Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection.

Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs). However, a major impediment to gNBS is imprecision due to variants classified as pathogenic (P) or likely pathogenic (LP) that are not SCGD causal. gNBS with 53,855 P/LP variants, 342 genes, 412 SCGDs, and 1,603 therapies was positive in 74% of UK Biobank (UKB470K) adults, suggesting 97% false positives.

Nanoscale Morphologies on the Surface of Substrates/Scaffolds Enhance Chondrogenic Differentiation of Stem Cells: A Systematic Review of the Literature.

Nanoscale morphologies on the surface of substrates/scaffolds have gained considerable attention in cartilage tissue engineering for their potential to improve chondrogenic differentiation and cartilage regeneration outcomes by mimicking the topographical and biophysical properties of the extracellular matrix (ECM). To evaluate the influence of nanoscale surface morphologies on chondrogenic differentiation of stem cells and discuss available strategies, we systematically searched evidence according to the PRISMA guidelines on PubMed, Embase, Web of Science, and Cochrane (until April 2024) and registered on the OSF (osf.io/3kvdb).

Supra- and sub-threshold intracellular-like recording of 2D and 3D neuronal networks using nanopillar electrode arrays.

The brain integrates activity across networks of interconnected neurons to generate behavioral outputs. Several physiological and imaging-based approaches have been previously used to monitor responses of individual neurons. While these techniques can identify cellular responses greater than the neuron's action potential threshold, less is known about the events that are smaller than this threshold or are localized to subcellular compartments.

Discovery of Potent and Selective Pyridone-Based Small Molecule Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains.

Kinetic stabilization of amyloidogenic immunoglobulin light chains (LCs) through small molecule binding may become the first treatment for the proteinopathy component of light chain amyloidosis (AL). Kinetic stabilizers selectively bind to the native state over the misfolding transition state, slowing denaturation. Prior λ full-length LC dimer (FL LC) kinetic stabilizers exhibited considerable plasma protein binding.

Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: A randomised, comparator-controlled, phase 2 trial.

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam assessed the immunogenicity of NDV-HXP-S (COVIVAC) relative to an authorized vaccine.

Perturbations in a pelagic food web during the NE pacific large marine heatwave and persistent harmful diatom blooms.

Unprecedented warm ocean conditions, driven by the Large Marine Heatwave (LMH) and the 2015-16 El Niño in the Northeast Pacific favored pervasive toxigenic Pseudo-nitzschia spp. blooms that caused widespread ecological impacts, but little is known about the magnitude to which marine food webs were altered. Here, we assessed the trophic transfer of domoic acid (DA; a neurotoxin) and changes in trophic position from multiple key species during the peak of the LMH and El Niño in 2015 in comparison with 2018, a reference non-anomalous warm year.

Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis.

During antigen-driven responses, B cells can differentiate at extra-follicular (EF) sites or initiate germinal centers (GCs) in processes that involve interactions with T cells. Here, we examined the roles of interleukin (IL)-2 secreted by T helper (Th) cells during cognate interactions with activated B cells. IL-2 boosted the expansion of EF plasma cells and the secretion of low-mutated immunoglobulin G (IgG).

Updated resources for exploring experimentally-determined PDB structures and Computed Structure Models at the RCSB Protein Data Bank.

The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB, RCSB.org), the US Worldwide Protein Data Bank (wwPDB, wwPDB.org) data center for the global PDB archive, provides access to the PDB data via its RCSB.

CLSY docking to Pol IV requires a conserved domain critical for small RNA biogenesis and transposon silencing.

Eukaryotes must balance the need for gene transcription by RNA polymerase II (Pol II) against the danger of mutations caused by transposable element (TE) proliferation. In plants, these gene expression and TE silencing activities are divided between different RNA polymerases. Specifically, RNA polymerase IV (Pol IV), which evolved from Pol II, transcribes TEs to generate small interfering RNAs (siRNAs) that guide DNA methylation and block TE transcription by Pol II.

A Repair Technique for Internal Nasal Valve Collapse Using Lateral Nasal Suspension Sutures.

One of the most common reasons a patient would see an otolaryngologist is for nasal obstruction. This article provides an overview of the physical principles related to nasal airflow as well as the critical role that the internal nasal valve plays in regulating airflow resistance. Common treatment options for internal nasal valve obstruction are discussed as well as an in-depth tutorial on an alternate lateral nasal suspension suture technique for internal nasal valve collapse.

Exploring Glycan-Lectin Interactions in Natural-Like Environments: A View Using NMR Experiments Inside Cell and on Cell Surface.

Glycan-mediated molecular recognition events are essential for life. NMR is widely used to monitor glycan binding to lectins in solution using isolated glycans and lectins. In this context, we herein explore diverse NMR methodologies, from both the receptor and ligand perspectives, to monitor glycan-lectin interactions under experimental conditions mimicking the native milieu inside cells and on cell surface.

A Genetically Encoded Redox-Active Nicotinamide Amino Acid.

Nicotinamide-containing cofactors play an essential role in many enzymes that catalyze two-electron redox reactions. However, it is difficult to engineer nicotinamide binding sites into proteins due to the extended nature of the cofactor-protein interface and the precise orientation of the nicotinamide moiety required for efficient electron transfer to or from the substrate. To address these challenges, we genetically encoded a noncanonical amino acid (ncAA) bearing a nicotinamide side chain in bacteria.

Acid Cleavable Biotin-Alkyne Improves Sensitivity for Direct Detection of Biotin Labeled Peptides in Biorthogonal Noncanonical Amino Acid Tagging Analysis.

Biorthogonal noncanonical amino acid tagging is a labeling strategy that covalently adds a biotin-alkyne (BA) to methionine analogs via a click reaction. When methionine analogs are incorporated into a proteome, enrichment of the BA-labeled proteins allows the detection of newly synthesized proteins (NSP) by mass spectrometry. We previously reported that our direct detection of biotin-containing tags strategy increased protein identifications by enriching for BA-peptides instead of BA-proteins.

Differential Effects of Confinement on the Dynamics of Normal and Tumor-Derived Pancreatic Ductal Organoids.

Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the epithelia comprising the ductal network of the pancreas. During disease progression, PDAC tumors recruit fibroblasts that promote fibrosis, increasing local tissue stiffness and subjecting epithelial cells to increased compressive forces. Previous in vitro studies have documented cytoskeletal and nuclear adaptation following compressive stresses in two-dimensional (2D) and three-dimensional (3D) environments.

Hemochromatosis neural archetype reveals iron disruption in motor circuits.

Our understanding of brain iron regulation and its disruption in disease is limited. Excess iron affects motor circuitry, contributing to Parkinson's disease (PD) risk. The molecular mechanisms regulating central iron levels, beyond a few well-known genes controlling peripheral iron, remain unclear.

Assessing approaches for ship noise reduction within critical whale habitat.

Ship noise pollution significantly overlaps with critical habitats of endangered whales in the Santa Barbara Channel, prompting the need for effective noise reduction strategies. Various ship noise reduction approaches were assessed by simulating both source-centric (e.g.

An mRNA Display Approach for Covalent Targeting of a Virulence Factor.

Staphylococcus aureus () is an opportunistic human pathogen that causes over one million deaths around the world each year. We recently identified a family of serine hydrolases termed fluorophosphonate binding hydrolases (Fphs) that play important roles in lipid metabolism and colonization of a host. Because many of these enzymes are only expressed in bacteria, they are valuable targets for diagnostics and therapeutics.