Genomic characteristics and evolution of Multicentric Esophageal and gastric Cardiac Cancer.

BACKGROUND: Esophageal carcinoma (EC) and gastric cardiac adenocarcinoma (GCA) have high incidence rates in the Chaoshan region of South China. Multifocal esophageal and cardiac cancer (MECC) is commonly observed in this region in clinical practice. However, the genomic characteristics of MECC remains unclear. MATERIALS AND METHODS: In this study, a total of 2123 clinical samples of EC and GCA were analyzed to determine the frequency of multifocal tumors, as well as their occurrence sites and pathological types. Cox proportional hazards regression was used to model the relationship between age, sex, and tumor state concerning survival in our analysis of the cohort of 541 patients with available follow-up data. We performed whole-genome sequencing on 20 tumor foci and 10 normal samples from 10 MECC patients to infer clonal structure on 6 MECC patients to explore genome characteristics. RESULT: The MECC rate of EC and GCA was 5.65% (121 of 2123). Age and sex were potential factors that may influence the risk of MECC (p < 0.001). Furthermore, MECC patients showed worse survival compared with single tumor patients. We found that 12 foci from 6 patients were multicentric origin model (MC), which exhibited significant heterogeneity of variations in paired foci and had an increased number of germline mutations in immune genes compared to metastatic model. In MC cases, different lesions in the same patient were driven by distinct mutation and copy number variation (CNV) events. Although TP53 and other driver mutation genes have a high frequency in the samples, their mutation sites show significant heterogeneity in paired tumor specimens. On the other hand, CNV genes exhibited higher concordance in paired samples, especially in the amplification of oncogenes and the deletion of tumor suppressor genes. CONCLUSIONS: The extent of inter-tumor heterogeneity suggests both monoclonal and polyclonal origins of MECC, which could provide insight into the genome diversity of MECC and guide clinical implementation.

Network analysis of occupational stress and job satisfaction among radiologists.

Background: Occupational stress and job satisfaction significantly impact the well-being and performance of healthcare professionals, including radiologists. Understanding the complex interplay between these factors through network analysis can provide valuable insights into intervention strategies to enhance workplace satisfaction and productivity. Method: In this study, a convenience sampling method was used to recruit 312 radiologists for participation. Data on socio-demographic characteristics, job satisfaction measured by the Minnesota job satisfaction questionnaire revised short version (MJSQ-RSV), and occupational stress assessed using the occupational stress scale. Network analysis was employed to analyze the data in this study. Results: The network analysis revealed intricate patterns of associations between occupational stress and job satisfaction symptoms among radiologists. Organizational management and occupational interests emerged as crucial nodes in the network, indicating strong relationships within these domains. Additionally, intrinsic satisfaction was identified as a central symptom with high connectivity in the network structure. The stability analysis demonstrated robustness in the network edges and centrality metrics, supporting the reliability of the findings. Conclusion: This study sheds light on the complex relationships between occupational stress and job satisfaction in radiologists, offering valuable insights for targeted interventions and support strategies to promote well-being and job satisfaction in healthcare settings.

Identification of novel biomarker hsa_circ_0003914 for rheumatoid arthritis from plasma exosomes.

Rheumatoid arthritis (RA) is a complex autoimmune disease featuring invasive and infiltrative fibroblast-like synoviocytes (FLS) that lead to joint damage. While current RA pathological mechanisms remain incompletely defined, exosomes have been implicated as having the potential to drive disease progression due to their ability to deliver different types of biomolecules to tissues effected by RA. One potentially disease exacerbating molecule type found in exosomes are Circular RNAs (circRNAs), which are highly stable and have been previously implicated in RA pathogenesis. Here, we examine hsa_circ_0003914, a circRNA found in exosomes located in blood plasma, for a role in RA. Plasma exosomes were isolated and injected into collagen-induced arthritis (CIA) mice, followed by functional experiments to analyze the influence of exosomes on FLS formation. Sequencing revealed the presence of hsa_circ_0003914 in exosomes, so we examined its association with clinical markers in RA. Finally, the role for hsa_circ_0003914 in RA was directly confirmed through in vivo and in vitro experiments. We found that plasma exosomes isolated from RA patients could aggravate the disease of CIA mice, compared to exosomes isolated from healthy control patients. Hsa_circ_0003914 was highly enriched in the exosomes of RA patients. Mechanistically, Hsa_circ_0003914 promoted abnormal cell proliferation, migration, invasion and stimulated the secretion of inflammatory cytokines in FLSs through targeting NF-κB/p65 signaling pathway. Interestingly, knockdown of hsa_circ_0003914 rescued disease phenotypes in CIA mice. Taken together, these data implicate hsa_circ_0003914 as a potential therapeutic target for the prevention and management of RA.

Serum 25-hydroxyvitamin D concentrations, vitamin D receptor polymorphisms, and risk of infections among individuals with type 2 diabetes: a prospective cohort study.

BACKGROUND: Evidence on the association between serum 25-hydroxyvitamin D [25(OH)D] and infections among patients with type 2 diabetes (T2D), a group susceptible to vitamin D deficiency and infections, is limited. OBJECTIVES: We aimed to examine this association in individuals with T2D, and to evaluate whether genetic variants in vitamin D receptor (VDR) would modify this association. METHODS: This study included 19,851 participants with T2D from United Kingdom Biobank. Infections were identified by linkage to hospital inpatient and death registers. Negative binomial regression models were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs), with adjustment of potential confounders. RESULTS: In patients with T2D, the incidence rate of infections was 29.3/1000 person-y. Compared with those with 25(OH)D of 50.0-74.9 nmol/L, the multivariable-adjusted IRRs and 95% CIs of total infections, pneumonia, gastrointestinal infections, and sepsis were 1.44 (1.31, 1.59), 1.49 (1.27, 1.75), 1.47 (1.22, 1.78), and 1.41 (1.14, 1.73), respectively, in patients with 25(OH)D <25.0 nmol/L. Nonlinear inverse associations between 25(OH)D concentrations and the risks of total infections (P-overall < 0.001; P-nonlinear = 0.002) and gastrointestinal infections (P-overall < 0.001; P-nonlinear = 0.040) were observed, with a threshold effect at ∼50.0 nmol/L. The vitamin D-infection association was not modified by genetic variants in VDR (all P-interaction > 0.050). CONCLUSIONS: In patients with T2D, lower serum 25(OH)D concentration (<50 nmol/L) was associated with higher risks of infections, regardless of genetic variants in VDR. Notably, nonlinear inverse associations between 25(OH)D concentrations and the risks of infections were found, with a threshold effect at ∼50.0 nmol/L. These findings highlighted the importance of maintaining adequate vitamin D in reducing the risk of infections in patients with T2D.

PD-1/PD-L1 axis is involved in the interaction between microglial polarization and glioma.

The tumor microenvironment plays a vital role in glioblastoma growth and invasion. PD-1 and PD-L1 modulate the immunity in the brain tumor microenvironment. However, the underlying mechanisms remain unclear. In the present study, in vivo and in vitro experiments were conducted to reveal the effects of PD-1/PD-L1 on the crosstalk between microglia and glioma. Results showed that glioma cells secreted PD-L1 to the peritumoral areas, particularly microglia containing highly expressed PD-1. In the early stages of glioma, microglia mainly polarized into the pro-inflammatory subtype (M1). Subsequently, the secreted PD-L1 accumulated and bound to PD-1 on microglia, facilitating their polarization toward the microglial anti-inflammatory (M2) subtype primarily via the STAT3 signaling pathway. The role of PD-1/PD-L1 in M2 polarization of microglia was partially due to PD-1/PD-L1 depletion or application of BMS-1166, a novel inhibitor of PD-1/PD-L1. Consistently, co-culturing with microglia promoted glioma cell growth and invasion, and blocking PD-1/PD-L1 significantly suppressed these processes. Our findings reveal that the PD-1/PD-L1 axis engages in the microglial M2 polarization in the glioma microenvironment and promotes tumor growth and invasion.

Prognosis of urgent initiation of peritoneal dialysis: a systematic review and meta-analysis.

OBJECTIVES: Currently, there is no consensus on the optimal timing for the initiation of peritoneal dialysis (PD) after catheter placement. DESIGN: Systematic review and meta-analysis. EXACT DATE OF DATA COLLECTION: From inception till July 31, 2023. MAIN OUTCOME MEASURES: To assess the outcomes and safety of unplanned PD initiation (<14/7 days after catheter insertion) in cohort studies. RESULTS: Fifteen studies involving 3054 participants were included. (1) The risk of unplanned initiation of leakage and Obstruction was no difference in both the break-in period (BI) <14 and BI < 7 groups. (2) Catheter displacement was more likely to occur in the emergency initiation group with BI < 7. (3) No significant differences were observed between the two groups regarding infectious complications. (4) There was no difference in transition to HD between patients with BI < 7 and BI < 14 d. CONCLUSION: Infectious complications of unplanned initiation of peritoneal dialysis did not differ from planned initiation. Emergency initiation in the BI < 7 group had higher catheter displacement, but heterogeneity was higher. There were no differences in leakage or obstruction in either group. Catheter survival was the same for emergency initiation of peritoneal dialysis compared with planned initiation of peritoneal dialysis and did not increase the risk of conversion to hemodialysis. REGISTRATION: This meta-analysis was registered on PROSPERO (https://www.crd.york.ac.uk/PROSPERO/, number: CRD42023431369).

Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography.

The proline biosynthetic enzyme Δ1-pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1) is one of the most consistently upregulated enzymes across multiple cancer types and central to the metabolic rewiring of cancer cells. Herein, we describe a fragment-based, structure-first approach to the discovery of PYCR1 inhibitors. Thirty-seven fragment-like carboxylic acids in the molecular weight range of 143-289 Da were selected from docking and then screened using X-ray crystallography as the primary assay. Strong electron density was observed for eight compounds, corresponding to a crystallographic hit rate of 22%. The fragments are novel compared to existing proline analog inhibitors in that they block both the P5C substrate pocket and the NAD(P)H binding site. Four hits showed inhibition of PYCR1 in kinetic assays, and one has lower apparent IC50 than the current best proline analog inhibitor. These results show proof-of-concept for our inhibitor discovery approach and provide a basis for fragment-to-lead optimization.

Prioritized single vitrified blastocyst to be warmed between grades 3 or 4 blastocyst on day 5 transfer cycles.

PURPOSE: Selecting the optimal blastocyst to implant during cryopreservation and warming is critial for in vitro fertilization success. Therefore, the aim of this study was to explore which blastocyst should be prioritized to be thawed when facing a single vitrified blastocyst on day 5 transfer. METHODS: A retrospective study including 1,976 single vitrified-warmed blastocyst transfer cycles was conducted from January 2016 to December 2020. RESULTS: We found that grade 4 vitrified blastocyst had a higher clinical pregnancy (60.64% vs. 49.48%, P < 0.001) and live birth rates (50.12% vs 39.59%, P < 0.001) than the grade 3 vitrified blastocyst. However, no statistical difference was found between groups in miscarriage rate, birth weight, or gestational age. Besides, the grade 4 vitrified-thawed blastocyst had significant potential to develop into grade 6 blastocyst after further culturing for 16 h (73.68% vs. 48.60%, P < 0.001). The grade 6 transferred blastocyst was markedly higher in both clinical pregnancy rate (61.88% vs. 51.53%, P < 0.001) and live birth rate (50.91% vs. 40.46%, P < 0.001) compared to grade 5 transferred blastocyst. CONCLUSIONS: Grade 4 vitrified blastocyst is recommended when facing single vitrified blastocyst on day 5 transfer. More importantly, the "embryonic escape hypothesis" was firstly proposed to reveal the findings.

Analysis of the Correlation and Prognostic Significance of Tertiary Lymphoid Structures in Breast Cancer: A Radiomics-Clinical Integration Approach.

BACKGROUND: Tertiary lymphoid structures (TLSs) are potential prognostic indicators. Radiomics may help reduce unnecessary invasive operations. PURPOSE: To analyze the association between TLSs and prognosis, and to establish a nomogram model to evaluate the expression of TLSs in breast cancer (BC) patients. STUDY TYPE: Retrospective. POPULATION: Two hundred forty-two patients with localized primary BC (confirmed by surgery) were divided into BC + TLS group (N = 122) and BC - TLS group (N = 120). FIELD STRENGTH/SEQUENCE: 3.0T; Caipirinha-Dixon-TWIST-volume interpolated breath-hold sequence for dynamic contrast-enhanced (DCE) MRI and inversion-recovery turbo spin echo sequence for T2-weighted imaging (T2WI). ASSESSMENT: Three models for differentiating BC + TLS and BC - TLS were developed: 1) a clinical model, 2) a radiomics signature model, and 3) a combined clinical and radiomics (nomogram) model. The overall survival (OS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were compared to evaluate the prognostic value of TLSs. STATISTICAL TESTS: LASSO algorithm and ANOVA were used to select highly correlated features. Clinical relevant variables were identified by multivariable logistic regression. Model performance was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC), and through decision curve analysis (DCA). The Kaplan-Meier method was used to calculate the survival rate. RESULTS: The radiomics signature model (training: AUC 0.766; test: AUC 0.749) and the nomogram model (training: AUC 0.820; test: AUC 0.749) showed better validation performance than the clinical model. DCA showed that the nomogram model had a higher net benefit than the other models. The median follow-up time was 52 months. While there was no significant difference in 3-year OS (P = 0.22) between BC + TLS and BC - TLS patients, there were significant differences in 3-year DFS and 3-year DMFS between the two groups. DATA CONCLUSION: The nomogram model performs well in distinguishing the presence or absence of TLS. BC + TLS patients had higher long-term disease control rates and better prognoses than those without TLS. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Effects of exercise on depression in patients with rheumatic diseases: a systematic review and meta-analysis.

OBJECTIVE: To assess the effects of exercise intervention on depression in rheumatic diseases by means of a meta-analysis. METHODS: The Cochrane Library, Embase, Medline, PubMed, and relevant records were searched. The qualities of randomized controlled trials were evaluated. Meta-analysis of the obtained related data was completed using RevMan 5.3. Heterogeneity was also evaluated with χ2 test and I2. RESULTS: Twelve RCTs were reviewed. Compared with baseline, the meta-analysis results showed that there was significant difference in the improvement of depression assessed by HADs, BDI, CES­D, and AIMS in patients with rheumatic diseases (post exercise vs. baseline, -0.73 [-1.05, -0.4], P < 0.0001, I2 = 0%). In subgroup analysis, although none of these trends in BDI and CES­D subgroups were significant at P < 0.05, there were clear trends towards improvement in depression. CONCLUSION: As an alternative or supplementary treatment, the effect of exercise on rheumatism is obvious. Rheumatologists can consider exercise as an integral part of the treatment of patients with rheumatism.

Single-Cell Profiling of Bone Marrow B Cells and Early B Cell Developmental Disorders Associated With Systemic Lupus Erythematosus.

OBJECTIVE: The peripheral B cell compartment is heavily disturbed in systemic lupus erythematosus (SLE), but whether B cells develop aberrantly in the bone marrow (BM) is largely unknown. METHODS: We performed single-cell RNA/B cell receptor (BCR) sequencing and immune profiling of BM B cells and classified patients with SLE into two groups: early B cell (Pro-B and Pre-B) normal (EBnor) and EB defective/low (EBlo) groups. RESULTS: The SLE-EBlo group exhibited more severe disease activity and proinflammatory status, overaction of type I interferon signaling and metabolic pathways within the B cell compartment, and aberrant BCR repertoires compared with the SLE-EBnor group. Moreover, in one patient with SLE who was initially classified in the SLE-EBlo group, early B cell deficiency and associated abnormalities were largely rectified in a second BM sample at the remission phase. CONCLUSION: In summary, this study suggests that early B cell loss in BM defines a unique pathological state in a subset of patients with SLE that may play an active role in the dysregulated autoimmune responses.

APOE Genotype Modifies the Association between Midlife Adherence to the Planetary Healthy Diet and Cognitive Function in Later Life among Chinese Adults in Singapore.

BACKGROUND: It remains unclear if adherence to the planetary healthy diet (PHD), designed to improve human and environmental health, is associated with better cognitive function in aging, and if this association differs by apolipoprotein E (APOE) genotype. OBJECTIVES: We aimed to examine the association between the PHD pattern and risk of poor cognitive function, and to further assess whether the APOE ε4 allele could modify this association. METHODS: The study included 16,736 participants from the Singapore Chinese Health Study. The PHD score was calculated using data from a validated 165-item food frequency questionnaire at baseline (1993-1998), with higher scores indicating greater adherence to the PHD. Cognitive function was assessed by the Singapore-modified Mini-Mental State Examination at follow-up 3 visits (2014-2016). A subset of 9313 participants had APOE genotype data. Logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders. RESULTS: We identified 2397 (14.3%) cases of poor cognitive function. In the total population, OR (95% CI) of poor cognitive function for each one-SD increment in the PHD score was 0.89 (0.85, 0.93). Carriers of APOE ε4 allele had increased risk of poor cognitive function (OR: 1.36, 95% CI: 1.15, 1.61). There was a significant interaction between the PHD score and the APOE ε4 allele (P-interaction = 0.042). Each one-SD increment in the PHD score was significantly associated with lower risk of poor cognitive function (OR: 0.89; 95% CI: 0.83, 0.96) in non-carriers of APOE ε4 allele, but not in APOE ε4 allele carriers (OR: 1.04, 95% CI: 0.89, 1.23). CONCLUSIONS: Midlife adherence to the PHD was associated with reduced risk of poor cognitive function in later life. However, this was not observed in carriers of APOE ε4 allele who had higher risk of poor cognitive function.

Convenient determination of serum HER-2 status in breast cancer patients using Raman spectroscopy.

Given the significant therapeutic efficacy of anti-HER-2 treatment, the HER-2 status is a crucial piece of information that must be obtained in breast cancer patients. Currently, as per guidelines, HER-2 status is typically acquired from breast tissue of patients. However, there is growing interest in obtaining HER-2 status from serum and other samples due to the convenience and potential for dynamic monitoring. In this study, we have developed a serum Raman spectroscopy technique that allows for the rapid acquisition of HER-2 status in a convenient manner. The established HER-2 negative and positive classification model achieved an area under the curve of 0.8334. To further validate the reliability of our method, we replicated the process using immunohistochemistry and in situ hybridization. The results demonstrate that serum Raman spectroscopy, coupled with artificial intelligence algorithms, is an effective technical approach for obtaining HER-2 status.

5-aminolevulinic acid-based photodynamic therapy in combination with antifungal agents for adult kerion and facial ulcer caused by Trichophyton rubrum.

Dermatophytosis is the most common fungal infectious disease in the world, which is commonly caused by Trichophyton rubrum in China. The traditional therapies for treating dermatophytosis include topical and oral antifungal agents like terbinafine, griseofulvin, and azole antifungal drugs. However, 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) as a new alternative therapy avoids the side effects and drug resistance of traditional antifungal agents. We report two cases diagnosed as kerion and tinea faciei secondary to ulcers with CARD 9 deficiency, both of whom were infected by T.rubrum. They were both successfully treated by ALA-PDT combined with antifungal drugs, providing a feasible strategy for therapeutic choice for adult kerion and ulcer treatment.

Brassisterol A, a new ergosterol from co-cultivation of fungi attenuates neuroinflammation via targeting NLRP3/caspase-1/GSDMD pathway.

Three new ergosterol derivatives brassisterol A-C (1-3) and two new epimeric bicycle-lactones brassictones A and B (4 and 5), were isolated from the co-cultivation of Alternaria brassicicola and Penicillium granulatum. The absolute configurations of these isolates were confirmed by extensive NMR spectra, TD-DFT ECD calculation, and the single crystal XRD data analysis. Amongst the metabolites, compound 1 exhibited potential anti-Parkinson's disease activity in both MPTP-induced zebrafish and MPP+-induced SH-SY5Y cells. Molecular mechanism studies in vitro showed that 1 attenuated the increase of α-synuclein, NLRP3, ASC, caspase-1, IL-1ß, IL-18, and GSDMD expression in the MPP+ induced PD model. Molecular docking in silico simulations exhibited that 1 was well accommodated to one of the binding pockets of NLRP3 8ETR in an appropriate conformation via forming typical hydrogen bonds as well as possessing a high negative binding affinity (-8.97 kcal/mol). Thus, our work suggested that 1 protected dopaminergic cell from neuroinflammation via targeting NLRP3/caspase-1/GSDMD signaling pathway.

Adherence to a Planetary Health Diet, Environmental Impacts, and Mortality in Chinese Adults.

Importance: Although the EAT-Lancet Commission has recently proposed a planetary health diet (PHD) to promote human and environmental health, little is known about how PHD affects environment and mortality risk among an Asian population. Objective: To investigate whether a PHD score is associated with environmental impacts and mortality outcomes in a Chinese cohort living in Singapore. Design, Setting, and Participants: This cohort study used data from the Singapore Chinese Health Study. Eligible participants were without known cardiovascular disease and cancer at baseline; they were recruited between 1993 and 1998 and followed up using record linkage data until 2020. Data were analyzed from September 2022 to April 2023. Exposures: PHD score was calculated based on the reference consumption of 14 dietary components in PHD and individual energy intake assessed using a validated food frequency questionnaire in this cohort. Main Outcomes and Measures: Diet-related environmental impacts were estimated using a food frequency questionnaire. Mortality outcomes (all-cause, cardiovascular disease, cancer, and respiratory disease) were identified via linkage with a nationwide registry. Results: A total of 57 078 participants were included in this study (mean [SD] age, 56.1 (7.9) years; 31 958 women [56.0%]). During a median (IQR) follow-up of 23.4 (18.7-26.2) years, 22 599 deaths occurred. Comparing the highest and lowest quintiles, higher PHD scores were associated with lower greenhouse gas emissions (ß = -0.13 kg CO2 equivalent; 95% CI, -0.14 to -0.12 kg CO2 equivalent), but with higher total water footprint (ß = 0.12 m3; 95% CI, 0.11-0.13 m3) and land use (ß = 0.29 m2; 95% CI, 0.28-0.31 m2). In the adjusted multivariable model, compared with the lowest quintile, participants in the highest quintile of PHD score had lower risk of all-cause mortality (hazard ratio [HR], 0.85; 95% CI, 0.81-0.89), cardiovascular disease mortality (HR, 0.79; 95% CI, 0.73-0.85), cancer mortality (HR, 0.93; 95% CI, 0.86-1.00), and respiratory disease mortality (HR, 0.81; 95% CI, 0.74-0.89). Conclusions and Relevance: In this study of Singapore Chinese adults, higher adherence to PHD was associated with reduced risk of chronic disease mortality. However, environmental impacts were uncertain, as higher adherence was associated with lower greenhouse gas emissions but higher total water footprint and land use.

Factors associated with fertility intention among women with systemic lupus erythematosus in China: A cross-sectional study.

OBJECTIVE: This study aims to explore the status and influencing factors of fertility intention in women of childbearing age with systemic lupus erythematosus (SLE). METHODS: A total of 158 SLE patients admitted to the Affiliated Hospital of Nantong University from February 2021 to February 2022 were selected for a cross-sectional study. The dependent variable in this study was the fertility intention of lupus women of childbearing age, so the questionnaire was selected: "In view of your disease, do you plan to have children? Yes/no" as the measurement statement. Lupus patients were divided into fertility intention groups and non-fertility intention groups. The questionnaire survey comprises following scales: Hospital Anxiety and Depression Scale (HADS), Multidimensional Fatigue Inventory (MFI-20), Female Sexual Distress Scale-Revised (FSDS-R), and others. Independent t-test, one-way ANOVA, Mann-Whitney U test, and binary logistic regression were used for analysis. RESULTS: The results showed that 20.9% of lupus patients in this study had a fertility intention. The fertility intention was associated with age, reproductive history, reproductive concerns, sexual distress, fatigue, family function, social support, depression, and sleep. Binary logistic regression showed that physical fatigue (OR 3.56, 95% CI 1.048-12.07) and personal health (OR 2.50, 95% CI 1.065-5.853) had significant predictors of fertility intention. CONCLUSION: Our study identified a lower fertility intention in SLE patients who had reproductive concerns, sexual distress, family dysfunction, and fatigue. We encourage healthcare institutions to provide counseling services to all the SLE patients who have fertility intention and focus more on those who have requirements for fertility.

Lipidomic analysis identifies long-chain acylcarnitine as a target for ischemic stroke.

INTRODUCTION: Lipid metabolism dysfunction is widely involved in the pathological process of acute ischemic stroke (AIS). The coordination of lipid metabolism between neurons and astrocytes is of great significance. However, the full scope of lipid dynamic changes and the function of key lipids during AIS remain unknown. Hence, identifying lipid alterations and characterizing their key roles in AIS is of great importance. METHODS: Untargeted and targeted lipidomic analyses were applied to profile lipid changes in the ischemic penumbra and peripheral blood of transient middle cerebral artery occlusion (tMCAO) mice as well as the peripheral blood of AIS patients. Infarct volume and neurological deficits were assessed after tMCAO. The cell viability and dendritic complexity of primary neurons were evaluated by CCK8 assay and Sholl analysis. Seahorse, MitoTracker Green, tetramethyl rhodamine methyl ester (TMRM), 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSOX were used as markers of mitochondrial health. Fluorescent and isotopic free fatty acid (FFA) pulse-chase assays were used to track FFA flux in astrocytes. RESULTS: Long-chain acylcarnitines (LCACs) were the lipids with the most dramatic changes in the ischemic penumbra and peripheral blood of tMCAO mice. LCACs were significantly elevated on admission in AIS patients and associated with poor outcomes in AIS patients. Increasing LCACs through a bolus administration of palmitoylcarnitine amplified stroke injury, while decreasing LCACs by overexpressing carnitine palmitoyltransferase 2 (CPT2) ameliorated stroke injury. Palmitoylcarnitine aggravated astrocytic mitochondrial damage after OGD/R, while CPT2 overexpression in astrocytes ameliorated cocultured neuron viability. Further study revealed that astrocytes stimulated by OGD/R liberated FFAs from lipid droplets into mitochondria to form LCACs, resulting in mitochondrial damage and lowered astrocytic metabolic support and thereby aggravated neuronal damage. CONCLUSION: LCACs could accumulate and damage neurons by inducing astrocytic mitochondrial dysfunction in AIS. LCACs play a crucial role in the pathology of AIS and are novel promising diagnostic and prognostic biomarkers for AIS.

Expression profiles of circular RNAs in spermatozoa from aging men.

BACKGROUND: Advanced paternal age (APA) is associated with decreased fertility, but the mechanism underlying APA remains unknown. CircRNAs have been reported to be ideal candidate biomarkers for diagnostic and therapeutic applications in many diseases and are also involved in spermatogenesis. Hence, we aimed to assess the circRNA expression profile of spermatozoa from aging men. METHODS AND RESULTS: We recruited 6 subjects, including 3 in the younger group (men age < 40) and 3 in the APA group (men age ≥ 40). RNA sequencing was exploited to identify the expression profiles of circRNAs between the two groups. The expression levels of circRNAs were validated using real-time quantitative polymerase chain reaction (RT-qPCR). Kyoto Encyclopedia of Genes and Genomes biological pathway analysis and Gene Ontology analysis were performed to evaluate the functions of differentially expressed circRNAs (DE-circRNAs) between the two groups. In total, 18,787 circRNAs were sequenced in the spermatozoa of two groups. Our analysis revealed that there were 1056 downregulated circRNAs and 1228 upregulated circRNAs between the two groups, and KEGG analysis showed they were mainly involved in pathways including the DNA repair signaling pathway, meiotic recombination signaling pathway, and PI3K/AKT signaling pathway. CONCLUSIONS: In conclusion, our study suggested that circRNAs play a vital role in spermatozoa from aging men and provided a fresh perspective on the specific regulatory mechanism of spermatozoa from aging men.

Trends in Self-Reported Adherence to Healthy Lifestyle Behaviors Among US Adults, 1999 to March 2020.

Importance: Adherence to a healthy lifestyle is associated with lower risks of adverse outcomes. However, trends in multiple lifestyle factors and overall healthy lifestyle status among US adults in recent years are unknown. Objective: To examine trends in multiple lifestyle factors and overall healthy lifestyle among US adults. Design, Setting, and Participants: This serial cross-sectional study used nationally representative data from 10 National Health and Nutrition Examination Survey (NHANES) cycles (nine 2-year cycles from 1999 to 2016 and 1 combined cycle from 2017 to March 2020) among adults 20 years or older. Data were analyzed from December 10, 2021, to January 11, 2023. Exposure: Survey cycle. Main Outcomes and Measures: Five healthy lifestyle factors: never smoking, moderate or lighter alcohol consumption (for women: ≤7 drinks/wk; for men: ≤14 drinks/wk), healthy diet (Healthy Eating Index-2015 scores ≥60.0), sufficient physical activity (≥150 min/wk of equivalent moderate physical activity), and healthy weight (body mass index [calculated as weight in kilograms divided by height in meters squared] 18.5-24.9). Results: A total of 47 852 adults were included in this study. The weighted mean [SE] age was 47.3 [0.2] years; 24 539 (weighted proportion, 51.5%) were women. From the 1999-2000 cycle to the 2017 to March 2020 cycle, the estimated prevalence of the 5 lifestyle factors showed divergent trends, with increasing prevalence of never smoking (from 49.4% [95% CI, 46.4%-52.4%] to 57.7% [95% CI, 55.5%-59.9%]; difference, 8.2% [95% CI, 4.5%-12.0%]), healthy diet (from 19.3% [95% CI, 16.0%-22.6%] to 24.5% [95% CI, 21.5%-27.5%]; difference, 5.2% [95% CI, 0.8%-9.7%]), and sufficient physical activity (from 55.7% [95% CI, 51.8%-59.6%] to 69.1% [95% CI, 67.2%-71.1%]; difference, 13.4% [95% CI, 9.0%-17.8%]), while prevalence of healthy weight decreased from 33.1% (95% CI, 30.5%-35.6%) to 24.6% (95% CI, 22.6%-26.7%; difference, -8.4% [95% CI, -11.8% to -5.1%]) (all P < .001 for trend). Meanwhile, there was no significant trend in moderate or lighter alcohol consumption. Overall, the estimated prevalence of at least 4 healthy lifestyle factors increased from 15.7% (95% CI, 12.8%-18.7%) to 20.3% (95% CI, 17.8%-22.7%; difference, 4.5% [95% CI, 0.7%-8.4%]; P < .001 for trend). Disparities in healthy lifestyle were widened by age group, with little improvement among adults 65 years and older (difference, 0.04% [95% CI, -4.28% to 4.35%]). There were persistent disparities in healthy lifestyle by race and ethnicity, educational level, and income level. Conclusions and Relevance: The findings of this cross-sectional study of NHANES data over a 22-year period suggest diverse change patterns across 5 healthy lifestyle factors and a modest improvement in overall lifestyle existed among US adults, with worsening or persistent disparities in lifestyle.