cancer cell line MDA-MB-231 and performed single-cell RNA sequencing. We clustered the cells based on their gene expression profiles and identified three subpopulations, including a CSC-like population. The cell clustering into these subpopulations overlapped with the cellular enrichment approach applied. To molecularly define these groups, we identified genes differentially expressed between the three subpopulations which could be matched to enriched gene sets. We also investigated the transition process from CSC-like cells into more differentiated cell states. In the CSC population we found 14 significantly upregulated genes. Some of these potential breast CSC markers are associated to reported stem cell properties and clinical survival data, but further experimental validation is needed to confirm their cellular functions. Detailed characterization of CSCs improve our understanding of mechanisms for tumor progression and contribute to the identification of new treatment targets.
Aspergillus fumigatus Challenged by Human Dendritic Cells: Metabolic and Regulatory Pathway Responses Testify a Tight Battle

Dendritic cells (DCs) are antigen presenting cells which serve as a passage between the innate and the acquired immunity. Aspergillosis is a major lethal condition in immunocompromised patients caused by the adaptable saprophytic fungus Aspergillus fumigatus. The healthy human immune system is capable to ward off A. fumigatus infections however immune-deficient patients are highly vulnerable to invasive aspergillosis. A. fumigatus can persist during infection due to its ability to survive the immune response of human DCs. Therefore, the study of the metabolism specific to the context of infection may allow us to gain insight into the adaptation strategies of both the pathogen and the immune cells. We established a metabolic model of A. fumigatus central metabolism during infection of DCs and calculated the metabolic pathway (elementary modes; EMs). Transcriptome data were used to identify pathways activated when A. fumigatus is challenged with DCs. In particular, amino acid metabolic pathways, alternative carbon metabolic pathways and stress regulating enzymes were found to be active. Metabolic flux modeling identified further active enzymes such as alcohol dehydrogenase, inositol oxygenase and GTP cyclohydrolase participating in different stress responses in A. fumigatus. These were further validated by qRT-PCR from RNA extracted under these different conditions. For DCs, we outlined the activation of metabolic pathways in response to the confrontation with A. fumigatus. We found the fatty acid metabolism plays a crucial role, along with other metabolic changes. The gene expression data and their analysis illuminate additional regulatory pathways activated in the DCs apart from interleukin regulation. In particular, Toll-like receptor signaling, NOD-like receptor signaling and RIG-I-like receptor signaling were active pathways. Moreover, we identified subnetworks and several novel key regulators such as UBC, EGFR, and CUL3 of DCs to be activated in response to A. fumigatus. In conclusion, we analyze the metabolic and regulatory responses of A. fumigatus and DCs when confronted with each other.
Impedance Control: An Approach to Manipulation: Part I—Theory

Manipulation fundamentally requires the manipulator to be mechanically coupled to the object being manipulated; the manipulator may not be treated as an isolated system. This three-part paper presents an approach to the control of dynamic in teraction between a manipulator and its environment. In Part I this approach is developed by considering the mechanics of interaction between physical systems. Control of position or force alone is inadequate; control of dynamic behavior is also required. It is shown that as manipulation is a fundamentally nonlinear problem, the distinction between impedance and admittance is essential, and given the environment contains inertial objects, the manipulator must be an impedance. A generalization of a Norton equivalent network is defined for a broad class of nonlinear manipulators which separates the control of motion from the control of impedance while preserving the superposition properties of the Norton network. It is shown that components of the manipulator impedance may be combined by superposition even when they are nonlinear.
Discovery of the extracytoplasmic function σ factors

This special issue of Molecular Microbiology marks the 25th anniversary of the discovery of the extracytoplasmic function (ECF) σ factors, proteins that subsequently emerged as the largest group of alternative σ factors and one of the three major pillars of signal transduction in bacteria, alongside one‐ and two‐component systems. A single bacterial genome can encode > 100 ECF σ factors, and combined with their cognate anti‐σ factors, they represent a modular design that primarily functions in transmembrane signal transduction. Here, we first describe the immediate events that led to the 1994 publication in the Proceeding of the National Academy of Sciences USA, and then set them in the broader context of key events in the history of σ biology research.
White matter endophenotype candidates for ADHD: a diffusion imaging tractography study with sibling design

Abstract Background Brain structural alterations are frequently observed in probands with attention-deficit/hyperactivity disorder (ADHD). Here we examined the microstructural integrity of 76 white matter tracts among unaffected siblings of patients with ADHD to evaluate the potential familial risk and its association with clinical and neuropsychological manifestations. Methods The comparison groups included medication-naïve ADHD probands (n = 50), their unaffected siblings (n = 50) and typically developing controls (n = 50, age-and-sex matched with ADHD probands). Whole brain tractography was reconstructed automatically by tract-based analysis of diffusion spectrum imaging (DSI). Microstructural properties of white matter tracts were represented by the values of generalized fractional anisotropy (GFA), fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD). Results Compared to the control group, ADHD probands showed higher AD values in the perpendicular fasciculus, superior longitudinal fasciculus I, corticospinal tract, and corpus callosum. The AD values of unaffected siblings were in the intermediate position between those of the ADHD and control groups. These AD values were significantly associated with ADHD symptoms, sustained attention and working memory, for all white matter tracks evaluated except for the perpendicular fasciculus. Higher FA and lower RD values in the right frontostriatal tract connecting ventrolateral prefrontal cortex (FS-VLPFC) were associated with better performance in spatial span only in the unaffected sibling group. Conclusions Abnormal AD values of specific white matter tracts among unaffected siblings of ADHD probands suggest the presence of familial risk in this population. The right FS-VLPFC may have a role in preventing the expression of the ADHD-related behavioral phenotype. ClinicalTrials.gov number NCT01682915
Development of a Combined Sensory-Cognitive Measure Based on the Common Cause Hypothesis: Heterogeneous Trajectories and Associated Risk Factors.

BACKGROUND AND OBJECTIVES There is a link between sensory and cognitive functioning across old age. However, there are no integrative measures for assessing common determinants of sensory-cognitive functioning. This study aims to develop a combined measure of sensory-cognitive functioning, and to identify heterogeneous trajectories and associated risk factors. RESEARCH DESIGN AND METHODS Two thousand two hundred and fifty-five individuals aged 60 years and over selected from the first six waves (2002-2012) of the English Longitudinal Study of Ageing completed a set of five self-reported visual and hearing functioning items and four cognitive items. Several health-related outcomes were also collected. RESULTS The common cause model presented longitudinal factorial invariance (Tucker-Lewis index [TLI] = 0.989; Comparative Fit Index [CFI] = 0.991; Root Mean Square Error of Approximation [RMSEA] = 0.026). A common factor explained 32%, 36%, and 26% of the visual, hearing, and cognitive difficulties, respectively. The developed sensory-cognitive measure predicted incident dementia over 10 years (area under the curve = .80; 95% confidence interval [CI] = .75, .86). A three-trajectory model was proved to fit better, according to growth mixture modeling. Low levels of education and household wealth, disability, diabetes, high blood pressure, depressive symptoms, and low levels of physical activity were risk factors associated with the classes showing trajectories with a steeper increase of sensory-cognitive difficulties. DISCUSSION AND IMPLICATIONS A time-invariant factor explains both sensory and cognitive functioning over 8 years. The sensory-cognitive measure derived from this factor showed a good performance for predicting dementia 10 years later. Several easily identifiable socioeconomic and health-related risk factors could be used as early markers of subsequent sensory-cognitive decline. Therefore, the proposed latent measure could be useful as a cost-effective indicator of sensory-cognitive functioning.