The alteration of gene expression is not restricted to transcriptional regulation but includes a variety of post-transcriptional mechanisms; however, the role of the latter in many diseases remains relatively unknown. By using an RNA-Seq dataset of 1510 brain samples from individuals with autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia (SCZ), and controls, we assessed the contribution of post-transcriptional dysregulation and identified top perturbators accountable for transcriptomic alterations in neuropsychiatric disorders. Approximately 30% of the expression variability was attributed to post-transcriptional dysregulation. Interestingly, mature mRNA levels tended to be post-transcriptionally downregulated in SCZ and BD, leading to the inhibition of neurogenesis and neural differentiation, while they were upregulated in ASD, resulting in enhanced activity of apoptosis. These findings imply contrasting pathologies involving RNA metabolism across neuropsychiatric disorders. An RNA-binding protein, ELAVL3, was predicted to be significantly involved in the disruption of post-transcriptional regulation in all three disorders. To validate this, we knocked down its expression in cerebral organoids. Not only did the differentially expressed genes in ELAVL3 knockdown cover a considerable proportion of predicted targets in the three disorders, but we also found that neurogenesis was significantly affected, given the diminished proliferation and consequently reduced size of the organoids. The present study extends the current understanding of the link between post-transcriptional regulation and neuropsychiatric disorders and provides new potential therapeutic targets for early intervention.

Cholestatic liver disease, caused by the accumulation of hazardous bile acids in the liver, may result in cirrhosis, fibrosis, or liver failure. Activation of sirtuin 6 (SIRT6) prevents cholestasis-associated pathological events, such as oxidative stress and mitochondrial biogenesis dysfunction, and inhibits bile acid synthesis to alleviate cholestatic liver injury. However, it remains uncertain which pathway mediates the therapeutic effect of SIRT6 in reducing cholestasis. Therefore, we treated liver-specific Sirt6 knockout mice with N-acetylcysteine, KEAP1-NRF2-IN-1, or acadesine to alleviate oxidative stress and/or promote mitochondrial biogenesis after modeling cholestatic liver disease, but these measures did not significantly improve cholestatic symptoms. However, MDL801, a SIRT6 agonist that downregulates cholesterol 7α-hydroxylase (CYP7A1, the key enzyme in bile acid synthesis) levels, exhibited favorable therapeutic effects. Additionally, the hepatic knockdown of Cyp7a1 further demonstrated that inhibiting hepatic bile acid synthesis might be the main pathway through which SIRT6 alleviates cholestatic liver disease. These findings provide a solid basis for the potential application of SIRT6 agonists in treating cholestatic liver disease.

Dent disease is a rare X-linked recessively inherited renal tubulopathy, caused by variants in the CLCN5 (Dent disease type 1, DD1) and OCRL (Dent disease type 2, DD2) genes, and characterized by low molecular weight proteinuria, hypercalciuria, microscopic hematuria, or nephrocalcinosis. In the current study, we collected and analyzed clinical data and genetic testing results of 21 children diagnosed with Dent disease, who were hospitalized at the Department of Nephrology, Children's Hospital of Nanjing Medical University between January 2014 and August 2023, aiming to assist in the early diagnosis and treatment of these patients. Among the 21 patients, 16 (76.19%) had CLCN5 variants, and five (23.81%) had OCRL variants, and four of the variants were novel. All patients presented with low molecular weight proteinuria, 14 (66.67%) of whom had nephrotic-range proteinuria. Eight patients underwent renal biopsies because of diagnostic uncertainty. We transfected the novel CLCN5 missense variant (p.G222R) and OCRL missense variant (p.I371T) plasmids into both HEK293 and HK-2 cells and found a significantly lower expression of the OCRL1 protein in the transfected cells than in the wild-type cells (P < 0.05). Moreover, we observed an extremely skewed X-chromosome inactivation pattern in a female patient carrying the same novel CLCN5 variant, as assessed by the human androgen receptor gene assay. These findings provide insight into the clinical characteristics of Dent disease in Chinese patients and may shed light on its pathogenesis.

Circular RNAs (circRNAs) are key regulators of reproductive biology. However, limited information is available regarding circRNA expression profiles in seminal plasma samples from individuals with male infertility. The present study aimed to identify circRNAs associated with infertility in seminal plasma samples and to clarify their potential as biomarkers, as well as the possible molecular mechanisms underlying their functions. Next-generation RNA sequencing was conducted to analyze circRNA profiles in seminal plasma from healthy controls, oligoasthenospermia (OAZ) patients, and non-obstructive azoospermia (NOA) patients. Bioinformatics analysis revealed that 637 circRNAs were differentially expressed between OAZ and control subjects, and 272 circRNAs were differentially expressed between NOA and control subjects. The expression of key circRNAs (hsa-SAP130_0002, hsa-TRPC1_0001, hsa-FBRS_0001, hsa-ACACA_0025, hsa-UTRN_0042, and hsa-ZNF532_0023) was then validated by qPCR, and their diagnostic accuracy for infertility was confirmed through receiver operating characteristic curve analysis. Additionally, a possible circRNA-miRNA-mRNA regulatory network was constructed for these candidate biomarkers. Collectively, this study identifies a novel set of circRNAs with potential as diagnostic biomarkers for male infertility and provides molecular insights that may facilitate both diagnostic and therapeutic efforts.

IBI351, a synthetic compound, exerts its anti-tumor effects by specifically, covalently, and irreversibly modifying the 12th cysteine residue of KRAS G12C. However, the pharmacokinetic profile of IBI351 in humans has not yet been reported. The current study aimed to investigate the pharmacokinetics and safety of IBI351 in healthy Chinese male subjects. A single oral dose of 600 mg combined with 150 μCi [¹⁴C]IBI351 was administered to six healthy male volunteers. Blood, urine, and fecal samples were collected at multiple time points to quantify the parent drug and its metabolites. IBI351 showed favorable pharmacokinetic characteristics and was well tolerated by all participants. Seventeen major metabolites were identified in plasma, urine, and feces. The main metabolic pathways included oxidation, hydrogenation, sulfonate conjugation, glucuronide conjugation, and cysteine conjugation. Excretion of IBI351 and its metabolites occurred mainly through feces. Collectively, this first-in-human study provides essential data on the metabolism and safety of IBI351 in Chinese subjects and lays the foundation for its further clinical development as a novel anti-tumor drug.

The current study aims to identify potential metabolic biomarkers that predict the progression to prediabetes in women with a history of gestational diabetes mellitus (GDM). We constructed a prediabetes group (n = 42) and a control group (n = 40) based on a 2-h 75 g oral glucose tolerance test for women with a history of GDM from six weeks to six months postpartum, and collected their clinical data and biochemical test results. We performed the plasma metabolomics analysis of the subjects at the fasting and 2-h post-load time points using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). We found that the prediabetes group was older and had higher 2-h post-load glucose levels during pregnancy than the control group. The metabolomic analysis identified 164 differential metabolites between the groups. Compared with the control group, 15 metabolites in the prediabetes group exhibited consistent change trends at both time points, including three increased and 12 decreased metabolites. By building a prediction model of the progression from GDM to prediabetes, we found that a combination of three clinical markers yielded an area under the curve (AUC) of 0.71 (95% confidence interval [CI], 0.60-0.82). We also assessed the discriminative power of the panel of 15 metabolites for distinguishing between postpartum prediabetes and normal glucose tolerance of the subjects at the fasting (AUC, 0.98; 95% CI, 0.94-1.00) and 2-h post-load (AUC, 0.99; 95% CI, 0.97-1.00) time points. The metabolic pathway analysis indicated that energy metabolism and branched-chain amino acids played a role in prediabetes development in women with a history of GDM during the early postpartum period. In conclusion, this study identified potential metabolic biomarkers and pathways associated with the progression from GDM to prediabetes in the early postpartum period. A panel of 15 metabolites showed promising discriminative power for distinguishing between postpartum prediabetes and normal glucose tolerance. These findings provide insights into the underlying pathophysiology of this transition and suggest the feasibility of developing a metabolic profiling test for the early identification of women at high risk of prediabetes following GDM.

The current study aimed to evaluate the efficacy and safety of Compound Danshen Dripping Pills (CDDP) in improving cardiac function in patients with acute anterior ST-segment elevation myocardial infarction (AAMI). Between February 2021 and February 2023, 247 eligible patients with AAMI after primary percutaneous coronary intervention were enrolled and randomly assigned (1∶1) to receive CDDP (n = 126) or placebo (n = 121), with a follow-up of 48 weeks. Compared with the placebo group, the CDDP group demonstrated a significant increase in left ventricular ejection fraction values after 24 weeks of treatment (least squares mean: 3.31; 95% confidence interval [CI]: 1.72-4.90; P < 0.001) and at the 48-week follow-up (least squares mean: 4.35; 95% CI: 2.76-5.94; P < 0.001). Significant reductions in N-terminal pro-B-type natriuretic peptide levels were observed in both groups at the 24- and 48-week visits with no significant difference between the two groups (P > 0.1 for all). The incidence of major adverse cardiovascular and cerebrovascular events was 6.35% in the CDDP group and 5.79% in the placebo group (P = 0.822). Notably, no serious adverse events were attributed to CDDP. These findings suggest that CDDP may be well tolerated and could improve left ventricular ejection fraction in patients with AAMI at 24 and 48 weeks.

Parvalbumin-positive (PV⁺) interneuron dysfunction is believed to be linked to autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by social deficits and stereotypical behaviors. However, the mechanisms behind PV⁺ interneuron dysfunction remain largely unclear. Here, we found that a deficiency of Biorientation Defective 1 (Bod1) in PV⁺ interneurons led to an ASD-like phenotype in Pvalb-Cre;Bod1^f/f mice. Mechanistically, we observed that Bod1 deficiency induced hypoactivity of PV⁺ interneurons and hyperactivity of calcium/calmodulin-dependent protein kinase Ⅱ alpha (CaMKⅡα) neurons in the medial prefrontal cortex, as determined by whole-cell patch-clamp recording. Additionally, Bod1 deficiency decreased the power of high-gamma oscillation, assessed by in vivo multi-channel electrophysiological recording. Furthermore, we found that Bod1 deficiency enhanced the inwardly rectifying K⁺ current, leading to an increase in the resting membrane potential of PV⁺ interneurons. Importantly, the gain-of-function of Bod1 improved social deficits and stereotypical behaviors in Pvalb-Cre;Bod1^f/f mice. These findings provide mechanistic insights into the PV⁺ interneuron dysfunction and suggest new strategies for developing PV⁺ interneuron-targeted therapies for ASD.

Viral myocarditis is a rare but life-threatening complication in patients with ulcerative colitis. Management of myocarditis is primarily supportive, because there are currently no established targeted therapies. Recent studies have increasingly highlighted the association between the gut microbiota and myocarditis. Here, we report a case of acute severe ulcerative colitis complicated by cytomegalovirus and Epstein-Barr virus co-infections that led to viral myocarditis. The patient experienced rapid remission of both intestinal and cardiac symptoms following washed microbiota transplantation, suggesting this intervention may serve as a potential alternative treatment for these life-threatening conditions.