Human Genetic Variation in F3 and Its Impact on Tissue Factor-Dependent Disease.

Tissue factor (TF) is the primary initiator of blood coagulation in humans. As improper intravascular TF expression and procoagulant activity underlie numerous thrombotic disorders, there has been longstanding interest in the contribution of heritable genetic variation in , the gene encoding TF, to human disease. This review seeks to comprehensively and critically synthesize small case-control studies focused on candidate single nucleotide polymorphisms (SNPs), as well as modern genome-wide association studies (GWAS) seeking to discover novel associations between variants and clinical phenotypes.

Behavioral Experience-Sampling Methods in Neuroimaging Studies With Movie and Narrative Stimuli.

Movies and narratives are increasingly utilized as stimuli in functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), and electroencephalography (EEG) studies. Emotional reactions of subjects, what they pay attention to, what they memorize, and their cognitive interpretations are all examples of inner experiences that can differ between subjects during watching of movies and listening to narratives inside the scanner. Here, we review literature indicating that behavioral measures of inner experiences play an integral role in this new research paradigm guiding neuroimaging analysis.

Convergence of infectious and non-communicable disease epidemics in rural South Africa: a cross-sectional, population-based multimorbidity study.

Background: There has been remarkable progress in the treatment of HIV throughout sub-Saharan Africa, but there are few data on the prevalence and overlap of other significant causes of disease in HIV endemic populations. Our aim was to identify the prevalence and overlap of infectious and non-communicable diseases in such a population in rural South Africa.

Methods: We did a cross-sectional study of eligible adolescents and adults from the Africa Health Research Institute demographic surveillance area in the uMkhanyakude district of KwaZulu-Natal, South Africa.

Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections.

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus.

Population-scale longitudinal mapping of COVID-19 symptoms, behaviour and testing.

Despite the widespread implementation of public health measures, coronavirus disease 2019 (COVID-19) continues to spread in the United States. To facilitate an agile response to the pandemic, we developed How We Feel, a web and mobile application that collects longitudinal self-reported survey responses on health, behaviour and demographics. Here, we report results from over 500,000 users in the United States from 2 April 2020 to 12 May 2020.

DOCK8 is essential for LFA-1-dependent positioning of T follicular helper cells in germinal centers.

T follicular helper (Tfh) cell migration into germinal centers (GCs) is essential for the generation of GC B cells and antibody responses to T cell-dependent (TD) antigens. This process requires interactions between lymphocyte function-associated antigen 1 (LFA-1) on Tfh cells and ICAMs on B cells. The mechanisms underlying defective antibody responses to TD antigens in DOCK8 deficiency are incompletely understood.

Partitioning of cancer therapeutics in nuclear condensates.

The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target.

A Simple, Robust, and High Throughput Single Molecule Flow Stretching Assay Implementation for Studying Transport of Molecules Along DNA.

We describe a simple, robust and high throughput single molecule flow-stretching assay for studying 1D diffusion of molecules along DNA. In this assay, glass coverslips are functionalized in a one-step reaction with silane-PEG-biotin. Flow cells are constructed by sandwiching an adhesive tape with pre-cut channels between a functionalized coverslip and a PDMS slab containing inlet and outlet holes.

Functional proteogenomics reveals biomarkers and therapeutic targets in lymphomas.

Identification of biomarkers and therapeutic targets is a critical goal of precision medicine. N-glycoproteins are a particularly attractive class of proteins that constitute potential cancer biomarkers and therapeutic targets for small molecules, antibodies, and cellular therapies. Using mass spectrometry (MS), we generated a compendium of 1,091 N-glycoproteins (from 40 human primary lymphomas and cell lines).

Single cell nanobiosensors for dynamic gene expression profiling in native tissue microenvironments.

A gold nanorod-locked nucleic acid nano-biosensor for dynamic single-cell gene expression analysis in living cells and tissues is developed. The nanoparticle facilitates endocytic delivery and dynamic monitoring of the gene expression in human umbilical cord endothelial cells, mouse skin tissues, mouse retina tissues, and mouse cornea tissues at the single-cell level.

Identification of signaling pathways related to drug efficacy in hepatocellular carcinoma via integration of phosphoproteomic, genomic and clinical data.

Hepatocellular Carcinoma (HCC) is one of the leading causes of death worldwide, with only a handful of treatments effective in unresectable HCC. Most of the clinical trials for HCC using new generation interventions (drug-targeted therapies) have poor efficacy whereas just a few of them show some promising clinical outcomes [1]. This is amongst the first studies where the mode of action of some of the compounds extensively used in clinical trials is interrogated on the phosphoproteomic level, in an attempt to build predictive models for clinical efficacy.

Construction of cell type-specific logic models of signaling networks using CellNOpt.

Mathematical models are useful tools for understanding protein signaling networks because they provide an integrated view of pharmacological and toxicological processes at the molecular level. Here we describe an approach previously introduced based on logic modeling to generate cell-specific, mechanistic and predictive models of signal transduction. Models are derived from a network encoding prior knowledge that is trained to signaling data, and can be either binary (based on Boolean logic) or quantitative (using a recently developed formalism, constrained fuzzy logic).

IL28B polymorphisms as a pretreatment predictor of response to HCV treatment.

Genome-wide association studies have identified polymorphisms located near the gene encoding IL28B, which turned out to be the best predictor of response to pegylated interferon plus ribavirin for chronic hepatitis C virus (HCV) genotype 1 infection. This association was extended to spontaneous clearance of HCV, suggesting shared mechanisms of treatment and natural control of this virus. In addition to the biologic implications for innate immunity and HCV, a variety of clinical studies have suggested possible translation to a useful genetic test for practitioners.

HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome.

Early immunological events during acute HIV infection are thought to fundamentally influence long-term disease outcome. Whereas the contribution of HIV-specific CD8 T cell responses to early viral control is well established, the role of HIV-specific CD4 T cell responses in the control of viral replication after acute infection is unknown. A growing body of evidence suggests that CD4 T cells-besides their helper function-have the capacity to directly recognize and kill virally infected cells.

Training signaling pathway maps to biochemical data with constrained fuzzy logic: quantitative analysis of liver cell responses to inflammatory stimuli.

Predictive understanding of cell signaling network operation based on general prior knowledge but consistent with empirical data in a specific environmental context is a current challenge in computational biology. Recent work has demonstrated that Boolean logic can be used to create context-specific network models by training proteomic pathway maps to dedicated biochemical data; however, the Boolean formalism is restricted to characterizing protein species as either fully active or inactive. To advance beyond this limitation, we propose a novel form of fuzzy logic sufficiently flexible to model quantitative data but also sufficiently simple to efficiently construct models by training pathway maps on dedicated experimental measurements.

Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites.

Conserved noncoding elements (CNEs) constitute the majority of sequences under purifying selection in the human genome, yet their function remains largely unknown. Experimental evidence suggests that many of these elements play regulatory roles, but little is known about regulatory motifs contained within them. Here we describe a systematic approach to discover and characterize regulatory motifs within mammalian CNEs by searching for long motifs (12-22 nt) with significant enrichment in CNEs and studying their biochemical and genomic properties.

Disruption of primary motor cortex before learning impairs memory of movement dynamics.

Although multiple lines of evidence implicate the primary motor cortex (M1) in motor learning, the precise role of M1 in the adaptation to novel movement dynamics and in the subsequent consolidation of a memory of those dynamics remains unclear. Here we used repetitive transcranial magnetic stimulation (rTMS) to dissociate the contribution of M1 to these distinct aspects of motor learning. Subjects performed reaching movements in velocity-dependent force fields over three epochs: a null-field baseline epoch, a clockwise-field learning epoch (15 min after the baseline epoch), and a clockwise-field retest epoch (24 h after the learning epoch).

The DAILY (Daily Automated Intensive Log for Youth) trial: a wireless, portable system to improve adherence and glycemic control in youth with diabetes.

Blood glucose (BG) monitoring (BGM) is an important component of diabetes management. New wireless technologies may facilitate BGM and help to optimize glycemic control. We evaluated an integrated wireless approach with and without a motivational game in youth with diabetes.

On reporting fold differences.

As we enter an age in which genomics and bioinformatics make possible the discovery of new knowledge about the biological characteristics of an organism, it is critical that we attempt to report newly discovered "significant" phenotypes only when they are actually of significance. With the relative youth of genome-scale gene expression technologies, how to make such distinctions has yet to be better defined. We present a "mask technology" by which to filter out those levels of gene expression that fall within the noise of the experimental techniques being employed.