摘要: Thrombosis and inflammation are primary contributors to the onset and progression of ischemic stroke. The contactkinin pathway, initiated by plasma kallikrein(PK) and activated factor Ⅻ(FⅫa), functions bidirectionally with the coagulation and inflammation cascades, providing a novel target for therapeutic drug development in ischemic stroke. In this study, we identified a bat-derived oligopeptide from Myotis myotis(Borkhausen, 1797),designated LE6(Leu-Ser-Glu-Glu-Pro-Glu, 702 Da), with considerable potential in stroke therapy due to its effects on the contact kinin pathway. Notably, LE6 demonstrated significant inhibitory effects on PK and FXIIa, with inhibition constants of 43.97 μmol/L and 6.37 μmol/L, respectively.In vitro analyses revealed that LE6 prolonged plasma recalcification time and activated partial thromboplastin time. In murine models, LE6 effectively inhibited carrageenan-induced mouse tail thrombosis, FeCl3-induced carotid artery thrombosis, and photochemically induced intracerebral thrombosis. Furthermore, LE6significantly decreased inflammation and stroke injury in transient middle cerebral artery occlusion models. Notably,the low toxicity, hemolytic activity, and bleeding risk of LE6, along with its synthetic simplicity, underscore its clinical applicability. In conclusion, as an inhibitor of FXIIa and PK, LE6 offers potential therapeutic benefits in stroke treatment by mitigating inflammation and preventing thrombus formation.

摘要: Acute kidney injury(AKI) and chronic kidney disease(CKD) are significant public health issues associated with a long-term increase in mortality risk, resulting from various etiologies including renal ischemia, sepsis, drug toxicity, and diabetes mellitus. Numerous preclinical models have been developed to deepen our understanding of the pathophysiological mechanisms and therapeutic approaches for kidney diseases. Among these, rodent models have proven to be powerful tools in the discovery of novel therapeutics, while the development of kidney organoids has emerged as a promising advancement in the field. This review provides a comprehensive analysis of the construction methodologies, underlying biological mechanisms, and recent therapeutic developments across different AKI and CKD models. Additionally, this review summarizes the advantages, limitations, and challenges inherent in these preclinical models, thereby contributing robust evidence to support the development of effective therapeutic strategies.

摘要: Infertility represents a significant health concern, with sperm quantity and quality being crucial determinants of male fertility. Oligoasthenoteratozoospermia(OAT) is characterized by reduced sperm motility, lower sperm concentration, and morphological abnormalities in sperm heads and flagella. Although variants in several genes have been implicated in OAT, its genetic etiologies and pathogenetic mechanisms remain inadequately understood. In this study, we identified a homozygous nonsense mutation(c.916C>T, p.Arg306*) in the coiledcoil domain containing 146(CCDC146) gene in an infertile male patient with OAT. This mutation resulted in the production of a truncated CCDC146 protein(amino acids1–305), retaining only two out of five coiled-coil domains.To validate the pathogenicity of the CCDC146 mutation,we generated a mouse model(Ccdc146mut/mut) with a similar mutation to that of the patient. Consistently, the Ccdc146mut/mut mice exhibited infertility, characterized by significantly reduced sperm counts, diminished motility,and multiple defects in sperm heads and flagella.Furthermore, the levels of axonemal proteins, including DNAH17, DNAH1, and SPAG6, were significantly reduced in the sperm of Ccdc146mut/mut mice. Additionally, both human and mouse CCDC146 interacted with intraflagellar transport protein 20(IFT20), but this interaction was lost in the mutated versions, leading to the degradation of IFT20.This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility, potentially by disrupting axonemal protein transportation. These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.

摘要: Bats, notable as the only flying mammals, serve as natural reservoir hosts for various highly pathogenic viruses in humans(e.g., SARS-CoV and Ebola virus). Furthermore,bats exhibit an unparalleled longevity among mammals relative to their size, particularly the Myotis bats, which can live up to 40 years. However, the mechanisms underlying these distinctive traits remain incompletely understood. In our prior research, we demonstrated that bats exhibit dampened STING-interferon activation, potentially conferring upon them the capacity to mitigate virus-or aging-induced inflammation. To substantiate this hypothesis, we established the first in vivo bat-mouse model for aging studies by integrating Myotis davidii bat STING(Md STING) into the mouse genome. We monitored the genotypes of these mice and performed a longitudinal comparative transcriptomic analysis on Md STING and wild-type mice over a 3-year aging process. Blood transcriptomic analysis indicated a reduction in agingrelated inflammation in female Md STING mice, as evidenced by significantly lower levels of pro-inflammatory cytokines and chemokines, immunopathology, and neutrophil recruitment in aged female Md STING mice compared to aged wild-type mice in vivo. These results indicated that Md STING knock-in attenuates the agingrelated inflammatory response and may also improve the healthspan in mice in a sex-dependent manner. Although the underlying mechanism awaits further study, this research has critical implications for bat longevity research, potentially contributing to our comprehension of healthy aging in humans.

摘要: Type Ⅳ interferon(IFN-υ) is a recently discovered cytokine crucial for host defense against viral infections. However,the role and mechanisms of IFN-υ in bacterial infections remain unexplored. This study investigated the antibacterial and antiviral functions and mechanisms of grass carp(Ctenopharyngodon idella) IFN-υ(CiIFN-υ) both in vivo and in vitro. The CiIFN-υ gene was first identified and characterized in grass carp. Subsequently, the immune expression of CiIFN-υ significantly increased following bacterial challenge, indicating its response to bacterial infections. The eukaryotic recombinant expression plasmid of CiIFN-υ was then constructed and transfected into fathead minnow(FHM) cells. Supernatants were collected and incubated with four bacterial strains,followed by plate spreading and colony counting. Results indicated that CiIFN-υ exhibited more potent antibacterial activity against gram-negative bacteria compared to grampositive bacteria and aggregated gram-negative bacteria but not gram-positive bacteria. In vivo experiments further confirmed the antibacterial function, showing high survival rates, low tissue edema and damage, reduced tissue bacterial load, and elevated proinflammatory response at the early stages of bacterial infection. In addition, the antiviral function of CiIFN-υ was confirmed through in vitro and in vivo experiments, including crystal violet staining,survival rates, tissue viral burden, and reverse transcription-quantitative real-time polymerase chain reaction(RT-qPCR). This study highlights the antibacterial function and preliminary mechanism of IFN-υ,demonstrating that IFN-υ possesses dual functions against bacterial and viral infections.

摘要: Most described Mesozoic ants belong to stem groups that existed only during the Cretaceous period. Previously, the earliest known crown ants were dated to the Turonian(Late Cretaceous, ca. 94–90 million years ago(Ma))deposits found in the USA, Kazakhstan, and Botswana.However, the recent discovery of an alate male ant in Kachin amber from the earliest Cenomanian(ca. 99 Ma),representing a new genus and species, Antiquiformica alata, revises the narrative on ant diversification.Antiquiformica can be distinctly differentiated from all known male stem ants by its geniculate antennae with elongated scape, extending far beyond the occipital margin of the head and half the length of the funiculus, as well as its partly reduced forewing venation. Furthermore, the combination of a one-segmented waist with a welldeveloped node, elongated scape extending beyond the occipital margin, and reduced forewing venation,particularly the completely reduced m-cu and rs-m crossveins and absence of rm and mcu closed cells, firmly places the fossil within the extant subfamily Formicinae.Fourier transform infrared spectroscopy(FTIR) confirmed that the amber containing Antiquiformica alata originated from the Kachin mines in Myanmar. This discovery significantly revises our understanding of the early evolution of Formicinae. The presence of Antiquiformica in Cenomanian amber indicates that the subfamily Formicinae emerged at least by the start of the Late Cretaceous, with crown ants likely originating earlier during the earliest Cretaceous or possibly the Late Jurassic,although paleontological evidence is lacking to support the latter hypothesis.

摘要: The von Hippel-Lindau tumor suppressor protein(VHL), an E3 ubiquitin ligase, functions as a critical regulator of the oxygen-sensing pathway for targeting hypoxia-inducible factors. Recent evidence suggests that mammalian VHL may also be critical to the NF-κB signaling pathway,although the specific molecular mechanisms remain unclear. Herein, the roles of mandarin fish(Siniperca chuatsi) VHL(sc VHL) in the NF-κB signaling pathway and mandarin fish ranavirus(MRV) replication were explored.The transcription of sc VHL was induced by immune stimulation and MRV infection, indicating a potential role in innate immunity. Dual-luciferase reporter gene assays and reverse transcription quantitative PCR(RT-qPCR) results demonstrated that sc VHL evoked and positively regulated the NF-κB signaling pathway. Treatment with NF-κB signaling pathway inhibitors indicated that the role of sc VHL may be mediated through sc IKKα, sc IKKβ, sc IκBα,or scp65. Co-immunoprecipitation(Co-IP) analysis identified sc IκBα as a novel target protein of sc VHL.Moreover, sc VHL targeted sc IκBα to catalyze the formation of K63-linked polyubiquitin chains to activate the NF-κB signaling pathway. Following MRV infection, NF-κB signaling remained activated, which, in turn, promoted MRV replication. These findings suggest that sc VHL not only positively regulates NF-κB but also significantly enhances MRV replication. This study reveals a novel function of sc VHL in NF-κB signaling and viral infection in fish.

摘要: DNA methylation plays a crucial role in environmental adaptations. Here, using whole-genome bisulfite sequencing, we generated comprehensive genome-wide DNA methylation profiles for the high-altitude Yunnan snub-nosed monkey（Rhinopithecus bieti） and the closely related golden snub-nosed monkey（R. roxellana）. Our findings indicated a slight increase in overall DNA methylation levels in golden snub-nosed monkeys compared to Yunnan snub-nosed monkeys, suggesting a higher prevalence of hypermethylated genomic regions in the former. Comparative genomic methylation analysis demonstrated that genes associated with differentially methylated regions were involved in membrane fusion,vesicular formation and trafficking, hemoglobin function,cell cycle regulation, and neuronal differentiation. These results suggest that the high-altitude-related epigenetic modifications are extensive, involving a complete adaptation process from the inhibition of single Ca²⁺channel proteins to multiple proteins collaboratively enhancing vesicular function or inhibiting cell differentiation and proliferation. Functional assays demonstrated that overexpression or down-regulation of candidate genes,such as SNX10, TIMELESS, and CACYBP, influenced cell viability under stress conditions. Overall, this research suggests that comparing DNA methylation across closely related species can identify novel candidate genomic regions and genes associated with local adaptations,thereby deepening our understanding of the mechanisms underlying environmental adaptations.

摘要: Glass catfish(Kryptopterus vitreolus) are notable in the aquarium trade for their highly transparent body pattern.This transparency is due to the loss of most reflective iridophores and light-absorbing melanophores in the main body, although certain black and silver pigments remain in the face and head. To date, however, the molecular mechanisms underlying this transparent phenotype remain largely unknown. To explore the genetic basis of this transparency, we constructed a chromosome-level haplotypic genome assembly for the glass catfish,encompassing 32 chromosomes and 23 344 protein-coding genes, using PacBio and Hi-C sequencing technologies and standard assembly and annotation pipelines. Analysis revealed a premature stop codon in the putative albinismrelated tyrp1b gene, encoding tyrosinase-related protein 1,rendering it a nonfunctional pseudogene. Notably, a synteny comparison with over 30 other fish species identified the loss of the endothelin-3(edn3b) gene in the glass catfish genome. To investigate the role of edn3b, we generated edn3b-/-mutant zebrafish, which exhibited a remarkable reduction in black pigments in body surface stripes compared to wild-type zebrafish. These findings indicate that edn3b loss contributes to the transparent phenotype of the glass catfish. Our high-quality chromosome-scale genome assembly and identification of key genes provide important molecular insights into the transparent phenotype of glass catfish. These findings not only enhance our understanding of the molecular mechanisms underlying transparency in glass catfish, but also offer a valuable genetic resource for further research on pigmentation in various animal species.

摘要: Serine protease 50（PRSS50/TSP50） is highly expressed in spermatocytes. Our study investigated its role in testicular development and spermatogenesis. Initially,PRSS50 knockdown was observed to impair DNA synthesis in spermatocytes. To further explore this, we generated PRSS50 knockout(Prss50^-/-) mice（Mus musculus）, which exhibited abnormal spermatid nuclear compression and reduced male fertility. Furthermore,dysplastic seminiferous tubules and decreased sex hormones were observed in 4-week-old Prss50^-/-mice,accompanied by meiotic progression defects and increased apoptosis of spermatogenic cells. Mechanistic analysis indicated that PRSS50 deletion resulted in increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2（ERK1/2） and elevated levels of MAP kinase phosphatase 3（MKP3）, a specific ERK antagonist, potentially accounting for testicular dysplasia in adolescent Prss50-/-mice. Taken together, these findings suggest that PRSS50 plays an important role in testicular development and spermatogenesis, with the MKP3/ERK signaling pathway playing a significant role in this process.