Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841).

Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling.

When is experiential avoidance harmful in the moment? Examining global experiential avoidance as a moderator.

Background And Objectives: Although experiential avoidance has been shown to predict a wide range of mental health problems, there has been minimal research to-date on the more immediate effects of engaging in experiential avoidance in the moment or the moderators that predict when it is more or less harmful.

Methods: An ecological momentary assessment (EMA) study was conducted with 70 undergraduate students who completed assessments three times a day, over 7 day as well as a baseline assessment of global questionnaires.

Results: Both greater global experiential avoidance and momentary experiential avoidance independently predicted greater momentary negative affect, lower positive affect, and lower valued action.

Mendelian randomization studies of cancer risk: a literature review.

Purpose Of Review: In this paper, we summarize prior studies that have used Mendelian Randomization (MR) methods to study the effects of exposures, lifestyle factors, physical traits, and/or biomarkers on cancer risk in humans. Many such risk factors have been associated with cancer risk in observational studies, and the MR approach can be used to provide evidence as to whether these associations represent causal relationships. MR methods require a risk factor of interest to have known genetic determinants that can be used as proxies for the risk factor (i.

Mapping Determinants of Virus Neutralization and Viral Escape for Rational Design of a Hepatitis C Virus Vaccine.

Hepatitis C virus (HCV) continues to spread worldwide with an annual increase of 1.75 million new infections. The number of HCV cases in the U.

Computational Modeling of Hepatitis C Virus Envelope Glycoprotein Structure and Recognition.

Hepatitis C virus (HCV) is a major global health concern, and though therapeutic options have improved, no vaccine is available despite decades of research. As HCV can rapidly mutate to evade the immune response, an effective HCV vaccine must rely on identification and characterization of sites critical for broad immune protection and viral neutralization. This knowledge depends on structural and mechanistic insights of the E1 and E2 envelope glycoproteins, which assemble as a heterodimer on the surface of the virion, engage coreceptors during host cell entry, and are the primary targets of antibodies.

Environmental cues and dietary antioxidants affect breeding behavior and testosterone of male European starlings (Sturnus vulgaris).

Environmental cues, such as photoperiod, regulate the timing of major life-history events like breeding through direct neuroendocrine control. Less known is how supplementary environmental cues (e.g.

TCRmodel: high resolution modeling of T cell receptors from sequence.

T cell receptors (TCRs), along with antibodies, are responsible for specific antigen recognition in the adaptive immune response, and millions of unique TCRs are estimated to be present in each individual. Understanding the structural basis of TCR targeting has implications in vaccine design, autoimmunity, as well as T cell therapies for cancer. Given advances in deep sequencing leading to immune repertoire-level TCR sequence data, fast and accurate modeling methods are needed to elucidate shared and unique 3D structural features of these molecules which lead to their antigen targeting and cross-reactivity.

Nitroxyl Modified Tobacco Mosaic Virus as a Metal-Free High-Relaxivity MRI and EPR Active Superoxide Sensor.

Superoxide overproduction is known to occur in multiple disease states requiring critical care; yet, noninvasive detection of superoxide in deep tissue remains a challenge. Herein, we report a metal-free magnetic resonance imaging (MRI) and electron paramagnetic resonance (EPR) active contrast agent prepared by "click conjugating" paramagnetic organic radical contrast agents (ORCAs) to the surface of tobacco mosaic virus (TMV). While ORCAs are known to be reduced in vivo to an MRI/EPR silent state, their oxidation is facilitated specifically by reactive oxygen species-in particular, superoxide-and are largely unaffected by peroxides and molecular oxygen.

Targeted inhibition of the BRAF pathway in a patient with stage IV melanoma.

This article describes the use of vemurafenib, a BRAF inhibitor, to achieve disease regression in a woman with extensive metastatic melanoma and the BRAF V600 gene mutation. Given the improved survival rates seen in these patients, clinicians need to be aware of long-term patient management and adverse reactions to the drug.

A study of telomere length, arsenic exposure, and arsenic toxicity in a Bangladeshi cohort.

Background: Chronic arsenic exposure is associated with increased risk for arsenical skin lesions, cancer, and other adverse health outcomes. One potential mechanism of arsenic toxicity is telomere dysfunction. However, prior epidemiological studies of arsenic exposure, telomere length (TL), and skin lesion are small and cross-sectional.

A novel pooled-sample multiplex luminex assay for high-throughput measurement of relative telomere length.

Objectives: Relative telomere length (RTL) is a potential biomarker of aging and risk for chronic disease. Previously, we developed a probe-based RTL assay on Luminex platform, where probes for Telomere (T) and reference gene (R) for a given DNA sample were tested in a single well. Here, we describe a method of pooling multiple samples in one well to increase the throughput and cost-effectiveness.

Co-occurring expression and methylation QTLs allow detection of common causal variants and shared biological mechanisms.

Inherited genetic variation affects local gene expression and DNA methylation in humans. Most expression quantitative trait loci (cis-eQTLs) occur at the same genomic location as a methylation QTL (cis-meQTL), suggesting a common causal variant and shared mechanism. Using DNA and RNA from peripheral blood of Bangladeshi individuals, here we use co-localization methods to identify eQTL-meQTL pairs likely to share a causal variant.

Screening for gene-environment (G×E) interaction using omics data from exposed individuals: an application to gene-arsenic interaction.

Identifying gene-environment interactions is a central challenge in the quest to understand susceptibility to complex, multi-factorial diseases. Developing an understanding of how inter-individual variability in inherited genetic variation alters the effects of environmental exposures will enhance our knowledge of disease mechanisms and improve our ability to predict disease and target interventions to high-risk sub-populations. Limited progress has been made identifying gene-environment interactions in the epidemiological setting using existing statistical approaches for genome-wide searches for interaction.

A meta-analysis approach with filtering for identifying gene-level gene-environment interactions.

There is a growing recognition that gene-environment interaction (G × E) plays a pivotal role in the development and progression of complex diseases. Despite a wealth of genetic data on various complex diseases/traits generated from association and sequencing studies, detecting G × E via genome-wide analysis remains challenging due to power issues. In genome-wide G × E studies, a common strategy to improve power is to first conduct a filtering test and retain only the genetic variants that pass the filtering step for subsequent G × E analyses.

Safety and efficacy of foscarnet for the management of ganciclovir-resistant or refractory cytomegalovirus infections: A single-center study.

Background: Infection with cytomegalovirus (CMV) is an important cause of morbidity and mortality following solid organ transplantation. Resistance to ganciclovir can rarely develop via mutations in UL97 or UL54. There are limited published studies assessing the safety and efficacy of foscarnet for the management of ganciclovir-resistant or refractory cytomegalovirus infection and many centers are reluctant to utilize this important therapy because of concerns about toxicity.

Designing a B Cell-Based Vaccine against a Highly Variable Hepatitis C Virus.

The ability to use structure-based design and engineering to control the molecular shape and reactivity of an immunogen to induce protective responses shows great promise, along with corresponding advancements in vaccine testing and evaluation systems. We describe in this review new paradigms for the development of a B cell-based HCV vaccine. Advances in test systems to measure and antibody-mediated virus neutralization include retroviral pseudotype particles expressing HCV E1E2 glycoproteins (HCVpp), infectious cell culture-derived HCV virions (HCVcc), and surrogate animal models mimicking acute HCV infection.

Improved rate of substrate oxidation catalyzed by genetically-engineered myoglobin.

This study showcases the potential of unnatural amino acids to enable non-natural functions when incorporated in the protein scaffold of heme metalloproteins. For this purpose, a genetically-engineered myoglobin (Mb) mutant was created by incorporating redox-active 3-amino-l-tyrosine (NHTyr) into its active site, replacing the distal histidine (H64) with NHTyr. In peroxide-shunt assays, this variant exhibits an increased rate of turnover for thioanisole and benzaldehyde oxidation as compared to the wild-type (WT) Mb.

Umbilical cord milking at birth for term newborns with acidosis: neonatal outcomes.

Objective: To determine if umbilical cord milking is detrimental in compromised term/near-term infants.

Study Design: A retrospective analysis of infants with abnormal cord gases (cord arterial or venous pH of ≤ 7.1 or base deficit > -12).

Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study.

 To determine if circulating concentrations of vitamin D are causally associated with risk of cancer. Mendelian randomisation study. Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).

Microfluidic-Enabled Intracellular Delivery of Membrane Impermeable Inhibitors to Study Target Engagement in Human Primary Cells.

Biochemical screening is a major source of lead generation for novel targets. However, during the process of small molecule lead optimization, compounds with excellent biochemical activity may show poor cellular potency, making structure-activity relationships difficult to decipher. This may be due to low membrane permeability of the molecule, resulting in insufficient intracellular drug concentration.

Evolving career choice narratives of new graduate nurses.

This article describes findings from one stage of a longitudinal study of the professional socialization experiences of Millennial nurses as they prepared for graduation and transition to practice. This study employed an interpretive narrative methodology guided by Polkinghorne's theory of narrative identity. Analysis of face-to-face interviews and journal entries by Millennial nursing students uncovered the formal professional socialization experiences over four years of nursing education.

Identifying -mediators for -eQTLs across many human tissues using genomic mediation analysis.

The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (-eQTLs). More research is needed to identify effects of genetic variation on distant genes (-eQTLs) and understand their biological mechanisms.

A Platelet Factor 4-Dependent Platelet Activation Assay Facilitates Early Detection of Pathogenic Heparin-Induced Thrombocytopenia Antibodies.

Heparin-induced thrombocytopenia (HIT) is a dangerous complication of heparin therapy. HIT diagnosis is established by recognizing thrombocytopenia and/or thrombosis in an affected patient and from the results of serological tests such as the platelet factor 4 (PF4)/heparin immunoassay (PF4 ELISA) and serotonin release assay (SRA). Recent studies suggest that HIT antibodies activate platelets by recognizing PF4 in a complex with platelet glycosaminoglycans (and/or polyphosphates) and that an assay based on this principle, the PF4-dependent P-selectin expression assay (PEA), may be even more accurate than the SRA for HIT diagnosis.

Incorporation of Biological Knowledge Into the Study of Gene-Environment Interactions.

A growing knowledge base of genetic and environmental information has greatly enabled the study of disease risk factors. However, the computational complexity and statistical burden of testing all variants by all environments has required novel study designs and hypothesis-driven approaches. We discuss how incorporating biological knowledge from model organisms, functional genomics, and integrative approaches can empower the discovery of novel gene-environment interactions and discuss specific methodological considerations with each approach.