Non-alcoholic fatty liver disease (NAFLD), a critical global health concern, continues to challenge medical researchers with limited treatment options. This letter examines on the study by Luo et al, demonstrating that vitamin D 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D-3] improves hepatic steatosis in NAFLD by inhibiting M1 macrophage polarization via the vitamin D receptor-peroxisome proliferator-activated receptor gamma signaling pathway. This letter critically appraises these findings, comparing them to similar studies, and discusses their potential implications for treating NAFLD. Furthermore, we highlight future directions, including dose optimization and mechanistic studies.

A mild photoredox/nickel dual-catalyzed cross-coupling of allyl trifluoroborates with vinyl bromides or -triflates has been developed. This catalytic protocol allows direct and efficient synthesis of 1,4-dienes with generally good to high yields, high regio- and stereo-selectivity, and wide substrate scope and functional group compatibility. The double bond configuration in both allyl trifluoroborates and vinyl bromides could be preserved, providing a practical means for 1E,4E-diene synthesis.

Axially chiral heterobiaryl moieties serve as core skeletons for bioactive molecules, chiral ligands, and organocatalysts. Enantioselective de novo formation of the heteroaromatic ring is one of the most straightforward approaches to access enantioenriched heterobiaryls. Herein, an enantioselective de novo construction of isoquinolines by rhodium-catalyzed C & horbar;H activation/annulation of aromatic imines with alkynes is disclosed. This approach is operationally simple, allowing for rapid access to a variety of axially chiral 1-aryl isoquinolines in excellent yields and enantioselectivity (up to 98% yield and 99:1 er). The synthetic application of the current method was demonstrated by functional group transformations and suitability for millimolar-scale reactions. Detailed experimental and theoretical studies revealed the turnover-limiting step and provided insight into the origin of the enantioselectivity for this reaction.

Pyroptosis, a lytic and programmed cell death pathway, is mediated by gasdermins (GSDMs), with GSDMD playing an important role in innate immunity and pathology. Upon activation, GSDMD is cleaved to release the active N-terminal fragment that oligomerizes into membrane pores, which promote pyroptosis and cytokine secretion, leading to inflammation. Emerging evidence indicates that post-translational modification (PTM) is an important regulatory mechanism of GSDMD activity. This review explores how PTMs, aside from proteolytic cleavage, control GSDMD activity and link biological contexts to pyroptosis in innate immunity and inflammation, which could inform future studies and therapeutic solutions for treating inflammatory conditions.

Phosphorus(V) stereocenters that are fully substituted by heteroatoms play important roles in bioactive molecules and organocatalysts. Existing methods to achieve such motifs rely almost entirely on resolution or diastereocontrol, and prefunctionalized substrates are usually required to generate specific P(V) stereocenters. In contrast, related catalytic methods are rare, and no generally applicable method is described. Here, we report a modular strategy to access a broad variety of stereogenic-at-phosphorus skeletons, including ProTide analogs, alkoxylphosphoramidates, phosphates, phosphorothioates, and phosphonamidates, through designed enantioselective continuous substitutions of simple P(V) precursors. The nucleophilic substitution sequence readily determined the stereoconfiguration of the products. Concise synthesis of ProTide analogs and drug molecules demonstrated the practical value of the protocol. Experimental and computational studies unveiled a unique pi-pi stacking effect and chalcogen bonding interaction between the catalyst and substrate as the origin of stereoselectivity.

The translocation of bacteria from intestinal tracts into blood vessels and distal organs plays pivotal roles in the pathogenesis of numerous severe diseases. Intravital monitoring of bacterial translocation, however, is not yet feasible, which greatly hinders us from comprehending this spatially and temporally dynamic process. Here we report an in vivo fluorogenic labeling method, which enables in situ imaging of mouse gut microbiota and real- time tracking of the translocated bacteria. By mimicking the peptidoglycan stem peptide in bacteria, a tetrapeptide probe composed of alternating Dand L- amino acids and separately equipped with a fluorophore and a quencher on the N- and C- terminal amino acid, is designed. Because of its resistance to host proteases, it can be directly used in gavage and achieves fluorogenic labeling of the microbiota in the gut via the functioning of the L,D- transpeptidases of the labeled bacteria. Using intravital two- photon microscopy, we then successfully visualize the translocation of gut bacteria into the bloodstream and liver in obesity mouse models. This technique can help further exploration into the spatiotemporal activities of gut microbiota in vivo, and be valuable in investigating the less understood pathogenicity of bacterial translocation in many severe diseases.

Upon encountering antigens, B cells may undergo multiple differentiation paths, including becoming plasma cells and memory B cells. Although it is well-known that transcription factors govern gene expression programs underpinning these fate decisions in transcriptional level, the role of post-transcriptional regulators, with a focus on RNA-binding proteins, in the fate determination are lesser known. Here we find by RNA interactome capture-coupled CRISPR/Cas9 functional screening that the Csde1-Strap complex plays an important role in plasma cell differentiation. Mechanistically, the Csde1-Strap complex establishes the expression kinetics of Bach2, a key regulator of plasma cell differentiation. Bach2 expression is rapidly induced to promote B cell expansion and then decreased to initiate plasma cell differentiation. The Csde1-Strap interaction is critical for their binding to Bach2 mRNA to couple its decay with translation to restrain the magnitude and duration of Bach2 protein expression. In the absence of Csde1 or Strap, Bach2 translation is de-coupled from mRNA decay, leading to elevated and prolonged expression of Bach2 protein and impaired plasma cell differentiation. This study thus establishes the functional RBP landscape in B cells and illustrates the fundamental importance of controlling protein expression kinetics in cell fate determination.

The innate immune sensor PKR for double-stranded RNA (dsRNA) is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a critical yet controversial role in this pathway. We show that PACT directly suppresses PKR activation by endogenous dsRNA ligands, such as inverted-repeat Alu RNAs, which robustly activate PKR in the absence of PACT. Instead of competing for dsRNA binding, PACT prevents PKR from scanning along dsRNA-a necessary step for PKR molecules to encounter and phosphorylate each other for activation. While PKR favors longer dsRNA for increased co-occupancy and scanning-mediated activation, longer dsRNA is also more susceptible to PACT-mediated regulation due to increased PACT-PKR co-occupancy. Unlike viral inhibitors that constitutively suppress PKR, this RNA-dependent mechanism allows PACT to fine-tune PKR activation based on dsRNA length and quantity, ensuring self-tolerance without sequestering most cellular dsRNA.