The YY1-CPT1C signaling axis modulates the proliferation and metabolism of pancreatic tumor cells under hypoxia.

Carnitine palmitoyltransferase 1C (CPT1C) is an enzyme that regulates tumor cell proliferation and metabolism by modulating mitochondrial function and lipid metabolism. Hypoxia, commonly observed in solid tumors, promotes the proliferation and progression of pancreatic cancer by regulating the metabolic reprogramming of tumor cells. So far, the metabolic regulation of hypoxic tumor cells by CPT1C and the upstream mechanisms of CPT1C remain poorly understood. Yin Yang 1 (YY1) is a crucial oncogene for pancreatic tumorigenesis and acts as a transcription factor that is involved in multiple metabolic processes. This study aimed to elucidate the relationship between YY1 and CPT1C under hypoxic conditions and explore their roles in hypoxia-induced proliferation and metabolic alterations of tumor cells. The results showed enhancements in the proliferation and metabolism of PANC-1 cells under hypoxia, as evidenced by increased cell growth, cellular ATP levels, up-regulation of mitochondrial membrane potential, and decreased lipid content. Interestingly, knockdown of YY1 or CPT1C inhibited hypoxia-induced rapid cell proliferation and vigorous cell metabolism. Importantly, for the first time, we reported that YY1 directly activated the transcription of CPT1C and clarified that CPT1C was a novel target gene of YY1. Moreover, the YY1 and CPT1C were found to synergistically regulate the proliferation and metabolism of hypoxic cells through transfection with YY1 siRNA to CRISPR/Cas9-CPT1C knockout PANC-1 cells. Taken together, these results indicated that the YY1-CPT1C axis could be a new target for the intervention of pancreatic cancer proliferation and metabolism.

Exploring the pharmacokinetics and tolerability of cyclooxygenase inhibitor ampiroxicam: a phase I study on single and multiple oral doses.

Introduction: Ampiroxicam is a long-acting, non-steroidal anti-inflammatory drug that selectively inhibits human cyclooxygenase, effectively mitigating fever, pain, and inflammation. This study evaluated the drug's tolerability and pharmacokinetics to support personalized dosing strategies. Methods: The study involved healthy participants and focused on the pharmacokinetics of ampiroxicam. Plasma levels of piroxicam, a key metabolite of ampiroxicam, were measured using ultra-performance liquid chromatography. Piroxicam was chosen due to its integral role in ampiroxicam's metabolic pathway. The analytical method underwent rigorous validation to ensure precision and accuracy, addressing potential interference from endogenous plasma substances. Results: Participants received ampiroxicam in single doses (low, medium, and high) and multiple doses. Pharmacokinetic parameters, including AUC0-216, AUC0-∞, and Cmax, exhibited a dose-dependent increase. No significant differences were noted across the dosage groups, and sex-specific differences were minimal, with the exception of mean residence time (MRT) in the multiple-dose group, which appeared influenced by body weight variations. Discussion: The findings affirm the safety and efficacy of ampiroxicam across different dosing regimens, validating its clinical utility and potential for personalized medicine in the treatment of pain and inflammation.

Babesia duncani Pyruvate Kinase Inhibitor Screening and Identification of Key Active Amino Acid Residues.

Babesia duncani (B. duncani), a protozoan parasite prevalent in North America, is a significant threat for human health. Given the regulatory role of pyruvate kinase I (PyK I) in glycolytic metabolism flux and ATP generation, PyK I has been considered the target for drug intervention for a long time. In this study, B. duncani PyK I (BdPyK I) was successfully cloned, expressed, and purified. Polyclonal antibodies were confirmed to recognize the native BdPyK I protein (56 kDa) using Western blotting. AlphaFold software predicted the three-dimensional structure of BdPyK I, and molecular docking with small molecules was conducted to identify potential binding sites of inhibitor on BdPyK I. Moreover, inhibitory effects of six inhibitors (tannic acid, apigenin, shikonin, PKM2 inhibitor, rosiglitazone, and pioglitazone) on BdPyK I were examined under the optimal enzymatic conditions of 3 mM PEP and 3 mM ADP, and significant activity reduction was found. Enzyme kinetics and growth inhibition assays further confirmed the reliability of these inhibitors, with PKM2 inhibitor, tannic acid, and apigenin exhibiting the highest selectivity index as specific inhibitors for B. duncani. Subsequently, key amino acid residues were mutated in both BdPyK I and Homo sapiens pyruvate kinase I (HPyK I), and two differential amino acid residues (isoleucine and phenylalanine) were identified between HPyK I and BdPyK I through PyK activity detection experiments. These findings lay foundation for understanding the role of PyK I in the growth and development of B. duncani, providing insights for babesiosis prevention and drug development.

The Effect of Transverse Sinus Stenosis Caused by Arachnoid Granulation on Patients with Venous Pulsatile Tinnitus: A Multiphysics Interaction Simulation Investigation.

This study aimed to investigate the effect of the transverse sinus (TS) stenosis (TSS) position caused by arachnoid granulation on patients with venous pulsatile tinnitus (VPT) and to further identify the types of TSS that are of therapeutic significance for patients. Multiphysics interaction models of six patients with moderate TSS caused by arachnoid granulation and virtual stent placement in TSS were reconstructed, including three patients with TSS located in the middle segment of the TS (group 1) and three patients with TTS in the middle and proximal involvement segment of the TS (group 2). The transient multiphysics interaction simulation method was applied to elucidate the differences in biomechanical and acoustic parameters between the two groups. The results revealed that the blood flow pattern at the TS and sigmoid sinus junction was significantly changed depending on the stenosis position. Preoperative patients had increased blood flow in the TSS region and TSS downstream where the blood flow impacted the vessel wall. In group 1, the postoperative blood flow pattern, average wall pressure, vessel wall vibration, and sound pressure level of the three patients were comparable to the preoperative state. However, the postoperative blood flow velocity decreased in group 2. The postoperative average wall pressure, vessel wall vibration, and sound pressure level of the three patients were significantly improved compared with the preoperative state. Intravascular intervention therapy should be considered for patients with moderate TSS caused by arachnoid granulations in the middle and proximal involvement segment of the TS. TSS might not be considered the cause of VPT symptoms in patients with moderate TSS caused by arachnoid granulation in the middle segment of the TS.

Deep learning model to discriminate diverse infection types based on pairwise analysis of host gene expression.

Accurate detection of pathogens, particularly distinguishing between Gram-positive and Gram-negative bacteria, could improve disease treatment. Host gene expression can capture the immune system's response to infections caused by various pathogens. Here, we present a deep neural network model, bvnGPS2, which incorporates the attention mechanism based on a large-scale integrated host transcriptome dataset to precisely identify Gram-positive and Gram-negative bacterial infections as well as viral infections. We performed analysis of 4,949 blood samples across 40 cohorts from 10 countries using our previously designed omics data integration method, iPAGE, to select discriminant gene pairs and train the bvnGPS2. The performance of the model was evaluated on six independent cohorts comprising 374 samples. Overall, our deep neural network model shows robust capability to accurately identify specific infections, paving the way for precise medicine strategies in infection treatment and potentially also for identifying subtypes of other diseases.

Repetitive Transcranial Magnetic Stimulation Reversing Abnormal Brain Function in Mood Disorders with Early Life Stress: from preclinical models to clinical applications.

BACKGROUND: Early life stress (ELS) significantly increases the risk of mood disorders and affects the neurodevelopment of the primary cortex. HYPOTHESIS: Modulating the primary cortex through neural intervention can ameliorate the impact of ELS on brain development and consequently alleviate its effects on mood disorders. METHOD: We induced the chronic unpredictable mild stress (CUMS) model in adolescent rats, followed by applying repetitive transcranial magnetic stimulation (rTMS) to their primary cortex in early adulthood. To assess the applicability of primary cortex rTMS in humans, we recruited individuals aged 17-25 with mood disorders who had experienced ELS and performed primary cortex rTMS on them. Functional magnetic resonance imaging (fMRI) and depression-related behavioral and clinical symptoms were conducted in both rats and human subjects before and after the rTMS. RESULTS: In animals, fMRI analysis revealed increased activation in the primary cortex of CUMS rats and decrease subcortical activation. Following the intervention of primary cortex rTMS, the abnormal functional activity was reversed. Similarly, in mood disorders patients with ELS, increased activation in the primary cortex and decreased activation in the frontal cortex were observed. During rTMS intervention, similar neuroimaging improvements were noted, particularly decreased activation in the primary cortex. This suggests that targeted rTMS in the primary cortex can reverse the abnormal neuroimaging. CONCLUSION: This cross-species translational study has identified the primary cortex as a key region in mood disorders patients with ELS. Targeting the primary cortex with rTMS can correct abnormal functional activity while improving symptoms. Our study provides translational evidence for therapeutics targeting the ELS factor of mood disorders patients.

Associations of serum uric acid variability with neuroimaging metrics and cognitive decline: a population-based cohort study.

BACKGROUND: The relationship between variation in serum uric acid (SUA) levels and brain health is largely unknown. This study aimed to examine the associations of long-term variability in SUA levels with neuroimaging metrics and cognitive function. METHODS: This study recruited 1111 participants aged 25-83 years from a multicenter, community-based cohort study. The SUA concentrations were measured every two years from 2006 to 2018. We measured the intraindividual SUA variability, including the direction and magnitude of change by calculating the slope value. The associations of SUA variability with neuroimaging markers (brain macrostructural volume, microstructural integrity, white matter hyperintensity, and the presence of cerebral small vessel disease) and cognitive function were examined using generalized linear models. Mediation analyses were performed to assess whether neuroimaging markers mediate the relationship between SUA variation and cognitive function. RESULTS: Compared with the stable group, subjects with increased or decreased SUA levels were all featured by smaller brain white matter volume (beta = - 0.25, 95% confidence interval [CI] - 0.39 to - 0.11 and beta = - 0.15, 95% CI - 0.29 to - 0.02). Participants with progressively increased SUA exhibited widespread disrupted microstructural integrity, featured by lower global fractional anisotropy (beta = - 0.24, 95% CI - 0.38 to - 0.10), higher mean diffusivity (beta = 0.16, 95% CI 0.04 to 0.28) and radial diffusivity (beta = 0.19, 95% CI 0.06 to 0.31). Elevated SUA was also associated with cognitive decline (beta = - 0.18, 95% CI - 0.32 to - 0.04). White matter atrophy and impaired brain microstructural integrity mediated the impact of SUA increase on cognitive decline. CONCLUSIONS: It is the magnitude of SUA variation rather than the direction that plays a critical negative role in brain health, especially for participants with hyperuricemia. Smaller brain white matter volume and impaired microstructural integrity mediate the relationship between increased SUA level and cognitive function decline. Long-term stability of SUA level is recommended for maintaining brain health and preventing cognitive decline.

Gray matter volume mediates the association of long-term blood pressure variability with cognitive function in an adult population.

INTRODUCTION: We delineated the associations among long-term blood pressure variability (BPV), brain structure, and cognitive function. METHODS: We included 1254 adult participants from the Kailuan study. BPV was calculated from 2006 to 2020. Brain magnetic resonance imaging (MRI) and Montreal Cognitive Assessment (MoCA) were conducted in 2020. RESULTS: Higher systolic BPV (SBPV) and diastolic BPV (DBPV) were associated with lower total and frontal gray matter (GM) volume, and higher SBPV was associated with lower temporal GM volume. Elevated DBPV was associated with lower volume of total brain and parietal GM, and higher white matter hyperintensity (WMH) volume. Higher SBPV and DBPV were associated with lower MoCA scores. Decreased total and regional GM volume and increased WMH volume were associated with lower MoCA scores. The association between SBPV and cognitive function was mediated by total, frontal, and temporal GM volume. DISCUSSION: GM volume may play key roles in the association between SBPV and cognitive function. HIGHLIGHTS: SBPV and DBPV were negatively associated with total and regional brain volume. SBPV and DBPV were negatively associated with cognitive function. Decreased brain volume was associated with cognitive decline. GM volume mediated the negative association between SBPV and cognitive function.

Differences in the intestinal microbiota and association of host metabolism with hair coat status in cattle.

Introduction: The hair coat status of cattle serves as an easily observed indicator of economic value in livestock production; however, the underlying mechanism remains largely unknown. Therefore, the objective of the current study was to determine differences in the intestinal microbiota and metabolome of cattle based on a division of with either slick and shining (SHC) or rough and dull (MHC) hair coat in Simmental cows. Methods: Eight SHC and eight MHC late-pregnancy Simmental cows (with similar parities, body weights, and body conditions) were selected based on their hair coat status, and blood samples (plasma) from coccygeal venipuncture and fecal samples from the rectum were collected. The intestinal microbiota (in the fecal samples) was characterized by employing 16S rRNA gene sequencing targeting the V3-V4 hypervariable region on the Illumina MiSeq PE300 platform, and plasma samples were subjected to LC-MS/MS-based metabolomics with Progenesis QI 2.3. Plasma macromolecular metabolites were examined for differences in the metabolism of lipids, proteins, mineral elements, and hormones. Results: Notable differences between the SHC and MHC groups related to host hair coat status were observed in the host metabolome and intestinal microbiota (P < 0.05). The host metabolome was enriched in histidine metabolism, cysteine and methionine metabolism, and purine metabolism in the SHC group, and the intestinal microbiota were also enriched in histidine metabolism (P < 0.05). In the MHC group, the symbiotic relationship transitioned from cooperation to competition in the MHC group, and an uncoupling effect was present in the microbe-metabolite association of intestine microbiota-host interactions. The hubs mediating the relationships between intestinal microbiota and plasma metabolites were the intestinal bacterial genus g__norank_f__Eubacterium_coprostanoligenes_group, plasma inosine, triiodothyronine, and phosphorus, which could be used to differentiate cows' hair coat status (P < 0.05). Conclusion: Overall, the present study identified the relationships between the features of the intestinal microbiota and host hair coat status, thereby providing evidence and a new direction (intestine microbiota-host interplay) for future studies aimed at understanding the hair coat status of cattle.

Hippocampal volume mediates the association of arterial stiffness with cognitive impairment in adult population.

OBJECTIVES: To investigate the association of arterial stiffness with brain perfusion, brain tissue volume and cognitive impairment in the general adult population. MATERIALS AND METHODS: This prospective study included 1488 adult participants (age range: 22.8-83.9 years) from the Kailuan study. All participants underwent brachial-ankle pulse wave velocity (PWV) measurement, brain MRI, and Montreal Cognitive Assessment (MoCA). The association of PWV with cerebral blood flow (CBF), brain tissue volume and MoCA score was investigated. Mediation analysis was used to determine whether CBF and brain tissue volume changes mediated the associations between PWV and MoCA score. RESULTS: A 1 standard deviation (SD) increase in PWV was associated with lower total brain CBF [ß (95% CI) -0.67 (-1.2 to -0.14)], total gray matter CBF [ß (95% CI) -0.7 [-1.27 to -0.13)], frontal lobe CBF [ß (95% CI) -0.59 (-1.17 to -0.01)], parietal lobe CBF [ß (95% CI) -0.8 (-1.43 to -0.18)], and temporal lobe CBF [ß (95% CI) -0.68 (-1.24 to -0.12)]. Negative associations were found for PWV and total brain volume [ß (95% CI) -4.8 (-7.61 to -1.99)] and hippocampus volume [ß (95% CI) -0.08 (-0.13 to -0.04)]. A 1 SD increase PWV was significantly associated with elevated odds of developing cognitive impairment [odds ratio (95% CI) 1.21 (1.01-1.45)]. Mediation analysis showed that hippocampal volume partially mediated the negative association between PWV and MoCA scores (proportion: 14.173%). CONCLUSION: High arterial stiffness was associated with decreased total and regional CBF, brain tissue volume, and cognitive impairment. Hippocampal volume partially mediated the effects of arterial stiffness on cognitive impairment.

Teaching diagnostic radiology to radiology majors: Implementation and evaluation of a flipped classroom model.

PURPOSE: Radiology instruction focuses on cultivating medical students' diagnostic thinking skills and practical competence, and lecture-based learning (LBL) is the most commonly used teaching approach. While fact-based, this type of traditional instruction is often non-engaging, leading to a shift toward student-centered models, one of which is the flipped classroom (FC). However, studies involving a comprehensive evaluation of students' experiences using the FC approach and its effects on their learning are lacking. Therefore, this study analyzed the teaching efficacy of the FC approach based on data of large groups of radiology students, accumulated over time. METHODS: Data from 636 medical radiology students taught using the FC and LBL models from 2012 to 2021 were retrospectively collected and analyzed. RESULTS: The test scores of the FC group were significantly higher than those of the LBL group, and improvements in learning initiative and learning ability were notably higher in the FC than in the LBL group. The two groups showed no significant difference in the critical thinking disposition indicator, and the proportion of students with positive critical thinking tendencies was higher in the FC than in the LBL group. The academic and social self-perception scores of the FC group were significantly higher than those of the LBL group, and there was a significant difference in Kolb's learning style. CONCLUSIONS: Based on evidence of completing pre-, in-, and after-class work, the FC approach improved students' academic performance, learning initiative, diagnostic ability, and satisfaction with learning and the teaching institution. Our findings suggest that FC instruction promotes students' assimilation and convergence of learning styles, and cultivates positive critical thinking.

Isolation, Identification, Genomic Diversity, and Antimicrobial Resistance Analysis of Streptococcus suis in Hubei Province of China from 2021 to 2023.

Streptococcus suis (S. suis) is a zoonotic pathogen capable of causing severe diseases in humans and pigs, including meningitis, sepsis, polyserositis, arthritis, and endocarditis. This study aimed to investigate the biological characteristics of 19 strains of S. suis isolated from diseased pigs in Hubei Province between 2021 and 2023. Through bioinformatics analysis, we investigated the serotype, MLST, pan-genome characteristics, SNP, AMR, and ICE of the 19 S. suis isolates. Among the 19 S. suis strains, ten serotypes were identified, and serotype 9 was the most prevalent (21.05%). Ten new alleles and nine new sequence types (STs) were discovered, with ST28 and ST243 emerging as the predominant STs. The results of the pan-genomic analysis of S. suis indicate that there are 943 core genes, 2259 shell genes, and 5663 cloud genes. Through SNP evolutionary analysis, we identified a strong genetic similarity between SS31 and the reference genome P1/7. The analysis of antibiotic resistance genes revealed widespread presence of erm(B) and tet(O) genes among 19 strains of S. suis. This association may be linked to the high resistance of S. suis to lincosamides, macrolides, and tetracyclines. Integrative and conjugative elements (ICEs) and integrative and mobilizable elements (IMEs) were identified in 16 strains, with a carriage rate of 84.21%, and resistance genes were identified within the ICE/IME elements of 8 strains. Antimicrobial susceptibility testing revealed that all strains showed sensitivity to vancomycin and lincomycin but resistance to tilmicosin, tiamulin, amoxicillin, and doxycycline. This study contributes to our understanding of the genomic diversity of S. suis in Hubei Province of China, providing essential data for the comprehensive prevention and control of S. suis infections in China.

Amygdala structural and functional reorganization as an indicator of affective dysfunction in patients with tinnitus.

The aim of this study was to systematically investigate structural and functional alterations in amygdala subregions using multimodal magnetic resonance imaging (MRI) in patients with tinnitus with or without affective dysfunction. Sixty patients with persistent tinnitus and 40 healthy controls (HCs) were recruited. Based on a questionnaire assessment, 26 and 34 patients were categorized into the tinnitus patients with affective dysfunction (TPAD) and tinnitus patients without affective dysfunction (TPWAD) groups, respectively. MRI-based measurements of gray matter volume, fractional anisotropy (FA), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), degree centrality (DC), and functional connectivity (FC) were conducted within 14 amygdala subregions for intergroup comparisons. Associations between the MRI properties and clinical characteristics were estimated via partial correlation analyses. Compared with that of the HCs, the TPAD and TPWAD groups exhibited significant structural and functional changes, including white matter integrity (WMI), fALFF, ReHo, DC, and FC alterations, with more pronounced WMI changes in the TPAD group, predominantly within the left auxiliary basal or basomedial nucleus (AB/BM), right central nucleus, right lateral nuclei (dorsal portion), and left lateral nuclei (ventral portion containing basolateral portions). Moreover, the TPAD group exhibited decreased FC between the left AB/BM and left middle occipital gyrus and right superior frontal gyrus (SFG), left basal nucleus and right SFG, and right lateral nuclei (intermediate portion) and right SFG. In combination, these amygdalar alterations exhibited a sensitivity of 65.4% and specificity of 96.9% in predicting affective dysfunction in patients with tinnitus. Although similar structural and functional amygdala remodeling were observed in the TPAD and TPWAD groups, the changes were more pronounced in the TPAD group. These changes mainly involved alterations in functionality and white matter microstructure in various amygdala subregions; in combination, these changes could serve as an imaging-based predictor of emotional disorders in patients with tinnitus.

Physiologically based absorption modeling to predict the bioequivalence of two apixaban formulations.

The equivalence of absorption rates and extents between generic drugs and their reference formulations is crucial for ensuring therapeutic comparability. Bioequivalence (BE) studies are widely utilized and play a pivotal role in substantiating the approval and promotional efforts for generic drugs. Virtual BE simulation is a valuable tool for mitigating risks and guiding clinical BE studies, thereby minimizing redundant in vivo BE assessments. Herein, we successfully developed a physiologically based absorption model for virtual BE simulations, which precisely predicts the BE of the apixaban test and reference formulations. The modeling results confirm that the test and reference formulations were bioequivalent under both fasted and fed conditions, consistent with clinical studies. This highlights the efficacy of physiologically based absorption modeling as a powerful tool for formulation screening and can be adopted as a methodological and risk assessment strategy to detect potential clinical BE risks.

The risk of endocrine immune-related adverse events induced by PD-1 inhibitors in cancer patients: a systematic review and meta-analysis.

Objective: Endocrinopathies are the most common immune-related adverse events (irAEs) observed during therapy with PD-1 inhibitors. In this study, we conducted a comprehensive systematic review and meta-analysis to evaluate the risk of immune-related endocrinopathies in patients treated with PD-1 inhibitors. Methods: We performed a systematic search in the PubMed, Embase, and Cochrane Library databases to retrieve all randomized controlled trials (RCTs) involving PD-1 inhibitors, spanning from their inception to November 24, 2023. The comparative analysis encompassed patients undergoing chemotherapy, targeted therapy, or receiving placebo as control treatments. This study protocol has been registered with PROSPERO (CRD42023488303). Results: A total of 48 clinical trials comprising 24,514 patients were included. Compared with control groups, patients treated with PD-1 inhibitors showed an increased risk of immune-related adverse events, including hypothyroidism, hyperthyroidism, hypophysitis, thyroiditis, diabetes mellitus, and adrenal insufficiency. Pembrolizumab was associated with an increased risk of all aforementioned endocrinopathies (hypothyroidism: RR=4.76, 95%CI: 3.55-6.39; hyperthyroidism: RR=9.69, 95%CI: 6.95-13.52; hypophysitis: RR=5.47, 95%CI: 2.73-10.97; thyroiditis: RR=5.95, 95%CI: 3.02-11.72; diabetes mellitus: RR=3.60, 95%CI: 1.65-7.88; adrenal insufficiency: RR=4.80, 95%CI: 2.60-8.88). Nivolumab was associated with an increased risk of hypothyroidism (RR=7.67, 95%CI: 5.00-11.75) and hyperthyroidism (RR=9.22, 95%CI: 4.71-18.04). Tislelizumab and sintilimab were associated with an increased risk of hypothyroidism (RR=19.07, 95%CI: 5.46-66.69 for tislelizumab and RR=18.36, 95%CI: 3.58-94.21 for sintilimab). For different tumor types, both hypothyroidism and hyperthyroidism were at high risks. Besides, patients with non-small cell lung cancer were at a higher risk of thyroiditis and adrenal insufficiency. Patients with melanoma were at a higher risk of hypophysitis and diabetes mellitus. Both low- and high-dose group increased risks of hypothyroidism and hyperthyroidism. Conclusion: Risk of endocrine irAEs may vary in different PD-1 inhibitors and different tumor types. Increased awareness and understanding of the risk features of endocrine irAEs associated with PD-1 inhibitors is critical for clinicians. Systematic review registration: crd.york.ac.uk/prospero, identifier PROSPERO (CRD42023488303).

The causal relationship between serum metabolites and acne vulgaris: a Mendelian randomization study.

In individuals with acne vulgaris, alterations occur in serum metabolite composition, yet the exact causal link between these metabolites and acne development remains elusive. Using genome-wide association datasets, we performed bidirectional Mendelian randomization (MR) to investigate the potential causal relationship between 309 serum metabolites and acne vulgaris. We performed sensitivity analysis to evaluate the presence of heterogeneity and pleiotropy. Forward MR analysis found 14 serum metabolites significantly associated with acne vulgaris, and reverse MR analysis found no significant association between acne vulgaris and these serum metabolites. Through validation using data from the FinnGen database of acne vulgaris studies, we found a conclusive and significant correlation between stearoylcarnitine and acne vulgaris. This provides new evidence in the search for new targets for the treatment of acne vulgaris.

A novel easy-to-desorb eluant contributes to address environmental contamination of African swine fever virus.

African swine fever virus (ASFV) is a highly pathogenic and rapidly disseminated virus with strong viability in the environment, suggesting the importance of environmental detection for prevention and control in all the pig industry. However, the detection results of environmental swabs cannot always reflect the accurate status of viral pollution, leading to persistent ASFV environmental contamination. In this study, we developed an ASFV eluant with higher environmental ASFV detection efficiency relative to 0.85% saline solution, which obtains the patent certificate issued by the China Intellectual Property Office (patent number:202010976050.9). qPCR analysis showed that in the environmental swab samples, the number of viral copies was 100 times higher for the ASFV eluant treatment than the traditional eluant treatment (0.85% saline solution). And besides, the high sensitivity of the ASFV eluant had be verified in a slaughterhouse environmental sampling detection. In soil samples, the ASFV eluent showed the same extraction effect as the TIANamp Soil DNA Kit, in contrast to no extraction effect for 0.85% saline solution. Simultaneously, this eluent could protect ASFV from degradation and allow the transportation of samples at ambient temperature without refrigeration. In clinical practice, we monitored the environmental contamination condition of the ASFV in a large-scale pig farm. The results shown that the ASFV load decreased after every disinfection in environment. This study provides an effective solution for surveilling the potential threat of ASFV in environment.

Characterizing the distinct imaging phenotypes, clinical behavior, and genetic vulnerability of brain maturational subtypes in mood disorders.

BACKGROUND: Mood disorders are characterized by great heterogeneity in clinical manifestation. Uncovering such heterogeneity using neuroimaging-based individual biomarkers, clinical behaviors, and genetic risks, might contribute to elucidating the etiology of these diseases and support precision medicine. METHODS: We recruited 174 drug-naïve and drug-free patients with major depressive disorder and bipolar disorder, as well as 404 healthy controls. T1 MRI imaging data, clinical symptoms, and neurocognitive assessments, and genetics were obtained and analyzed. We applied regional gray matter volumes (GMV) and quantile normative modeling to create maturation curves, and then calculated individual deviations to identify subtypes within the patients using hierarchical clustering. We compared the between-subtype differences in GMV deviations, clinical behaviors, cell-specific transcriptomic associations, and polygenic risk scores. We also validated the GMV deviations based subtyping analysis in a replication cohort. RESULTS: Two subtypes emerged: subtype 1, characterized by increased GMV deviations in the frontal cortex, cognitive impairment, a higher genetic risk for Alzheimer's disease, and transcriptionally associated with Alzheimer's disease pathways, oligodendrocytes, and endothelial cells; and subtype 2, displaying globally decreased GMV deviations, more severe depressive symptoms, increased genetic vulnerability to major depressive disorder and transcriptionally related to microglia and inhibitory neurons. The distinct patterns of GMV deviations in the frontal, cingulate, and primary motor cortices between subtypes were shown to be replicable. CONCLUSIONS: Our current results provide vital links between MRI-derived phenotypes, spatial transcriptome, genetic vulnerability, and clinical manifestation, and uncover the heterogeneity of mood disorders in biological and behavioral terms.

OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition.

Ovarian cancer is an aggressive gynecological tumor characterized by a high relapse rate and chemoresistance. Ovarian cancer exhibits the cancer hallmark of elevated glycolysis, yet effective strategies targeting cancer cell metabolic reprogramming to overcome therapeutic resistance in ovarian cancer remain elusive. Here, we revealed that epigenetic silencing of Otubain 2 (OTUB2) is a driving force for mitochondrial metabolic reprogramming in ovarian cancer, which promotes tumorigenesis and chemoresistance. Mechanistically, OTUB2 silencing destabilizes sorting nexin 29 pseudogene 2 (SNX29P2), which subsequently prevents hypoxia-inducible factor-1 alpha (HIF-1α) from von Hippel-Lindau tumor suppressor-mediated degradation. Elevated HIF-1α activates the transcription of carbonic anhydrase 9 (CA9) and drives ovarian cancer progression and chemoresistance by promoting glycolysis. Importantly, pharmacological inhibition of CA9 substantially suppressed tumor growth and synergized with carboplatin in the treatment of OTUB2-silenced ovarian cancer. Thus, our study highlights the pivotal role of OTUB2/SNX29P2 in suppressing ovarian cancer development and proposes that targeting CA9-mediated glycolysis is an encouraging strategy for the treatment of ovarian cancer.

Mendelian randomization analyses support causal relationships between tinnitus of different stages and severity and structural characteristics of specific brain regions.

This study aims to delineate the causal relationships between idiopathic tinnitus in different stages and severity and the morphological properties in specific brain regions. We utilized a two-sample bidirectional Mendelian randomization (MR) analysis to ascertain the causal effects of brain structural attributes on varying severities and stages of tinnitus. Our approach involved harnessing genetic variables derived from extensive genome-wide association studies as instrumental variables, centered mainly on pertinent single-nucleotide polymorphisms associated with tinnitus. Subsequently, we integrated this data with brain structural imaging inputs to facilitate the MR analysis. We also applied reverse MR analysis to pinpoint the critical brain regions implicated in the onset of tinnitus. Our analysis revealed a demonstrable causal relationship between tinnitus and brain structural alterations, including changes primarily within the auditory cortex and hub regions of the limbic system, as well as portions of the frontal-temporal-occipital circuit. We found that individuals exhibiting cortical thickness alterations in the bilateral peri-calcarine and right superior occipital gyrus might have previously experienced tinnitus. Changes in the cortical areas of the right rectus, left inferior frontal gyrus, and right pars-orbitalis appeared unrelated to tinnitus. Furthermore, moderate tinnitus patients showed more pronounced structural alterations. This study substantiates that tinnitus could instigate substantial structural alterations mainly within the auditory-limbic-frontal-visual system, while the reciprocal causality was not supported. Moreover, the data underscores that moderate, rather than severe, tinnitus precipitates the most significant structural changes. Morphological alterations in several specific brain areas either indicate a history of tinnitus or bear no relation to it.