Structural Pharmacology of TRPV4 Antagonists.

The nonselective calcium-permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many severe diseases, including edema, pain, gastrointestinal disorders, lung diseases, and inherited neurodegeneration. Emerging TRPV4 antagonists show potential clinical benefits.

Fast cross-linking by DOPA2 promotes the capturing of a stereospecific protein complex over nonspecific encounter complexes.

Transient and weak protein-protein interactions are essential to many biochemical reactions, yet are technically challenging to study. Chemical cross-linking of proteins coupled with mass spectrometry analysis (CXMS) provides a powerful tool in the analysis of such interactions. Central to this technology are chemical cross-linkers.

Bone age recognition based on mask R-CNN using xception regression model.

Bone age detection plays an important role in medical care, sports, judicial expertise and other fields. Traditional bone age identification and detection is according to manual interpretation of X-ray images of hand bone by doctors. This method is subjective and requires experience, and has certain errors.

Subcellular Interactomes Revealed by Merging APEX with Cross-Linking Mass Spectrometry.

Subcellular protein-protein interactions (PPIs) are essential to understanding the mechanism of diverse cellular signaling events and the pathogenesis of diseases. Herein, we report an integrated APEX proximity labeling and chemical cross-linking coupled with mass spectrometry (CXMS) platform named APEX-CXMS for spatially resolved subcellular interactome profiling in a high-throughput manner. APEX proximity labeling rapidly captures subcellular proteomes, and the highly reactive chemical cross-linkers can capture weak and dynamic interactions globally without extra genetic manipulation.

Characterization of protein unfolding by fast cross-linking mass spectrometry using di-ortho-phthalaldehyde cross-linkers.

Chemical cross-linking of proteins coupled with mass spectrometry is widely used in protein structural analysis. In this study we develop a class of non-hydrolyzable amine-selective di-ortho-phthalaldehyde (DOPA) cross-linkers, one of which is called DOPA2. Cross-linking of proteins with DOPA2 is 60-120 times faster than that with the N-hydroxysuccinimide ester cross-linker DSS.

Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis.

Background & Aims: Obesity is a well-established risk factor for type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH), but the underlying mechanisms remain incompletely understood. Herein, we aimed to identify novel pathogenic factors (and possible therapeutic targets) underlying metabolic dysfunction in the liver.

Methods: We applied a tandem quantitative proteomics strategy to enrich and identify transcription factors (TFs) induced in the obese liver.

Evaluation of chemical cross-linkers for in-depth structural analysis of G protein-coupled receptors through cross-linking mass spectrometry.

Chemical cross-linking would conceivably cause structural disruption of a protein, but few cross-linkers have been fully evaluated in this aspect. Furthermore, integral membrane proteins may differ from soluble proteins in the selection of suitable cross-linkers, which has never been investigated. In this study, we systematically evaluated the impact of five conventional cross-linkers targeting Lys, Asp and Glu, and two Arg-reactive cross-linkers on the structural and functional integrity of two G protein-coupled receptors (GPCRs).

Improving mass spectrometry analysis of protein structures with arginine-selective chemical cross-linkers.

Chemical cross-linking of proteins coupled with mass spectrometry analysis (CXMS) is widely used to study protein-protein interactions (PPI), protein structures, and even protein dynamics. However, structural information provided by CXMS is still limited, partly because most CXMS experiments use lysine-lysine (K-K) cross-linkers. Although superb in selectivity and reactivity, they are ineffective for lysine deficient regions.

T-ALL leukemia stem cell 'stemness' is epigenetically controlled by the master regulator SPI1.

Leukemia stem cells (LSCs) are regarded as the origins and key therapeutic targets of leukemia, but limited knowledge is available on the key determinants of LSC 'stemness'. Using single-cell RNA-seq analysis, we identify a master regulator, SPI1, the LSC-specific expression of which determines the molecular signature and activity of LSCs in the murine -null T-ALL model. Although initiated by PTEN-controlled β-catenin activation, expression and LSC 'stemness' are maintained by a β-catenin-SPI1-HAVCR2 regulatory circuit independent of the leukemogenic driver mutation.

Copper-Catalyzed Radical/Radical C(sp 3)-H/P-H Cross-Coupling: α-Phosphorylation of Aryl Ketone O-Acetyloximes.

The selective radical/radical cross-coupling of two different organic radicals is a great challenge due to the inherent activity of radicals. In this paper, a copper-catalyzed radical/radical C(sp 3)-H/P-H cross-coupling has been developed. It provides a radical/radical cross-coupling in a selective manner.