Common Genetic Variant Associated With Atrial Fibrillation Lowers Expression of Nesprin-2α1 With Downstream Effects on Nuclear and Electrophysiological Traits.

Background: Atrial fibrillation GWAS (genome-wide association studies) identified significant associations for rs1152591 and linked variants in the gene encoding Nesprin-2, which connects the nuclear membrane with the cytoskeleton.

Methods: Reporter gene vector transfection and CRISPR-Cas9 editing were used to identify the causal variant regulating the expression of . After knockdown or overexpression in human stem cell-derived cardiomyocytes, nuclear phenotypes were assessed by imaging and atomic force microscopy.

CRISPR-Cas9 knockout screen informs efficient reduction of the Komagataella phaffii secretome.

Background: The yeast Komagataella phaffii is widely used for manufacturing recombinant proteins, but secreted titers of recombinant proteins could be improved by genetic engineering. In this study, we hypothesized that cellular resources could be redirected from production of endogenous proteins to production of recombinant proteins by deleting unneeded endogenous proteins. In non-model microorganisms such as K.

Discovery of Potent, Orally Bioavailable Sphingosine-1-Phosphate Transporter (Spns2) Inhibitors.

Targeting the S1P pathway has resulted in the development of S1P1 receptor modulators for the treatment of multiple sclerosis and ulcerative colitis. We hypothesize that targeting an upstream node of the S1P pathway may provide an improved adverse event profile. In this report, we performed a structure-activity relationship study focusing on the benzoxazole scaffold in , which lead to the discovery of () as a potent inhibitor of S1P release from HeLa cells (IC: 51 ± 3 nM).

Osimertinib after Chemoradiotherapy in Stage III -Mutated NSCLC.

Background: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor () mutation and as adjuvant treatment for resected -mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III -mutated NSCLC.

Methods: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable -mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued.

MicroRNA-1 Deficiency Is a Primary Etiological Factor Disrupting Cardiac Contractility and Electrophysiological Homeostasis.

Background: MicroRNA-1 (miR1), encoded by the genes and , is the most abundant microRNA in the heart and plays a critical role in heart development and physiology. Dysregulation of miR1 has been associated with various heart diseases, where a significant reduction (>75%) in miR1 expression has been observed in patient hearts with atrial fibrillation or acute myocardial infarction. However, it remains uncertain whether miR1-deficiency acts as a primary etiological factor of cardiac remodeling.

Imidazole-based sphingosine-1-phosphate transporter Spns2 inhibitors.

Sphingosine-1-phosphate (S1P) is a chemotactic lipid that influences immune cell positioning. S1P concentration gradients are necessary for proper egress of lymphocytes from the thymus and secondary lymphoid tissues. This trafficking is interdicted by S1P receptor modulators, and it is expected that S1P transporter (Spns2) inhibitors, by reshaping S1P concentration gradients, will do the same.

Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment.

Background: Here, we assessed the role of cellular senescence and the senescence associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction.

Methods: We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6N mice with the senolytic ABT-263.

Sympathetic Neural Overdrive, Aortic Stiffening, Endothelial Dysfunction, and Impaired Exercise Capacity in Severe COVID-19 Survivors: A Mid-Term Study of Cardiovascular Sequelae.

Background: COVID-19 has become a dramatic health problem during this century. In addition to high mortality rate, COVID-19 survivors are at increased risk for cardiovascular diseases 1-year after infection. Explanations for these manifestations are still unclear but can involve a constellation of biological alterations.

Is novel research worth doing? Evidence from peer review at 49 journals.

There are long-standing concerns that peer review, which is foundational to scientific institutions like journals and funding agencies, favors conservative ideas over novel ones. We investigate the association between novelty and the acceptance of manuscripts submitted to a large sample of scientific journals. The data cover 20,538 manuscripts submitted between 2013 and 2018 to the journals and and 6,785 manuscripts submitted in 2018 to 47 journals published by the .

Differentiation of Intracerebral Tumor Entities with Quantitative Contrast Attenuation and Iodine Mapping in Dual-Layer Computed Tomography.

Purpose: To investigate if quantitative contrast enhancement and iodine mapping of common brain tumor (BT) entities may correctly differentiate between tumor etiologies in standardized stereotactic CT protocols. Material and Methods: A retrospective monocentric study of 139 consecutive standardized dual-layer dual-energy CT (dlDECT) scans conducted prior to the stereotactic needle biopsy of untreated primary brain tumor lesions. Attenuation of contrast-enhancing BT was derived from polyenergetic images as well as spectral iodine density maps (IDM) and their contrast-to-noise-ratios (CNR) were determined using ROI measures in contrast-enhancing BT and healthy contralateral white matter.

Sphingosine Kinase 2 Inhibitors: Rigid Aliphatic Tail Derivatives Deliver Potent and Selective Analogues.

Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with five native G-protein coupled receptors (S1P1-5) to regulate cell growth, survival, and proliferation. S1P has been implicated in a variety of pathologies including cancer, kidney fibrosis, and multiple sclerosis. As key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmacologic intervention.

Improvement in the Capacity for Activity Versus Improvement in Performance of Activity in Daily Life During Outpatient Rehabilitation.

Unlabelled: We addressed questions about the potential discrepancy between improvements in activity capacity and improvements in activity performance in daily life. We asked whether this discrepancy is: 1. Common in routine, outpatient care, or an artifact of intervention studies? 2.

Observational Study of Neuroimaging Biomarkers of Severe Upper Limb Impairment After Stroke.

Background And Objectives: It is difficult to predict poststroke outcome for individuals with severe motor impairment because both clinical tests and corticospinal tract (CST) microstructure may not reliably indicate severe motor impairment. Here, we test whether imaging biomarkers beyond the CST relate to severe upper limb (UL) impairment poststroke by evaluating white matter microstructure in the corpus callosum (CC). In an international, multisite hypothesis-generating observational study, we determined if (1) CST asymmetry index (CST-AI) can differentiate between individuals with mild-moderate and severe UL impairment and (2) CC biomarkers relate to UL impairment within individuals with severe impairment poststroke.

-Based Direct-Fed Microbial Reduces the Pathogenic Synergy of a Coinfection with Salmonella enterica Serovar Choleraesuis and Porcine Reproductive and Respiratory Syndrome Virus.

Viral respiratory infections predispose lungs to bacterial coinfections causing a worse outcome than either infection alone. Porcine reproductive and respiratory syndrome virus (PRRSV) causes pneumonia in pigs and is often associated with bacterial coinfections. We examined the impact of providing weanling pigs a -based direct-fed microbial (DFM) on the syndrome resulting from infection with either Salmonella enterica serotype Choleraesuis alone, or in combination with PRRSV.

Simplified Gene Knockout by CRISPR-Cas9-Induced Homologous Recombination.

Genetic engineering of industrial cell lines often requires knockout of multiple endogenous genes. Tools like CRISPR-Cas9 have enabled serial or parallelized gene disruption in a wide range of industrial organisms, but common practices for the screening and validation of genome edits are lacking. For gene disruption, DNA repair by homologous recombination offers several advantages over nonhomologous end joining, including more efficient screening for knockout clones and improved genomic stability.

Engineered SARS-CoV-2 receptor binding domain improves manufacturability in yeast and immunogenicity in mice.

Global containment of COVID-19 still requires accessible and affordable vaccines for low- and middle-income countries (LMICs). Recently approved vaccines provide needed interventions, albeit at prices that may limit their global access. Subunit vaccines based on recombinant proteins are suited for large-volume microbial manufacturing to yield billions of doses annually, minimizing their manufacturing cost.

Domain-Specific Outcomes for Stroke Clinical Trials: What the Modified Rankin Isn't Ranking.

Global outcome measures that are widely used in stroke clinical trials, such as the modified Rankin Scale (mRS), lack sufficient detail to detect changes within specific domains (e.g., sensory, motor, visual, linguistic, or cognitive function).

Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer.

Background: This pooled analysis of MONALEESA trials evaluated the safety of ribociclib plus endocrine therapy (RIB + ET) with a focus on dose reductions in first-line patients.

Methods: In the dose reduction analysis, data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET) and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy was analysed by ribociclib relative dose intensity (DI).

Safety and Outcomes of Thrombectomy in Ischemic Stroke With vs Without IV Thrombolysis.

Objective: To test the hypothesis that IV thrombolysis (IVT) treatment before endovascular thrombectomy (EVT) is associated with better outcomes in patients with anterior circulation large artery occlusion (LAO) stroke, we examined a large real-world database, the Safe Implementation of Treatment in Stroke-International Stroke Thrombectomy Register (SITS-ISTR).

Methods: We identified centers recording ≥10 consecutive patients in the SITS-ISTR, with at least 70% available modified Rankin Scale (mRS) scores at 3 months during 2014 to 2019. We defined LAO as intracranial internal carotid artery, first and second segment of middle cerebral artery, and first segment of anterior cerebral artery.

Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirus.

Background: Vaccines comprising recombinant subunit proteins are well-suited to low-cost and high-volume production for global use. The design of manufacturing processes to produce subunit vaccines depends, however, on the inherent biophysical traits presented by an individual antigen of interest. New candidate antigens typically require developing custom processes for each one and may require unique steps to ensure sufficient yields without product-related variants.

Impact of social isolation on mortality and morbidity in 20 high-income, middle-income and low-income countries in five continents.

Objective: To examine the association between social isolation and mortality and incident diseases in middle-aged adults in urban and rural communities from high-income, middle-income and low-income countries.

Design: Population-based prospective observational study.

Setting: Urban and rural communities in 20 high income, middle income and low income.