Microbial bile acid metabolite ameliorates mycophenolate mofetil-induced gastrointestinal toxicity through vitamin D3 receptor.

Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of lithocholic acid on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, a Food and Drug Administration-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.

Unveiling the hidden role of disulfidptosis in kidney renal clear cell carcinoma: a prognostic signature for personalized treatment.

The role of disulfidptosis in kidney renal clear cell carcinoma (KIRC) remains unknown. This study investigated disulfidptosis-related biomarkers for KIRC prognosis prediction and individualized treatment. KIRC patients were clustered by disulfidptosis profiles. Differential expression analysis, survival models, and machine learning were used to construct the disulfidptosis-related prognostic signature (DRPS). Characterizations of the tumor immune microenvironment, genetic drivers, drug sensitivity, and immunotherapy response were explored according to the DRPS risk stratification. Markers included in the signature were validated using single-cell, spatial transcriptomics, quantitative RT-qPCR, and immunohistochemistry. In the discovery cohort, we unveiled two clusters of KIRC patients that differed significantly in disulfidptosis regulator expressions and overall survival (OS). After multiple feature selection steps, a DRPS prognostic model with four features (CHAC1, COL7A1, FOXM1, SHOX2) was constructed and validated. Combined with clinical factors, the model demonstrated robust performance in the discovery and external validation cohorts (5-year AUC = 0.793 and 0.846, respectively). KIRC patients with high-risk scores are characterized by inferior OS, less tumor purity, and increased infiltrations of fibroblasts, M1 macrophages, and B cells. High-risk patients also have higher frequencies of BAP1 and AHNAK2 mutation. Besides, the correlation between the DRPS score and the chemotherapy-response signature indicated the potential effect of Gefitinib for high-risk patients. Among the signature genes, FOXM1 is highly expressed in cycling tumor cells and exhibits spatial aggregation, while others are expressed sparsely within tumor samples. The DRPS model enables improved clinical management and personalized KIRC therapy. The identified biomarkers and immune characteristics offer new mechanistic insight into disulfidptosis in KIRC.

Multimodal neuroimaging exploration of the mechanisms of sleep quality deterioration after SARS-CoV-2 Omicron infection.

BACKGROUND: To evaluate the neurological alterations induced by Omicron infection, to compare brain changes in chronic insomnia with those in exacerbated chronic insomnia in Omicron patients, and to examine individuals without insomnia alongside those with new-onset insomnia. METHODS: In this study, a total of 135 participants were recruited between January 11 and May 4, 2023, including 26 patients with chronic insomnia without exacerbation, 24 patients with chronic insomnia with exacerbation, 40 patients with no sleep disorder, and 30 patients with new-onset insomnia after infection with Omicron (a total of 120 participants with different sleep statuses after infection), as well as 15 healthy controls who were never infected with Omicron. Neuropsychiatric data, clinical symptoms, and multimodal magnetic resonance imaging data were collected. The gray matter thickness and T1, T2, proton density, and perivascular space values were analyzed. Associations between changes in multimodal magnetic resonance imaging findings and neuropsychiatric data were evaluated with correlation analyses. RESULTS: Compared with healthy controls, gray matter thickness changes were similar in the patients who have and do not have a history of chronic insomnia groups after infection, including an increase in cortical thickness near the parietal lobe and a reduction in cortical thickness in the frontal, occipital, and medial brain regions. Analyses showed a reduced gray matter thickness in patients with chronic insomnia compared with those with an aggravation of chronic insomnia post-Omicron infection, and a reduction was found in the right medial orbitofrontal region (mean [SD], 2.38 [0.17] vs. 2.67 [0.29] mm; P < 0.001). In the subgroups of Omicron patients experiencing sleep deterioration, patients with a history of chronic insomnia whose insomnia symptoms worsened after infection displayed heightened medial orbitofrontal cortical thickness and increased proton density values in various brain regions. Conversely, patients with good sleep quality who experienced a new onset of insomnia after infection exhibited reduced cortical thickness in pericalcarine regions and decreased proton density values. In new-onset insomnia patients post-Omicron infection, the thickness in the right pericalcarine was negatively correlated with the Self-rating Anxiety Scale (r = - 0.538, P = 0.002, PFDR = 0.004) and Self-rating Depression Scale (r = - 0.406, P = 0.026, PFDR = 0.026) scores. CONCLUSIONS: These findings help us understand the pathophysiological mechanisms involved when Omicron invades the nervous system and induces various forms of insomnia after infection. In the future, we will continue to pay attention to the dynamic changes in the brain related to insomnia caused by Omicron infection.

Chromosome-level genome assembly and demographic history of Euryodendron excelsum in monotypic genus endemic to China.

Euryodendron excelsum is in a monotypic genus Euryodendron, endemic to China. It has intermediate morphisms in the Pentaphylacaceae or Theaceae families, which make it distinct. Due to anthropogenic disturbance, E. excelsum is currently found in very restricted and fragmented areas with extremely small populations. Although much research and effort has been applied towards its conservation, its long-term survival mechanisms and evolutionary history remain elusive, especially from a genomic aspect. Therefore, using a combination of long/short whole genome sequencing, RNA sequencing reads, and Hi-C data, we assembled and annotated a high-quality genome for E. excelsum. The genome assembly of E. excelsum comprised 1,059,895,887 bp with 99.66% anchored into 23 pseudo-chromosomes and a 99.0% BUSCO completeness. Comparative genomic analysis revealed the expansion of terpenoid and flavonoid secondary metabolite genes, and displayed a tandem and/or proximal duplication framework of these genes. E. excelsum also displayed genes associated with growth, development, and defence adaptation from whole genome duplication. Demographic analysis indicated that its fluctuations in population size and its recent population decline were related to cold climate changes. The E. excelsum genome assembly provides a highly valuable resource for evolutionary and ecological research in the future, aiding its conservation, management, and restoration.

Gene methylation status in focus of advanced prostate cancer diagnostics and improved individual outcomes.

Background: Prostate cancer (PCa) is the most prevalent type of male genitourinary tumor, remains the second leading cause of deaths due to cancer in the United States in men. The aim of this study was to perform an integrative epigenetic analysis to explore the epigenetic abnormalities involved in the development and progression of PCa, and present advanced diagnostics and improved individual outcomes. Methods: Genome-wide DNA methylation profiles obtained from The Cancer Genome Atlas (TCGA) were analyzed and a diagnostic model was constructed. For validation, we employed profiles from the Gene Expression Omnibus (GEO) and methylation data derived from clinical samples. Gene set enrichment analysis (GSEA) and the Tumor Immune Estimation Resource (TIMER) were employed for GSEA and to assess immune cell infiltration, respectively. Results: An accurate diagnostic method for PCa was established based on the methylation level of Cyclin-D2 (CCND2) and glutathione S-transferase pi-1 (GSTP1), with an impressive area under the curve (AUC) value of 0.937. The model's reliability was further confirmed through validation using four GEO datasets GSE76938 (AUC =0.930), GSE26126 (AUC =0.906), GSE112047 (AUC =1.000), GSE84749 (AUC =0.938) and clinical samples (AUC =0.980). Notably, the TIMER analysis indicated that hypermethylation of CCND2 and GSTP1 was associated with reduced immune cell infiltration, higher tumor purity, and an increased risk of tumor progression. Conclusions: In conclusion, our study provides a robust and reliable methylation-based diagnostic model for PCa. This model holds promise as an improved approach for screening and diagnosing PCa, potentially enhancing early detection and patient outcomes, as well as for an advanced clinical management for PCa in the framework of predictive, preventive and personalised medicine.

Effects of abstinence on locomotor activity and contextual fear conditioning in morphine-dependent mice / 第二军医大学学报

Objective: To study the impact of different abstinence periods on locomotor activity and contextual fear conditioning in morphine-dependent mice. Methods: Morphine hydrochloride was administrated (sc) to mice at a gradually increasing dose for 7 d to establish morphine-dependent model. After the last injection, animals were divided into MW1 d (Morphine Withdrawal for 1 d), MW7 d, MW21 d, SW1 d (Saline Withdrawal for 1 d), SW7 d and SW21 d groups randomly; the spontaneous activities of mice, including the numbers of crossing and rearing, grooming times, the number of center entries and time spent in center area, and the time spent in peripheral area, were observed in the open field box after different periods of abstinence. After the observation, the mice were trained using eight unconditioned stimulus (0.5 s; 0.5 mA foot shock) and contextual fear conditioning was tested 24 h later. Results: The times of crossing and center entries decreased in MW1 d and MW7 d mice (W1 d: P<0.001, P<0.001; W7 d: P<0.001, P<0.05); the time of rearing in MW1 d group was also decreased significantly (P<0.001); mice in MW1 d group had more grooming behaviors (P<0.05). The periods spent in the center and peripheral areas were not significantly different between all the 3 morphine-dependent groups and their corresponding saline withdrawal groups. In addition, a history of morphine injection selectively impaired the contextual fear conditioning in mice of MW1 d group (P <0.05). Conclusion: During the early period of morphine abstinence, mice have a decreased spontaneous activity and an impaired contextual fear conditioning.