Endothelial cell Piezo1 promotes vascular smooth muscle cell differentiation on large arteries.

Vascular stabilization is a mechanosensitive process, in part driven by blood flow. Here, we demonstrate the involvement of the mechanosensitive ion channel, Piezo1, in promoting arterial accumulation of vascular smooth muscle cells (vSMCs) during zebrafish development. Using a series of small molecule antagonists or agonists to temporally regulate Piezo1 activity, we identified a role for the Piezo1 channel in regulating klf2a, a blood flow responsive transcription factor, expression levels and altered targeting of vSMCs between arteries and veins.

Regulation of pathway choice in DNA repair after double-strand breaks.

DNA damage signaling is a highly coordinated cellular process which is required for the removal of DNA lesions. Amongst the different types of DNA damage, double-strand breaks (DSBs) are the most harmful type of lesion that attenuates cellular proliferation. DSBs are repaired by two major pathways-homologous recombination (HR), and non-homologous end-joining (NHEJ) and in some cases by microhomology-mediated end-joining (MMEJ).

A Novel Crosslinking Approach for Biomanufacturing of a Collagen-Based Skin Dermal Template.

Third-degree burns result in extensive damage to the skin's epidermal and dermal layers, with limited treatment options available. Currently, xenogeneic collagen-based skin grafts are used as scaffolds to integrate into the wound bed and provide a template for neodermis formation. Existing commercial products like Integra dermal templates rely on a time-consuming and variable dehydrothermal (DHT) crosslinking process.

Switchable Adhesion of Hydrogels to Plant and Animal Tissues.

The ability to "switch on" adhesion between a thin hydrogel and a biological tissue can be useful in biomedical applications such as surgery. One way to accomplish this is with an electric field, a phenomenon termed electroadhesion (EA). Here, it is shown that cationic gels can be adhered by EA to tissues across all of biology.

Cardiovascular Health Score and Atherosclerotic Cardiovascular Disease in the Million Veteran Program.

Importance: The American Heart Association proposed Life's Essential 8 (LE8) as an enhanced measurement tool for cardiovascular health.

Objective: To examine the association of LE8 with risk of atherosclerotic cardiovascular disease (ASCVD) incidence and prognosis in veterans.

Design, Setting, And Participants: This was a prospective cohort study of US veterans enrolled in the Department of Veterans Affairs (VA) Million Veteran Program (MVP) between 2011 and 2022.

Goals of chronic obstructive pulmonary disease management: a focused review for clinicians.

Purpose Of Review: The diagnosis of chronic obstructive pulmonary disease (COPD) encompasses heterogeneous pathophysiological mechanisms which can shape an individual patient's experience. This paper reviews available therapeutic options for the clinician intending to individualize care toward patient goals.

Recent Findings: The contemporary targeted interventions for COPD include the novel phosphodiesterase inhibitor ensifentrine, the interleukin-4 receptor (IL4R alpha subunit) antibody dupilumab, augmentation therapy for alpha-1 antitrypsin deficiency.

Broadly inhibitory antibodies to severe malaria virulence proteins.

Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins of the parasite. A subset of PfEMP1 variants that bind to human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis.

Cigarette smoke alters calcium flux to induce PP2A membrane trafficking and endothelial cell permeability.

Alveolar capillary barrier disruption induces local edema and inflammation that impairs pulmonary function and promotes alveolar destruction in COPD. This study aimed to determine how cigarette smoke modulated the serine-threonine phosphatase protein phosphatase 2 A (PP2A) to alter the barrier function of human lung microvascular endothelial cells (HLMVECs). Cigarette smoke exposure lowered overall PP2A activity and enhanced endothelial permeability in HLMVECs.

Oncogenic KRAS Mutations Confer a Unique Mechanotransduction Response to Peristalsis in Colorectal Cancer Cells.

Colorectal cancer (CRC) tumors start as polyps on the inner lining of the colorectum, where they are exposed to the mechanics of peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in CRC cells. However, this malignant mechanotransductive response was confined to select CRC lines that harbored an oncogenic mutation in the KRAS gene.

Targeting the Leloir Pathway with Galactose-Based Antimetabolites in Glioblastoma.

Background: Glioblastoma (GBM) uses Glut3 and/or Glut14 and the Leloir pathway to catabolize D-Galactose (Gal). UDP-4-deoxy-4-fluorogalactose (UDP-4DFG) is a potent inhibitor of the two key enzymes, UDP-galactose-4-epimerase (GALE) and UDP-Glucose 6-dehydrogenase (UGDH), involved in Gal metabolism and in glycan synthesis. The Gal antimetabolite 4-deoxy-4-fluorogalactose (4DFG) is a good substrate for Glut3/Glut14 and acts as a potent glioma chemotherapeutic.

Scalable, compressed phenotypic screening using pooled perturbations.

High-throughput phenotypic screens using biochemical perturbations and high-content readouts are constrained by limitations of scale. To address this, we establish a method of pooling exogenous perturbations followed by computational deconvolution to reduce required sample size, labor and cost. We demonstrate the increased efficiency of compressed experimental designs compared to conventional approaches through benchmarking with a bioactive small-molecule library and a high-content imaging readout.

Community heals: Lessons from qualitative narratives of first-generation college students.

First-generation college students struggle to navigate the college experience. Prior research suggests that social capital plays a critical role in college success such that students benefit from building networks of support within the university. We investigated whether social capital, in the form of engagement with university services, had positive implications for college students' mental health and academic performance, particularly for first-generation college students.

Broadly potent spike-specific human monoclonal antibodies inhibit SARS-CoV-2 Omicron sub-lineages.

The continuous emergence of SARS-CoV-2 variants of concern has rendered many therapeutic monoclonal antibodies (mAbs) ineffective. To date, there are no clinically authorized therapeutic antibodies effective against the recently circulating Omicron sub-lineages BA.2.

Multiplexed immunohistochemical evaluation of small bowel inflammatory and epithelial parameters in environmental enteric dysfunction.

Background: Environmental enteric dysfunction (EED) is characterized by reduced absorptive capacity and barrier function of the small intestine, leading to poor ponderal and linear childhood growth.

Objectives: To further define gene expression patterns that are associated with EED to uncover new pathophysiology of this disorder.

Methods: Duodenal biopsies from cohorts of children with EED from Bangladesh, Pakistan and Zambia were analyzed by immunohistochemistry (IHC) to interrogate gene products that distinguished differentiation and various biochemical pathways in immune and epithelial cells, some identified by prior bulk RNA sequence analyses.

Can integration of Alzheimer's plasma biomarkers with MRI, cardiovascular, genetics, and lifestyle measures improve cognition prediction?

There is increasing interest in Alzheimer's disease related plasma biomarkers due to their accessibility and scalability. We hypothesized that integrating plasma biomarkers with other commonly used and available participant data (MRI, cardiovascular factors, lifestyle, genetics) using machine learning (ML) models can improve individual prediction of cognitive outcomes. Further, our goal was to evaluate the heterogeneity of these predictors across different age strata.

Clinical and Genomic Features of Classical and Basal Transcriptional Subtypes in Pancreatic Cancer.

Purpose: Transcriptional profiling of pancreatic cancers has defined two main transcriptional subtypes: classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX and gemcitabine plus nab-paclitaxel by transcriptional subtype.

Experimental Design: We examined 8,743 patients with RNA sequencing from pancreatic cancers performed at Caris Life Sciences.

Suspension electrospinning of decellularized extracellular matrix: A new method to preserve bioactivity.

Decellularized extracellular matrices (dECM) have strong regenerative potential as tissue engineering scaffolds; however, current clinical options for dECM scaffolds are limited to freeze-drying its native form into sheets. Electrospinning is a versatile scaffold fabrication technique that allows control of macro- and microarchitecture. It remains challenging to electrospin dECM, which has led researchers to either blend it with synthetic materials or use enzymatic digestion to fully solubilize the dECM.

Understanding the Role of miR-29a in the Regulation of RAG1, a Gene Associated with the Development of the Immune System.

The process of Ag receptor diversity is initiated by RAGs consisting of RAG1 and RAG2 in developing lymphocytes. Besides its role as a sequence-specific nuclease during V(D)J recombination, RAGs can also act as a structure-specific nuclease leading to genome instability. Thus, regulation of RAG expression is essential to maintaining genome stability.

Tumor-agnostic cancer therapy using antibodies targeting oncofetal chondroitin sulfate.

Molecular similarities between embryonic and malignant cells can be exploited to target tumors through specific signatures absent in healthy adult tissues. One such embryonic signature tumors express is oncofetal chondroitin sulfate (ofCS), which supports disease progression and dissemination in cancer. Here, we report the identification and characterization of phage display-derived antibody fragments recognizing two distinct ofCS epitopes.