Prevention and therapy of SARS-CoV-2 and the B.1.351 variant in mice.

Improving the standard of clinical care for individuals infected with SARS-CoV-2 variants is a global health priority. Small molecule antivirals like remdesivir (RDV) and biologics such as human monoclonal antibodies (mAb) have demonstrated therapeutic efficacy against SARS-CoV-2, the causative agent of COVID-19. However, it is not known if combination RDV/mAb will improve outcomes over single agent therapies or whether antibody therapies will remain efficacious against variants.

Massively Parallel Sequencing of Esophageal Brushings Enables an Aneuploidy-Based Classification of Patients With Barrett's Esophagus.

Background & Aims: Aneuploidy has been proposed as a tool to assess progression in patients with Barrett's esophagus (BE), but has heretofore required multiple biopsies. We assessed whether a single esophageal brushing that widely sampled the esophagus could be combined with massively parallel sequencing to characterize aneuploidy and identify patients with disease progression to dysplasia or cancer.

Methods: Esophageal brushings were obtained from patients without BE, with non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (EAC).

Roadmap on emerging concepts in the physical biology of bacterial biofilms: from surface sensing to community formation.

Bacterial biofilms are communities of bacteria that exist as aggregates that can adhere to surfaces or be free-standing. This complex, social mode of cellular organization is fundamental to the physiology of microbes and often exhibits surprising behavior. Bacterial biofilms are more than the sum of their parts: single-cell behavior has a complex relation to collective community behavior, in a manner perhaps cognate to the complex relation between atomic physics and condensed matter physics.

Estrogen and sex-dependent loss of the vocal learning system in female zebra finches.

Sex hormones alter the organization of the brain during early development and coordinate various behaviors throughout life. In zebra finches, song learning is limited to males, with the associated song learning brain pathways only maturing in males and atrophying in females. While this atrophy can be prevented by treating females with exogenous estrogen during early post-hatch development, the requirement of estrogen during normal male song system development is uncertain.

The Association Between Alpha-1 Adrenergic Receptor Antagonists and In-Hospital Mortality from COVID-19.

Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and preclinical data suggest alpha-1 adrenergic receptor antagonists (α-AR antagonists) may be effective in reducing mortality related to hyperinflammation independent of etiology. Using a retrospective cohort design with patients in the Department of Veterans Affairs healthcare system, we use doubly robust regression and matching to estimate the association between baseline use of α-AR antagonists and likelihood of death due to COVID-19 during hospitalization. Having an active prescription for any α-AR antagonist (tamsulosin, silodosin, prazosin, terazosin, doxazosin, or alfuzosin) at the time of admission had a significant negative association with in-hospital mortality (relative risk reduction 18%; odds ratio 0.

Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium.

Towards Decoding the Sequence-Based Grammar Governing the Functions of Intrinsically Disordered Protein Regions.

A substantial portion of the proteome consists of intrinsically disordered regions (IDRs) that do not fold into well-defined 3D structures yet perform numerous biological functions and are associated with a broad range of diseases. It has been a long-standing enigma how different IDRs successfully execute their specific functions. Further putting a spotlight on IDRs are recent discoveries of functionally relevant biomolecular assemblies, which in some cases form through liquid-liquid phase separation.

Alterations of 5-hydroxymethylcytosines in circulating cell-free DNA reflect retinopathy in type 2 diabetes.

Diabetic retinopathy (DR) is a common microvascular complication that may cause severe visual impairment and blindness in patients with type 2 diabetes mellitus (T2DM). Early detection of DR will expand the range of potential treatment options and enable better control of disease progression. Epigenetic dysregulation has been implicated in the pathogenesis of microvascular complications in patients with T2DM.

Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19.

We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity.

Injectable Hydrogels for Sustained Codelivery of Subunit Vaccines Enhance Humoral Immunity.

Vaccines aim to elicit a robust, yet targeted, immune response. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system's natural response to extended pathogen exposure during infection by designing an easily administered slow-delivery vaccine platform.

Interactions among microbes, the immune system, and the circadian clock.

The circadian clock couples physiological processes and behaviors to environmental light cycles. This coupling ensures the synchronization of energetically expensive processes to the time of day at which an organism is most active, thus improving overall fitness. Host immunity is an energetically intensive process that requires the coordination of multiple immune cell types to sense, communicate, and respond to a variety of microorganisms.

The Lineage Before Time: Circadian and Nonclassical Clock Influences on Development.

Diverse factors including metabolism, chromatin remodeling, and mitotic kinetics influence development at the cellular level. These factors are well known to interact with the circadian transcriptional-translational feedback loop (TTFL) after its emergence. What is only recently becoming clear, however, is how metabolism, mitosis, and epigenetics may become organized in a coordinated cyclical precursor signaling module in pluripotent cells prior to the onset of TTFL cycling.

An improved whole life cycle culture protocol for the hydrozoan genetic model .

The jellyfish species (Cnidaria, Hydrozoa) has emerged as a new experimental model animal in the last decade. Favorable characteristics include a fully transparent body suitable for microscopy, daily gamete production and a relatively short life cycle. Furthermore, whole genome sequence assembly and efficient gene editing techniques using CRISPR/Cas9 have opened new possibilities for genetic studies.

The Vibrio cholerae Quorum-Sensing Protein VqmA Integrates Cell Density, Environmental, and Host-Derived Cues into the Control of Virulence.

Quorum sensing is a chemical communication process in which bacteria use the production, release, and detection of signal molecules called autoinducers to orchestrate collective behaviors. The human pathogen requires quorum sensing to infect the small intestine. There, encounters the absence of oxygen and the presence of bile salts.

Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR).

The chimeric antigen receptor (CAR) directs T cells to target and kill specific cancer cells. Despite the success of CAR T therapy in clinics, the intracellular signaling pathways that lead to CAR T cell activation remain unclear. Using CD19 CAR as a model, we report that, similar to the endogenous T cell receptor (TCR), antigen engagement triggers the formation of CAR microclusters that transduce downstream signaling.

Deciphering the regulatory landscape of fetal and adult γδ T-cell development at single-cell resolution.

γδ T cells with distinct properties develop in the embryonic and adult thymus and have been identified as critical players in a broad range of infections, antitumor surveillance, autoimmune diseases, and tissue homeostasis. Despite their potential value for immunotherapy, differentiation of γδ T cells in the thymus is incompletely understood. Here, we establish a high-resolution map of γδ T-cell differentiation from the fetal and adult thymus using single-cell RNA sequencing.

Cell position fates and collective fountain flow in bacterial biofilms revealed by light-sheet microscopy.

Bacterial biofilms represent a basic form of multicellular organization that confers survival advantages to constituent cells. The sequential stages of cell ordering during biofilm development have been studied in the pathogen and model biofilm-former It is unknown how spatial trajectories of individual cells and the collective motions of many cells drive biofilm expansion. We developed dual-view light-sheet microscopy to investigate the dynamics of biofilm development from a founder cell to a mature three-dimensional community.

BCR selection and affinity maturation in Peyer's patch germinal centres.

The antigen-binding variable regions of the B cell receptor (BCR) and of antibodies are encoded by exons that are assembled in developing B cells by V(D)J recombination. The BCR repertoires of primary B cells are vast owing to mechanisms that create diversity at the junctions of V(D)J gene segments that contribute to complementarity-determining region 3 (CDR3), the region that binds antigen. Primary B cells undergo antigen-driven BCR affinity maturation through somatic hypermutation and cellular selection in germinal centres (GCs).

Ocular hypertension suppresses homeostatic gene expression in optic nerve head microglia of DBA/2 J mice.

Glaucoma is the leading cause of irreversible vision loss. Ocular hypertension is a major risk factor for glaucoma and recent work has demonstrated critical early neuroinflammatory insults occur in the optic nerve head following ocular hypertension. Microglia and infiltrating monocytes are likely candidates to drive these neuroinflammatory insults.