摘要: Porcine reproductive and respiratory syndrome（PRRS） is a globally prevalent contagious disease caused by the positive-strand RNA PRRS virus（PRRSV）, resulting in substantial economic losses in the swine industry.Modifying the CD163 SRCR5 domain, either through deletion or substitution, can eff1ectively confer resistance to PRRSV infection in pigs. However, large fragment modifications in pigs inevitably raise concerns about potential adverse effects on growth performance.Reducing the impact of genetic modifications on normal physiological functions is a promising direction for developing PRRSV-resistant pigs. In the current study, we identified a specific functional amino acid in CD163 that influences PRRSV proliferation. Viral infection experiments conducted on Marc145 and PK-15^CD163 cells illustrated that the mE535G or corresponding pE529G mutations markedly inhibited highly pathogenic PRRSV（HP-PRRSV）proliferation by preventing viral binding and entry.Furthermore, individual viral challenge tests revealed that pigs with the E529G mutation had viral loads two orders of magnitude lower than wild-type（WT） pigs, confirming effective resistance to HP-PRRSV. Examination of the physiological indicators and scavenger function of CD163 verified no significant differences between the WT and E529G pigs. These findings suggest that E529G pigs can be used for breeding PRRSV-resistant pigs, providing novel insights into controlling future PRRSV outbreaks.

摘要: Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells（NSCs）. Interestingly, while complete deletion of Fip200 severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as Atg5, Atg16l1, and Atg7, or blockade of canonical interactions between FIP200 and ATG13（designated as FIP200-4A mutant or FIP200 KI）does not produce comparable detrimental effects. This highlights the likely critical involvement of the noncanonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates noncanonical autophagic degradation of p62/sequestome1,primarily via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200^hGFAP conditional knock-in（cKI） mice led to NSC deficiency, resembling the fip200^hGFAP conditional knockout（cKO） mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200^hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of Tax1bp1in fip200^hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200^hGFAP cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the noncanonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.

摘要: Tumor necrosis factor α(TNFα) exhibits diverse biological functions; however, its regulatory roles in myogenesis are not fully understood. In the present study, we explored the function of TNFα in myoblast proliferation, differentiation,migration, and myotube fusion in primary myoblasts and C2C12 cells. To this end, we constructed TNFα muscle-conditional knockout(TNFα-CKO) mice and compared them with flox mice to assess the effects of TNFα knockout on skeletal muscles. Results indicated that TNFα-CKO mice displayed phenotypes such as accelerated muscle development, enhanced regenerative capacity, and improved exercise endurance compared to flox mice, with no significant differences observed in major visceral organs or skeletal structure. Using label-free proteomic analysis, we found that TNFα-CKO altered the distribution of several muscle development-related proteins, such as Hira, Casz1, Casp7, Arhgap10, Gas1, Diaph1, Map3k20,Cfl2, and Igf2, in the nucleus and cytoplasm. Gene set enrichment analysis(GSEA) further revealed that TNFαdeficiency resulted in positive enrichment in oxidative phosphorylation and MyoD targets and negative enrichment in JAK-STAT signaling. These findings suggest that TNFα-CKO positively regulates muscle growth and development, possibly via these newly identified targets and pathways.

摘要: The organ-specific toxicity resulting from microplastic(MP)exposure has been extensively explored, particularly concerning the gut, liver, testis, and lung. However, under natural conditions, these effects are not restricted to specific organs or tissues. Investigating whether MP exposure presents a systemic threat to an entire organism,impacting factors such as lifespan, sleep, and fecundity, is essential. In this study, we investigated the effects of dietary exposure to two different doses of MPs(1–5 μm)using the terrestrial model organism Drosophila melanogaster. Results indicated that the particles caused gut damage and remained within the digestive system.Continuous MP exposure significantly shortened the lifespan of adult flies. Even short-term exposure disrupted sleep patterns, increasing the length of daytime sleep episodes. Additionally, one week of MP exposure reduced ovary size, with a trend towards decreased egg-laying in mated females. Although MPs did not penetrate the brain or ovaries, transcriptome analysis revealed altered gene expression in these tissues. In the ovary, Gene Ontology(GO) analysis indicated genotoxic effects impacting inflammation, circadian regulation, and metabolic processes, with significant impacts on extracellular structure-related pathways. In the brain, GO analysis identified changes in pathways associated with proteolysis and carbohydrate metabolism. Overall, this study provides compelling evidence of the systemic negative effects of MP exposure, highlighting the urgent need to address and mitigate environmental MP pollution.

摘要: Litopenaeus vannamei is the most extensively cultured shrimp species globally, recognized for its scale,production, and economic value. However, its aquaculture is plagued by frequent disease outbreaks, resulting in rapid and massive mortality. etiological research often lags behind the emergence of new diseases, leaving the causal agents of some shrimp diseases unidentified and leading to nomenclature based on symptomatic presentations,especially in cases involving co-and polymicrobial pathogens. Comprehensive data on shrimp disease statuses remain limited. In this review, we summarize current knowledge on shrimp diseases and their effects on the gut microbiome. Furthermore, we also propose a workflow integrating primary colonizers, “driver” taxa in gut networks from healthy to diseased states, diseasediscriminatory taxa, and virulence genes to identify potential polymicrobial pathogens. We examine both abiotic and biotic factors(e.g., external and internal sources and specific-disease effects) that influence shrimp gut microbiota, with an emphasis on the “holobiome”concept and common features of gut microbiota response to diverse diseases. After excluding the effects of confounding factors, we provide a diagnosis model for quantitatively predicting shrimp disease incidence using disease common-discriminatory taxa, irrespective of the causal agents. Due to the conservation of functional genes used in designing specific primers, we propose a practical strategy applying qPCR-assayed abundances of disease common-discriminatory functional genes. This review updates the roles of the gut microbiota in exploring shrimp etiology, polymicrobial pathogens, and disease incidence, offering a refined perspective for advancing shrimp aquaculture health management.

摘要: Mild traumatic brain injury(mTBI)-induced post-traumatic headache(PTH) is a pressing public health concern and leading cause of disability worldwide. Although PTH is often accompanied by neurological disorders, the exact underlying mechanism remains largely unknown.Identifying potential biomarkers may prompt the diagnosis and development of effective treatments for mTBI-induced PTH. In this study, a mouse model of m TBI-induced PTH was established to investigate its effects on cerebral structure and function during short-term recovery. Results indicated that mice with mTBI-induced PTH exhibited balance deficits during the early post-injury stage.Metabolic kinetics revealed that variations in neurotransmitters were most prominent in the cerebellum,temporal lobe/cortex, and hippocampal regions during the early stages of PTH. Additionally, variations in brain functional activities and connectivity were further detected in the early stage of PTH, particularly in the cerebellum and temporal cortex, suggesting that these regions play central roles in the mechanism underlying PTH. Moreover,our results suggested that GABA and glutamate may serve as potential diagnostic or prognostic biomarkers for PTH.Future studies should explore the specific neural circuits involved in the regulation of PTH by the cerebellum and temporal cortex, with these two regions potentially utilized as targets for non-invasive stimulation in future clinical treatment.

摘要: Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem, including tumor cells and microenvironment. Breast cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics, including their capacity for self-renewal and differentiation. Studies have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast cancer. The tumor microenvironment(TME), composed of stromal cells,immune cells, blood vessel cells, fibroblasts, and microbes in proximity to cancer cells, is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth, and dissemination, thereby influencing metastatic ability. Hence, a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer metastasis. In this review, we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis, as well as the underlying regulatory mechanisms. Furthermore, we provide an overview of relevant mouse models used to study breast cancer metastasis, as well as treatment strategies and clinical trials addressing BCSC-TME interactions during metastasis. Overall, this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

摘要: Hepatocellular carcinoma(HCC), a prevalent solid carcinoma of significant concern, is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes. The etiology and pathological progression of non-alcoholic steatohepatitis(NASH)-related HCC is multifactorial and multistage.However, no single animal model can accurately mimic the full NASH-related HCC pathological progression, posing considerable challenges to transition and mechanistic studies. Herein, a novel conditional inducible wild-type human HRAS overexpressed mouse model(HRAS-HCC)was established, demonstrating 100% morbidity and mortality within approximately one month under normal dietary and lifestyle conditions. Advanced symptoms of HCC such as ascites, thrombus, internal hemorrhage,jaundice, and lung metastasis were successfully replicated in mice. In-depth pathological features of NASH-related HCC were demonstrated by pathological staining,biochemical analyses, and typical marker gene detections.Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival, further confirming the accuracy and reliability of the model. Based on proteinprotein interaction(PPI) network and RNA sequencing analyses, we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis, with subsequent progression to HCC.Collectively, our study successfully duplicated natural sequential progression in a single murine model over a very short period, providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

摘要: Drug addiction refers to a state of dependence that arises from habitual drug intake and can result in specific withdrawal symptoms upon cessation. The most commonly abused substances include psychostimulants, cannabinoids, and opioids. When drugs are consumed, they stimulate the release of dopamine, a neurotransmitter crucial for the pleasure and reward centers of the brain. With repeated drug use, the brain undergoes various changes, leading to tolerance,

摘要: A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment. Davunetide, an active fragment of the activitydependent neuroprotective protein（ADNP）, has been implicated in social and cognitive protection. However, the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood. In this study,ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice. The neuropathological basis was also explored using Golgi staining,morphological analysis, western blotting,electrophysiological analysis, and behavioral analysis.Results indicated that ADNP was significantly downregulated following developmental exposure to sevoflurane. In adulthood, anterior cingulate cortex（ACC）neurons exposed to sevoflurane exhibited a decrease in dendrite number, total dendrite length, and spine density.Furthermore, the expression levels of Homer, PSD95,synaptophysin, and vglut2 were significantly reduced in the sevoflurane group. Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents（mEPSCs）.Notably, davunetide significantly ameliorated the synaptic defects, social behavior deficits, and cognitive impairments induced by sevoflurane. Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca²⁺ activity via the Wnt/β-catenin signaling, resulting in decreased expression of synaptic proteins. Suppression of Wnt signaling was restored in the davunetide-treated group. Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.