Challenging Reported Frizzled-Targeting Compounds in Selective Assays Reveals Lack of Functional Inhibition and Claimed Profiles.

Selective inhibitors of Frizzled (FZD) GPCRs are highly sought after as potentially highly efficacious and safe treatments for cancer as well as tools in regenerative medicine and fundamental science. In recent years, there have been several reports claiming the identification of small molecule agents that are selective toward certain FZD proteins using a variety of approaches. However, the majority of these studies lacked a selective functional assay to validate their functionality.

High-Statistics Measurement of Collins and Sivers Asymmetries for Transversely Polarized Deuterons.

New results are presented on a high-statistics measurement of Collins and Sivers asymmetries of charged hadrons produced in deep inelastic scattering of muons on a transversely polarized ^{6}LiD target. The data were taken in 2022 with the COMPASS spectrometer using the 160 GeV muon beam at CERN, statistically balancing the existing data on transversely polarized proton targets. The first results from about two-thirds of the new data have total uncertainties smaller by up to a factor of three compared to the previous deuteron measurements.

Structural investigation of the complexation between vitamin B12 and per- and polyfluoroalkyl substances: Insights into degradation using density functional theory.

Environmental remediation of per- and polyfluoroalkyl substances (PFAS) has become a significant research topic in recent years due to the fact that these materials are omnipresent, resistant to degradation and thus environmentally persistent. Unfortunately, they have also been shown to cause health concerns. PFAS are widely used in industrial applications and consumer products.

Final COMPASS Results on the Transverse-Spin-Dependent Azimuthal Asymmetries in the Pion-Induced Drell-Yan Process.

The COMPASS Collaboration performed measurements of the Drell-Yan process in 2015 and 2018 using a 190  GeV/c π^{-} beam impinging on a transversely polarized ammonia target. Combining the data of both years, we present final results on the amplitudes of five azimuthal modulations, which correspond to transverse-spin-dependent azimuthal asymmetries (TSAs) in the dimuon production cross section. Three of them probe the nucleon leading-twist Sivers, transversity, and pretzelosity transverse-momentum dependent (TMD) parton distribution functions (PDFs).

Zinc for GNAO1 encephalopathy: Preclinical profiling and a clinical case.

Background: De novo pathogenic variants in GNAO1-the gene encoding the major neuronal G protein Gαo-cause pediatric encephalopathies and other neurological deficiencies largely refractory to available therapies. Zn emerged to restore guanosine triphosphate hydrolysis and cellular interactions of pathogenic Gαo; dietary zinc salt supplementation improves lifespan and motoric function in a Drosophila disease model.

Methods: Using biochemical, animal, and first-in-human studies, we provide support for the patient stratification and application of zinc acetate in GNAO1-associated disorders.

Periodic DFT calculations to compute the attributes of a quantum material: honeycomb ruthenium trichloride.

Quantum spin liquids (QSLs) have become prominent materials of interest in the pursuit of fault-tolerant materials for quantum computing applications. This is due to the fact that these materials are theorized to host an interesting variety of quantum phenomena such as quasi-particles that may behave as anyons as a result of the high entangled nature of the spin states within the systems. Computing the electronic and magnetic properties of these materials is necessary in order to understand the underlying interactions of the materials.

Clinical and Molecular Profiling in GNAO1 Permits Phenotype-Genotype Correlation.

Background: Defects in GNAO1, the gene encoding the major neuronal G-protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain the different phenotypes.

Objectives: We aimed to analyze the clinical phenotype and the molecular characterization of GNAO1-related disorders.

Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies.

GNAO1 mutated in pediatric encephalopathies encodes the major neuronal G protein Gαo. Of the more than 80 pathogenic mutations, most are single amino acid substitutions spreading across the Gαo sequence. We performed extensive characterization of Gαo mutants, showing abnormal GTP uptake and hydrolysis and deficiencies in binding Gβγ and RGS19.

Integration of Wnt-inhibitory activity and structural novelty scoring results to uncover novel bioactive natural products: new Bicyclo[3.3.1]non-3-ene-2,9-diones from the leaves of .

In natural products (NPs) research, methods for the efficient prioritization of natural extracts (NEs) are key for discovering novel bioactive NPs. In this study a biodiverse collection of 1,600 NEs, previously analyzed by UHPLC-HRMS metabolite profiling was screened for Wnt pathway regulation. The results of the biological screening drove the selection of a subset of 30 non-toxic NEs with an inhibitory IC ≤ 5 g/mL.

Cis-regulatory polymorphism at fiz ecdysone oxidase contributes to polygenic evolutionary response to malnutrition in Drosophila.

We investigate the contribution of a candidate gene, fiz (fezzik), to complex polygenic adaptation to juvenile malnutrition in Drosophila melanogaster. Experimental populations maintained for >250 generations of experimental evolution to a nutritionally poor larval diet (Selected populations) evolved several-fold lower fiz expression compared to unselected Control populations. Here we show that this divergence in fiz expression is mediated by a cis-regulatory polymorphism.

GNAO1 Mutations Affecting the N-Terminal α-Helix of Gαo Lead to Parkinsonism.

Background: Patients carrying pathogenic variants in GNAO1 present a phenotypic spectrum ranging from severe early-onset epileptic encephalopathy and developmental delay to mild adolescent/adult-onset dystonia. Genotype-phenotype correlation and molecular mechanisms underlying the disease remain understudied.

Methods: We analyzed the clinical course of a child carrying the novel GNAO1 mutation c.

Biochemical Properties of a Promising Milk-Clotting Enzyme, Moose () Recombinant Chymosin.

Moose () recombinant chymosin with a milk-clotting activity of 86 AU/mL was synthesized in the expression system. After precipitation with ammonium sulfate and chromatographic purification, a sample of genetically engineered moose chymosin with a specific milk-clotting activity of 15,768 AU/mg was obtained, which was used for extensive biochemical characterization of the enzyme. The threshold of the thermal stability of moose chymosin was 55 °C; its complete inactivation occurred after heating at 60 °C.

DeMixSC: a deconvolution framework that uses single-cell sequencing plus a small benchmark dataset for improved analysis of cell-type ratios in complex tissue samples.

Bulk deconvolution with single-cell/nucleus RNA-seq data is critical for understanding heterogeneity in complex biological samples, yet the technological discrepancy across sequencing platforms limits deconvolution accuracy. To address this, we introduce an experimental design to match inter-platform biological signals, hence revealing the technological discrepancy, and then develop a deconvolution framework called DeMixSC using the better-matched, i.e.

Major revision version 12.0 of the European AIDS Clinical Society guidelines 2023.

Background: The European AIDS Clinical Society (EACS) guidelines were revised in 2023 for the 19th time, and all aspects of HIV care were updated.

Key Points Of The Guidelines Update: Version 12.0 of the guidelines recommend the same six first-line treatment options for antiretroviral treatment (ART)-naïve adults as versions 11.

Clofazimine: A journey of a drug.

Among different strategies to develop novel therapies, drug repositioning (aka repurposing) aims at identifying new uses of an already approved or investigational drug. This approach has the advantages of availability of the extensive pre-existing knowledge of the drug's safety, pharmacology and toxicology, manufacturing and formulation. It provides advantages to the risk-versus-rewards trade-off as compared to the costly and time-consuming de novo drug discovery process.

Surveillance of Vermont wildlife in 2021-2022 reveals no detected SARS-CoV-2 viral RNA.

Previous studies have documented natural infections of SARS-CoV-2 in various domestic and wild animals. More recently, studies have been published noting the susceptibility of members of the Cervidae family, and infections in both wild and captive cervid populations. In this study, we investigated the presence of SARS-CoV-2 in mammalian wildlife within the state of Vermont.

Improved approaches to channel capacity estimation discover compromised GPCR signaling in diverse cancer cells.

Intracellular signaling orchestrates an organism's development and functioning and underlies various pathologies, such as cancer, when aberrant. A universal cell signaling characteristic is channel capacity - the measure of how much information a given transmitting system can reliably transduce. Here, we describe improved approaches to quantify GPCR signaling channel capacity in single cells, averaged across cell population.

Wnt-Independent SARS-CoV-2 Infection in Pulmonary Epithelial Cells.

The Wnt signaling pathway within host cells regulates infections by several pathogenic bacteria and viruses. Recent studies suggested that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection depends on β-catenin and can be inhibited by the antileprotic drug clofazimine. Since clofazimine has been identified by us as a specific inhibitor of Wnt/β-catenin signaling, these works could indicate a potential role of the Wnt pathway in SARS-CoV-2 infection.

Surveillance of Vermont wildlife in 2021-2022 reveals no detected SARS-CoV-2 viral RNA.

Previous studies have documented natural infections of SARS-CoV-2 in various domestic and wild animals. More recently, studies have been published noting the susceptibility of members of the Cervidae family, and infections in both wild and captive cervid populations. In this study, we investigated the presence of SARS-CoV-2 in mammalian wildlife within the state of Vermont.

Spiroligomer-Based Macrocycles for Atomically Precise Membranes.

Here, we report a new class of peptidomimetic macrocycles with well-defined three-dimensional structures and low conformational flexibility. They are assembled from fused-ring spiro-ladder oligomers (spiroligomers) by modular solid-phase synthesis. Two-dimensional nuclear magnetic resonance confirms their shape persistency.