Journal of Biomedical Research最新文献

Postoperative acute kidney injury (AKI) and postoperative delirium (POD) are two of the most common complications after surgery. It is essential to understand their common mechanisms not only to prevent and predict the occurrence of these complications, but also to guide perioperative management and improve surgical outcomes. This review summarizes the recent literature focused on these postoperative complications and explores the relationship between AKI and POD. Numerous clinical studies have used AKI and POD as primary outcomes and have found that AKI and POD often occur simultaneously in the perioperative period in susceptible groups undergoing major surgery. Some research findings indicate that the brain and the kidney exhibit bidirectional communication that is affected by systemic inflammation, drug accumulation, uremic toxins, vascular endothelial injury, and fluid volume redistribution during the perioperative period. AKI and POD share common mechanisms involving a variety of complex physiological and pathological pathways, leading to impairment of renal and cerebral function.

Medulloblastoma (MB) is the most common malignant tumor of the cerebellum in children. The SHH subgroup of MB (SHH-MB) is driven by aberrant activation of the Sonic Hedgehog (SHH) pathway; however, mutations in genes related to this pathway are relatively rare, posing challenges for therapeutic development. Glypican-6 (GPC6), a heparan sulfate proteoglycan, is highly expressed in SHH-MB. In this study, we demonstrate the synchronous expression of GPC6 with GLI1 in both the developing cerebellum and medulloblastoma. GPC6 promoted the cell proliferation, migration, and invasion in SHH-MB cell lines (DAOY and ONS-76). Consistently, GPC6 enhanced SHH pathway activity by upregulating GLI1 expression, supported ciliogenesis that is essential for signal transduction, and facilitated the secretion of SHH ligands via extracellular vesicles. These findings establish GPC6 as a critical regulator of SHH-MB progression and highlight its potential as a therapeutic target.

Neutralizing antibodies are essential tools in antiviral therapy and epidemic preparedness, capable of directly inhibiting viral entry and limiting disease progression. However, traditional antibody discovery strategies-such as animal immunization or B cell isolation from infected individuals-are often hindered by biosafety concerns, lengthy development timelines, and limited adaptability during outbreaks. In the present study, we aimed to establish a robust and rapid in vitro platform for the efficient isolation of neutralizing antibodies targeting conserved viral epitopes. We developed an epitope-guided negative screening strategy that integrate phage display technology with rational antigen mutagenesis to exclude antibodies against variable regions while enriching those that recognize functionally constrained epitopes. When applied to the receptor-binding domain (RBD) of SARS-CoV-2, this method enabled the identification of six neutralizing antibodies (one IgG and five nanobodies) exhibiting broad-spectrum neutralizing activity across multiple viral variants. Notably, antibodies recognizing distinct epitopes demonstrated significant synergistic neutralization when used in combination ( P < 0.05). This screening approach facilitates the rapid discovery of potent and mutation-resistant antibodies and holds promise for applications to other emerging pathogens. Our findings underscore the potential of epitope-guided, in vitro platforms in expediting therapeutic antibody development under conditions of high biosafety requirement.

This study aimed to characterize frequency- and latency-dependent network dysregulation in migraine using magnetoencephalography (MEG)-based static and dynamic functional connectivity analyses during auditory stimulation. Thirty interictal migraine patients and 30 matched healthy controls underwent whole-head MEG recordings during a lateralized auditory task. Static and dynamic functional connectivities were calculated using the corrected amplitude envelope correlation in seven canonical frequency bands (delta 2-120 Hz). Group differences were examined using nonparametric permutation tests, with false discovery rate and Bonferroni correction applied to account for multiple comparisons. Static functional connectivity abnormalities were confined to high-frequency bands (low-gamma, 30-59 Hz; high-gamma, 60-90 Hz; and ripple, 90-120 Hz), showing enhanced frontal-limbic and cross-hemispheric connectivity in migraine patients (Cohen's d = 1.05-1.37). Low-frequency bands showed no significant differences. Dynamic functional connectivity revealed rapid, frequency-specific abnormalities: early (25-50 ms) gamma/ripple hyperconnectivity and late delta/beta alterations, with hemispheric asymmetry. Thus, migraine is characterized by high-frequency oscillatory imbalance during auditory processing, with both persistent (static) and transient (dynamic) network disruptions concentrated in gamma/ripple bands, consistent with impaired predictive coding and sensory hypersensitivity.

A major threat to the global human population is zoonosis, which refers to viral infections transmitted from animals. Pigs are crucial to the transmission of the influenza A virus (IAV) because they express both human-type (α-2,6-linked) and avian-type (α-2,3-linked) sialic acid (SA) receptors, making them a direct source of zoonosis and providing essential "mixing vessels" for avian and swine viruses. We aimed to mitigate the IAV threat by disrupting pig influenza infection through gene targeting of the viral receptors in pigs. We utilized CRISPR/Cas9 to knock out the ST6GAL1 and ST3GAL4 genes, which encode enzymes responsible for synthesizing both the human and avian SA receptors in pigs. We observed a significant reduction in these SA receptors in the respiratory tract of the genetically modified pigs. The deletion of these genes conferred partial resistance to IAV infection in vitro, substantially decreasing viral susceptibility. Post-infection transcriptomic analysis revealed distinct expression profiles in ST6GAL1 ^-/- /ST3GAL4 ^-/- pigs compared with those of wild-type pig cells. Creating ST6GAL1 ^-/- /ST3GAL4 ^-/- pigs provides a large-animal model for studying cross-species transmission of IAV, offering a novel strategy to reduce pandemic risks by disrupting influenza transmission between pigs and humans. This approach suggests a new method for controlling pandemics by targeting animals rather than humans, making it potentially safer than many current alternatives.

The study aimed to assess the taxonomic diversity and composition of gut microbiota in Arkhangelsk residents, Northwestern Russia, with varying metabolic statuses. A population-based cross-sectional "Know Your Heart" study (2015-2017, participants aged 35-69 years) included a health examination and gut microbiota analysis ( n = 685). Participants were divided into four metabolic phenotypes: metabolically healthy non-obese (MHN), metabolically unhealthy non-obese (MUN), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). Analyses were performed using RStudio software (v.4.2.0) with the vegan and phyloseq packages (v.1.42.0) for microbiota analysis. The sample was distributed across phenotypes as follows: MHN (47.6%), MUN (22.1%), MHO (10.4%), and MUO (19.9%). Beta-diversity analysis revealed significant differences in overall microbiome composition between MUO and MHN participants, while alpha-diversity did not differ significantly across phenotypes. The MHN group was characterized by a higher abundance of beneficial commensals such as Christensenellaceae R-7 group, Ruminococcaceae UCG-005, and Eubacterium xylanophilum group, which are taxa previously associated with metabolic health and longevity. In contrast, the MUO group showed an increased abundance of Streptococcus salivarius and Negativibacillus, taxa linked to gut dysbiosis and metabolic disorders. Blautia spp. emerged as a major hub in the microbiota of obese participants, consistent with its reported association with visceral fat. In conclusion, microbial composition was similar in obese participants despite metabolic dysfunction, whereas unidirectional taxonomic shifts were observed in those with metabolic dysfunction alone. The differences in the predominance of microbial taxa across metabolic phenotypes suggest that these taxa have a role in the development of metabolic disorders and obesity.

The highly conserved human leukocyte antigen-A2 (HLA-A2)-restricted epitope NS3-1073 represents a promising candidate for a therapeutic vaccine against hepatitis C virus (HCV). In this study, we engineered a set of fusion proteins based on the artificial peptide SAP, which were expressed in Escherichia coli and spontaneously self-assembled into nanosized particles displaying HCV epitopes, including NS3-1073. To enhance immunogenicity, the T helper epitope PADRE was incorporated into the construct. Alpha-helical linkers were introduced between SAP and the epitopes to facilitate proper protein folding. Notably, a helical linker with a high supercoiling propensity enabled soluble expression of the fusion protein containing both the NS3-1073 and PADRE, allowing purification of the in vivo-formed nanoparticles by metal affinity chromatography. Human dendritic cells derived from peripheral blood monocytes showed robust activation in response to the fusion proteins and preferentially stimulated T lymphocytes toward a Th1-biased immune response. In mice, immunization with nanoparticles carrying NS3-1073 induced splenocyte proliferation in response to in vitro stimulation with a mixture of NS3 peptides. These results demonstrate that recombinant nanoparticle-based carriers presenting the NS3-1073 epitope can be produced in bacterial systems and hold strong potential as a foundation for a therapeutic HCV vaccine.

The genetic landscape of male infertility is highly complex. It is estimated that at least 1000-2000 genes are involved in human and mouse infertility. Although functional analyses have been performed on hundreds of genes, many others still have unknown functions. Generating gene-editing mice is a powerful tool for exploring whether a given gene is essential for male reproduction in vivo. In this study, we investigated the function of six genes, Efcab7, Tekt3, Mlf1, Rp1l1, Agbl2, and Tmsb15a, using the CRISPR/Cas9 system. Mating tests with mutant mice revealed that all six genes are dispensable for male fecundity when individually ablated. Meanwhile, phenotypic analyses of testicular appearance and weight, testis and epididymis morphology, and sperm motility parameters in these six mutant mice also showed no significant differences compared with wild-type mice. In summary, our results suggested that these six genes could be deprioritized for other researchers when they are interested in their roles in male infertility, thereby preventing duplicative research efforts.