Weiwei Wu

Exercise can improve health via skeletal muscle remodeling. Elucidating the underlying mechanism may lead to new therapeutics for aging-related loss of skeletal muscle mass. Here, we show that endurance exercise suppresses expression of YT521-B homology domain family (Ythdf1) in skeletal muscle, which recognizes the N6-methyladenosine (m6A). Ythdf1 deletion phenocopies endurance exercise-induced muscle hypertrophy in mice increases muscle mitochondria content and type I fiber specification. At the molecular level, Ythdf1 recognizes and promotes the translation of m6A-modified Mstn mRNA, which encodes a muscle growth inhibitor, Myostatin. Loss of Ythdf1 leads to hyperactivation of skeletal muscle stem cells (MuSCs), also called satellite cells (SCs), enhancing muscle growth and injury-induced regeneration. Our data reveal Ythdf1 as a key regulator of skeletal muscle homeostasis, provide insights into the mechanism by which endurance exercise promotes skeletal muscle remodeling and highlight potential strategies to prevent aging-related muscle degeneration.

The highly conserved Notch signaling pathway affects embryonic development, neurogenesis, homeostasis, tissue repair, immunity, and numerous other essential processes. Although previous studies have demonstrated the location and function of the core components of Notch signaling in various animal phyla, a more comprehensive summary of the Notch core components in lower organisms is still required. In this review, we objectively summarize the molecular features of the Notch signaling pathway constituents, their current expression profiles, and their functions in invertebrates, with emphasis on their effects on neurogenesis and regeneration. We also analyze the evolution and other facets of Notch signaling and hope that the contents of this review will be useful to interested researchers.

Apoptosis, also named programmed cell death, is a highly conserved physiological mechanism. Apoptosis plays crucial roles in many life processes, such as tissue development, organ formation, homeostasis maintenance, resistance against external aggression, and immune responses. Apoptosis is regulated by many genes, among which Apoptosis Inhibitor-5 (API5) is an effective inhibitor, though the structure of API5 is completely different from the other known Inhibitors of Apoptosis Proteins (IAPs). Due to its high expression in many types of tumors, API5 has received extensive attention, and may be an effective target for cancer treatment. In order to comprehensively and systematically understand the biological roles of API5, we summarized the evolution and structure of API5 and its roles in anti-apoptosis in this review.

ZRSR2 is a small nuclear riboprotein necessary for assembly of the minor spliceosome and subsequent splicing of U12-type introns. It is involved in the recognition of 3' splice sites during the assembly of the spliceosome. Somatic mutations in ZRSR2 gene are present in hematopoietic malignancies, most notably myelodysplastic syndrome (MDS). These mutations are spread throughout the gene, indicating that its function is critical for hematopoiesis. In spite of these clinical associations, the role of ZRSR2 in hematopoiesis has not been well studied. Zebrafish make an excellent animal model for investigating this gene as all of the functional domains in the human protein are conserved with a high level of protein similarity in zebrafish. Additionally, hematopoietic development is well understood in this species. We used CRISPR/Cas9 to generate a zebrafish zrsr2 knockout model with an 11 base pair deletion (zrsr2Δ11) that results in frameshift with premature truncation and loss of all functional domains (p.W167fs*175). The zrsr2Δ11/Δ11 mutants began to appear morphologically different from their siblings by 4 days post fertilization (dpf), showing aberrant development in the mandible and pharyngeal arches. The zrsr2Δ11/Δ11 mutants developed mild to severe edema by 6 dpf and died by 8 dpf. To understand its role in hematopoiesis, we performed o-dianisidine staining and whole mount in situ hybridization (WISH) with lineage-specific markers during embryonic development. Our data showed that zrsr2Δ11/Δ11 embryos exhibit mild anemia by 2 dpf, suggesting that primitive hematopoiesis is defective. WISH showed that zrsr2Δ11/Δ11 mutants have normal early hematopoietic stem cell (HSC) emergence (c-myb) at 36 hours post fertilization. However, these cells are absent through 3 and 5 dpf. At 5 dpf zrsr2Δ11/Δ11 mutants had severely reduced expression of hematopoietic markers for erythroid (hbae1), lymphoid (rag1), and myeloid (mpo) lineages. This verifies that knockout of zrsr2 in zebrafish disrupted normal hematopoiesis and leads to cytopenias - emulating the symptoms of MDS. We then investigated the transcriptional and splicing changes underlying these phenotypes using RNA sequencing on zrsr2Δ11/Δ11 mutant embryos at 3dpf. We found a total of 285 intron retention events in zrsr2Δ11/Δ11 mutants as compared to the control embryos, with about 76% of those events occurring within U12-type introns. Genes with retained introns were associated with mRNA decay and destabilization. We also found that genes related to cell cycle arrest were upregulated in zrsr2Δ11/Δ11 mutants . These results indicate that aberrant mRNA splicing and cell cycle deregulation contribute to arrested hematopoiesis when zrsr2 is knocked out in zebrafish. Disclosures No relevant conflicts of interest to declare.

The crystal structures of the antimicrobial drug tinidazole [TNZ; systematic name: 1-(2-ethylsulfonylethyl)-2-methyl-5-nitroimidazole, C₈H₁₃N₃O₄S] and the 1:1 cocrystal ofTNZwith the naturally occurring compound vanillic acid (VA; systematic name: 4-hydroxy-3-methoxybenzoic acid, C₈H₈O₄), namely, theTNZ–VAcocrystal, were determined by single-crystal X-ray analysis at 100 K. The supramolecular structure of theTNZ–VAcocrystal is composed of a carboxylic acid dimer and an O—H...N(heterocycle) synthon in the form of layers made up of O—H...N and O—H...O hydrogen bonds. The layers are joinedviaC—H...O hydrogen bonds, π–π stacking and C—H...π interactions. The energy framework analysis, together with interaction energy calculations using the DLPNO-CCSD(T) method, indicates that theTNZ–VAcocrystal inherits strong interactions from theTNZandVAcrystals, which accounts for the enhanced thermal stability and reduced dissolution rate. To the best of our knowledge, this is the first example of a cocrystal containingTNZ.

The placenta, responsible for the nutrient and gas exchange between the mother and fetus, is pivotal for successful pregnancy. It has been shown that Rbpj, the core transcriptional mediator of Notch signaling pathway, is required for normal placentation in mice. However, it remains largely unclear how Rbpj signaling in different placental compartments coordinates with other important regulators to ensure normal placental morphogenesis. In this study, we found that systemic deletion of Rbpj led to abnormal chorioallantoic morphogenesis and defective trophoblast differentiation in the ectoplacental cone (EPC). Employing mouse models with selective deletion of Rbpj in the allantois versus trophoblast, combining tetraploid aggregation assay, we demonstrated that allantois-expressed Rbpj is essential for chorioallantoic attachment and subsequent invagination of allantoic blood vessels into the chorionic ectoderm. Further studies uncovered that allantoic Rbpj regulates chorioallantoic fusion and morphogenesis via targeting Vcam1 in a Notch-dependent manner. Meanwhile, we also revealed that trophoblast-expressed Rbpj in EPC facilitates Mash2’s transcriptional activity, promoting the specification of Tpbpα-positive trophoblasts, which differentiate into trophoblast subtypes responsible for interstitial and endovascular invasion at the later stage of placental development. Collectively, our study further shed light on the molecular network governing placental development and functions, highlighting the necessity of a spatiotemporal coordination of Rbpj signaling for normal placental morphogenesis.