Sex-specific Differences Research Articles

Role of myofiber-specific FoxP1 in pancreatic cancer-induced muscle wasting.

Cancer cachexia affects up to 80% of cancer patients and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored. To address this gap, we generated a conditional mouse line with myofiber-specific ablation of FoxP1 (FoxP1SkmKO) and found that in cancer-free mice, deletion of FoxP1 in skeletal myofibers resulted in increased myofiber size in both males and females, with a significant increase in muscle mass in males. In response to murine KPC pancreatic tumor burden, we found that myofiber-derived FoxP1 is required for cancer-induced muscle wasting and diaphragm muscle weakness in male mice. In summary, our findings identify myofiber-specific FoxP1 as a negative regulator of skeletal muscle with sex-specific differences in the context of cancer.

Sex differences in overweight and obese patients undergoing high-power short-duration pulmonary vein isolation for atrial fibrillation: an observational cohort study.

Atrial fibrillation (AF) is the most common heart rhythm disorder worldwide. As treatment methods evolve, optimizing personalized therapy based on patient characteristics, such as sex, becomes crucial. This study investigates sex differences in high-power short-duration (HPSD) pulmonary vein isolation (PVI) in overweight and obese patients. We analyzed data from 189 overweight and obese patients who underwent HPSD PVI for AF, comparing demographic information, procedural details, outcomes, and complications between male and female patients. Our analysis revealed fewer women underwent PVI compared to men, with women typically older and showing more pronounced changes in the left atrial substrate. Despite these differences, the safety and efficacy of PVI were comparable between sexes, including in the BMI ≥ 30kg/m2 subgroup and after age adjustment. The findings emphasize the need for early AF screening in women to prevent treatment delays and show that considering sex-specific differences in fat distribution can improve procedural outcomes. These insights support the need for tailored management strategies for AF in overweight and obese populations, addressing sex-specific risks and anatomical variations.

Parent-child interaction frequency: associations with age, sibling presence, and child health.

Parent-child interaction plays a crucial role in child development. This study investigated associations between the frequency of parent-child-interactions and sociodemographic characteristics (age, sex, socio-economic status, family structure, number and age of siblings), physical and psychological symptoms in children, and mental health of parents. The frequencies of 11 different parent-child interactions (shared reading, singing, moving, painting, building, puzzle, playing ball, role games, language games, number games and talking about problems) were assessed in 739 children aged 2-6.5 years-old using a standardised parental questionnaire, within a population-based cohort study in Leipzig, Germany. Physical and psychological symptoms were investigated using the HBSC Symptom-Checklist and parental depression symptoms using the Patient Health Questionnaire. We applied regression analyses to assess associations between variables. Shared reading was the parent-child interaction reported most frequently, with an average occurrence of several times a week. Number games were reported least frequently, with an average occurrency of every two weeks. Fewer parent-child interactions were significantly associated with higher child age, higher number of siblings, presence of older siblings and a lower level of physical and psychological symptoms. The other variables (sex, SES, living situation, presence of younger siblings or both (younger and older), depression symptoms of parents) were not significantly associated with the frequency of parent-child interactions. The findings show that age of children and number as well as age of siblings at home may shape the frequency of parent-child interaction in preschool children. In addition, the findings suggest that parent-child interaction might be related to the health of children rather than the (mental) health of parents. This study assessed the associations between the frequency of different types of parent-child interactions and sociodemographic as well as health-related parameters in a large sample of children. There still exist sex-specific differences in the frequency of parent-child interactions related to traditional role models of girls and boys. A higher frequency of parent-child interactions is associated with more physical and psychological symptoms in children. Parent-child interactions are less frequent in families with more children, especially when older siblings are present.

Characterizing DNA methylation and hydroxymethylation in cord blood and identifying sex-specific differences using the Illumina EPIC array

Characterizing DNA methylation and hydroxymethylation in cord blood and identifying sex-specific differences using the Illumina EPIC array

Meningiomas: Sex-Specific Differences and Prognostic Implications of a Chromosome X Loss.

Meningiomas are the most common primary intracranial tumours in adults. Several studies proposed new stratification systems with a more accurate risk prediction than the WHO grading, e.g. based on methylation and copy number variations (CNVs). Yet, common shortcomings in these analyses are either a lack of stratification by sex of patients or excluding the gonososmes from CNV assessment. Within this study, DNA methylation array data from 7,424 meningioma samples as well as targeted sequencing, clinical annotations and morphology subtyping of 796 samples were examined for differences between females and males regarding mutations, methylation classes, copy number variations and histology. Meningiomas from females accounted for about 53 % of the malignant tumours and present a loss of one X chromosome in 57 % of these malignant cases. In the group of benign tumours, females comprised about 75 % of the patients. Therein, a loss of one X chromosome was detected in only about 10 % of the cases but was associated with a significantly worse progression free survival. Although genomic instability is a common feature of malignant meningiomas, particularly loss of the X chromosome in tumours of female patients in otherwise histologically and molecularly low-risk tumours confers higher risk. Hence, the gonosomal copy number status can be leveraged for increased diagnostic accuracy.

CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction.

Microgliosis plays a critical role in diet-induced hypothalamic inflammation. A few hours after a high-fat diet (HFD), hypothalamic microglia shift to an inflammatory phenotype, and prolonged fat consumption leads to the recruitment of bone marrow-derived cells to the hypothalamus. However, the transcriptional signatures and functions of these cells remain unclear. Using dual-reporter mice, this study reveals that CX3CR1-positive microglia exhibit minimal changes in response to a HFD, while significant transcriptional differences emerge between microglia and CCR2-positive recruited myeloid cells, particularly affecting chemotaxis. These recruited cells also show sex-specific transcriptional differences impacting neurodegeneration and thermogenesis. The chemokine receptor CXCR3 is emphasized for its role in chemotaxis, displaying notable differences between recruited cells and resident microglia, requiring further investigation. Central immunoneutralization of CXCL10, a ligand for CXCR3, resulted in increased body mass and decreased energy expenditure, especially in females. Systemic chemical inhibition of CXCR3 led to significant metabolic changes, including increased body mass, reduced energy expenditure, elevated blood leptin, glucose intolerance, and decreased insulin levels. This study elucidates the transcriptional differences between hypothalamic microglia and CCR2-positive recruited myeloid cells in diet-induced inflammation and identifies CXCR3-expressing recruited immune cells as protective in metabolic outcomes linked to HFD consumption, establishing a new concept in obesity-related hypothalamic inflammation.

CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction

Microgliosis plays a critical role in diet-induced hypothalamic inflammation. A few hours after a high-fat diet (HFD), hypothalamic microglia shift to an inflammatory phenotype, and prolonged fat consumption leads to the recruitment of bone marrow-derived cells to the hypothalamus. However, the transcriptional signatures and functions of these cells remain unclear. Using dual-reporter mice, this study reveals that CX3CR1-positive microglia exhibit minimal changes in response to a HFD, while significant transcriptional differences emerge between microglia and CCR2-positive recruited myeloid cells, particularly affecting chemotaxis. These recruited cells also show sex-specific transcriptional differences impacting neurodegeneration and thermogenesis. The chemokine receptor CXCR3 is emphasized for its role in chemotaxis, displaying notable differences between recruited cells and resident microglia, requiring further investigation. Central immunoneutralization of CXCL10, a ligand for CXCR3, resulted in increased body mass and decreased energy expenditure, especially in females. Systemic chemical inhibition of CXCR3 led to significant metabolic changes, including increased body mass, reduced energy expenditure, elevated blood leptin, glucose intolerance, and decreased insulin levels. This study elucidates the transcriptional differences between hypothalamic microglia and CCR2-positive recruited myeloid cells in diet-induced inflammation and identifies CXCR3-expressing recruited immune cells as protective in metabolic outcomes linked to HFD consumption, establishing a new concept in obesity-related hypothalamic inflammation.

Sex-dependent variability of isoniazid and rifampicin serum levels in patients with tuberculosis.

Drug-sensitive TB (DS-TB) is treated with isoniazid, rifampicin, ethambutol, and pyrazinamide. Factors like fast-metabolizing enzymes, malabsorption, and drug interactions can influence serum drug levels. Current TB treatment guidelines recommend weight-adapted dosing without considering sex differences. This study examines drug levels of isoniazid and rifampicin in TB patients treated between 2019 and 2023 at our center focusing on sex-specific aspects. Patients diagnosed with TB and available serum levels of isoniazid or rifampicin between 2019 and 2023 were retrospectively identified. Serum levels were measured using liquid chromatography-mass spectrometry and high-performance liquid chromatography. Patients were stratified by sex and a linear regression mixed effect model was used to assess predictors for different serum levels. The study included 281 single therapeutic drug monitoring (TDM) measurements from 59 patients (28 women, 47.5%). For isoniazid, no sex-specific differences in serum drug levels were identified. On the other hand, female sex was a significant predictor of higher rifampicin plasma levels (coefficient 4.16, 95% CI 0.74-7.59, p = 0.009). Only 38.2% of rifampicin serum level measurements in male patients were within target range, the majority (40/68, 58.8%) were below range and only 2 (2.9%) TDM-levels were above range. Women displayed higher overall rifampicin serum levels than men (median 13.7mg/l vs. 7.1mg/l, p = 0.04), although weight adjusted doses were not significantly different (median 10.0mg/kg vs. 9.8mg/kg p = 0.56). Adverse effects were noted in 42.9% (42/98) of measurements in women and 29.5% (54/183) of measurements in men (p = 0.03). Rifampicin levels were significantly lower in men compared to women, despite weight-adjusted dosing. Clinicians should consider TDM and potential sex differences when treating patients with TB.

Abstract 4137646: Transcriptomic Profiling of Human Myocardium at Sudden Death to Define Vulnerable Substrate for Lethal Arrhythmias

Background: While some chronic pathological substrates for sudden cardiac death (SCD) are well-known (e.g., coronary disease and left ventricular [LV] dysfunction), the vulnerable myocardial state predisposing to fatal arrhythmia remains a critical barrier to near-term SCD prevention. Hypothesis: Myocardium of autopsy-defined SCDs exhibit distinct expression profiles vs. non-cardiac sudden deaths and trauma deaths that reflect its acute vulnerable state in the hours to days before SCD, as expression arrests upon death. Goals/Aims: Define the vulnerable myocardial substrate for lethal arrhythmia by targeted RNA profiling. Methods: We used autopsy to adjudicate arrhythmic from non-arrhythmic causes in 1,265 sudden deaths in San Francisco from 2011-2018. We performed a transcriptomic evaluation of LV sampled at the time of SCD from 245 consented cases using a curated panel of 448 genes with known or hypothesized association with SCD. Results: Comparison between Arrhythmic (n=129) and Non-Arrhythmic (n=116) cohorts revealed 31 differentially upregulated and 36 downregulated genes (p-adj<0.05), related to collagen-containing extracellular matrix (upregulation of FAP , FMOD , LTBP2 ), ion transport (upregulation of KCNA5 and KCNN3 , and downregulation of KCNJ8, KCNK1, KCNJ5 ), and contraction (downregulation of MYH6 ). Fibrosis-related genes showed the highest magnitude increased expression in Arrhythmic vs. Non-arrhythmic deaths and vs. published transcriptomes from end-stage heart failure. After molecular stratification by known markers for mature ( COL1A1, COL1A2, COL3A1) and active ( POSTN , MEOX1 ) fibrosis, cases with highest expression of both had the highest proportion of arrhythmic cause of death (27/36 [75%]) vs. cases with low expression of both (87/181 [38%], p=0.006) or vs. mature only (10/14 [71%]) or active only (5/14 [36%]). Activated fibroblast gene expression was enriched in Arrhythmic female vs. Arrhythmic male cases, among other sex-specific differences in ion channel and myosin (upregulation of SCN4B , SCN8A , KCNAB1 in females, KCNJ4 and MYH7B in males) expression. Conclusions: RNA profiling of myocardium at SCD identifies active fibrosis, undetectable by conventional clinical methods, in the presence of fixed scar and selected ion channel dysregulation (more pronounced among female cases) as an acute vulnerable substrate for fatal arrhythmias, and may identify patients at elevated near-term risk for SCD and novel pathways for intervention.

Abstract 4138397: Gender Difference in Prevalence and Survival of Pulmonary Hypertension: A Prospective Cohort Study of 502,173 UK Biobank Participants

Background: Research into pulmonary hypertension (PH) reveals significant sex-based disparities in long-term survival rates. Notably, women, despite being more susceptible to PH, often experience better survival outcomes than men—a phenomenon possibly linked to the "estrogen paradox." This study leverages the comprehensive UK Biobank to examine the role of sex in influencing these outcomes. By exploring differences in PH incidence and survival rates across genders, our research aims to provide a deeper understanding of the mechanisms at play and inform more effective, gender-specific analysis. Methods: This prospective cohort study utilized data from the UK Biobank, with baseline assessment between 2006 and 2010 and follow-up until November 30, 2023, for England and Scotland, and May 31, 2022, for Wales. Through diagnostic codes, medical records, and imaging studies, 3,296 PH cases and 497,580 cases without PH were identified . We followed them for the mortality rates over a period of 10 years. Survival analysis was conducted using Kaplan-Meier curves and Cox proportional hazards models to assess sex-specific survival differences, adjusting for confounders like age, BMI, ethnic, menopause, smoking status, and comorbidities. Results: During 7,978,349 person-years of follow-up, of 502,173 participants in this prospective cohort, 3,296 were diagnosed with PH, while 497,580 did not receive the PH diagnosis. The prevalence of PH in the male cohort and the female cohort were 0.76% (1743 of 228,991 men) and 0.57% (1553 of 273,182 women), respectively, with significant difference between the two groups (p<0.001). In the PH cohort, the mortality rates of patients were 47.06%. In the male patients with PH, the mortality rate was significantly higher than the female PH patients (51.78% vs. 41.53%, p<0.001). After stratifying women into menopause and no-menopause group, Kaplan-Meier curves showed that even the age of male group was significantly younger than the menopause group (p<0.001), the male still had worse survival situation. Conclusion: To conclude, the prevalence of PH in the male participants was significantly higher than the female participants. While the mortality rate in the male participants was also significantly higher than the female participants.

Assessment of Prenatal Transportation Stress and Sex on Gene Expression Within the Amygdala of Brahman Calves

As the amygdala is associated with fear and anxiety, it is important to determine the potential effects of gestational stressors on behavior and stress responses in offspring. The objective of this study was to investigate the effects of prenatal transportation stress on amygdala gene expression in 25-day-old Brahman calves, focusing on sex-specific differences. Amygdala tissue samples from prenatally stressed (PNS) and control bull and heifer calves were analyzed using RNA sequencing. A thorough outlier detection process, utilizing visual inspection of multidimensional scaling plots, robust principal component analysis, and PCAGrid methods, led to the exclusion of 5 of 32 samples from subsequent analyses. Differential expression analysis revealed no significant treatment differences between the control and PNS groups within either sex. However, sex-specific differences in gene expression were identified in both the control and PNS groups. The control group showed seven differentially expressed genes between sexes, while ten were identified between PNS males and females, with seven located on the X chromosome. Among these was the ubiquitin-specific peptidase 9 X-linked gene, which plays a role in neurodevelopmental pathways. When comparing males to females, regardless of treatment, a total of 58 genes were differentially expressed, with 45 showing increased expression in females. Gene enrichment analysis indicated that many differentially expressed genes are associated with infectious disease-related pathways. Future research should explore amygdala size and functional responses to various postnatal stimuli.

EPCO-49. SEX-SPECIFIC CHROMATIN REMODELING DRIVES TUMORIGENESIS IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most prevalent primary malignant brain cancer and has higher incidence and lower survival in males compared to females. The SWI/SNF chromatin remodeling complexes, including canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), play a critical role in multiple cancers including gliomas. However, their role in gliomagenesis and progression remains largely unknown. We analyzed 18 human glioma specimens for BAF complex mRNA expression by CNS WHO grade and used these data to guide CRISPRi knockdown of BAF components in syngeneic murine male and female GBM astrocytes. BAF complex knockdown revealed marked sex-specific differences in proliferation. Specifically, Smarce1 or Smarcb1 knockdown (cBAF & PBAF) resulted in increased growth in male astrocytes but decreased growth in females. Brd7 (PBAF) knockdown enhanced growth in both sexes, while Brd9 (ncBAF) had minimal impact. We utilized extreme limiting dilution analysis (ELDA) to assess the clonogenic potential of GBM cells with depleted BAF components. Notably, cells with BRD7 knockdown displayed enhanced sphere-forming capacity in both male and female cells. Male cells with Smarce1or Smarcb1 knockdown showed increased clonogenic frequency, whereas females with Smarce1 knockdown had a marked reduction in sphere formation. Brd9 knockdown did not affect the sphere-forming capacity in male or female cells, in part due to compensatory plasticity of an alternate BAF complex. Epitranscriptomic analysis is ongoing and demonstrates sex-specific differences in chromatin accessibility and downstream gene expression programs based on BAF complex knockdown. Immunoprecipitation coupled with mass spectrometry was performed to elucidate the structure and assembly of the BAF complex in GBM cells. Understanding sex-specific mechanisms of BAF chromatin remodeling complex in glioma pathogenesis may yield critical insights for the development of precision therapeutics that have the potential to improve patient outcomes.

Exploring Sex-Based Neuropsychological Outcomes in Pediatric Brain Cancer Survivors: A Pilot Study

Background: The increasing survival rates among pediatric cancer patients underscore the critical need to understand the long-term psychosocial impacts of cancer treatments, such as cisplatin and carboplatin. While these treatments are lifesaving, they may pose risks to neurodevelopmental processes. Despite the substantial body of research highlighting cognitive impairments associated with cancer treatments, there remains a gap in understanding how these effects differ by sex. As sex differences could inform tailored interventions and support mechanisms for affected individuals, this pilot study aimed to examine the sex differences in neuropsychological outcomes in patients treated for brain cancer with cisplatin and/or carboplatin. Methods: Our study employed rigorous/structured neuropsychological assessments to evaluate executive functions in pediatric cancer survivors treated with cisplatin and/or carboplatin. We utilized the BRIEF and TOL tests to assess the key domains of executive function, including inhibitory control, cognitive flexibility, and problem-solving abilities. Additionally, psychosocial factors were evaluated using the Resiliency Scale to measure resilience and the PAT test to assess family psychosocial risk. Results: In our cohort of 17 patients, significant sex differences emerged, where males outperformed females in areas such as inhibitory control, impulse regulation, and strategic planning. Conclusions: These findings highlight the complexity of cognitive outcomes in pediatric cancer survivors. Understanding sex-specific differences is essential for developing tailored interventions that optimize cognitive and psychosocial outcomes. Future research should focus on larger cohorts and longitudinal studies to validate these findings and guide targeted interventions to improve survivorship outcomes.

DISP-04. SEX DIFFERENCES IN LUNG CANCER BRAIN METASTASES ADVERSE EVENTS

Abstract While sexual dimorphism is evident among adverse events (AEs) in response to treatments for many cancers, including brain tumors, little is known about sexual dimorphism among AE in brain metastases (BrM). As over 50% of BrM cases arise from lung cancer (LC), we examined sex differences in AEs associated with LC-BrM among individuals in the SEER-Medicare dataset aged ≥66 years at the time of LC diagnosis. Multivariable logistic regression models adjusted for demographic variables and Elixhauser comorbidity scores were used to analyze sex differences in AEs among individuals with BrM derived from primary LC. Analyses were stratified by the following histological subtypes: small-cell, adenocarcinoma, squamous cell carcinoma, or other non-small cell carcinomas. Additional variables analyzed included BrM treatment, age at BrM diagnosis, and year of diagnosis (at or before 2013/after 2013) to account for the introduction of targeted therapies. Differences in AE profiles, based by sex, in individuals diagnosed with LC-BrM were observed. Females diagnosed after 2013 with either small-cell, squamous cell, or other non-small cell carcinoma BrMs were more likely to experience headaches compared to males. Males diagnosed after 2013 with adenocarcinoma were more likely to experience brain herniation compared to females. Additionally, females aged 76 and older with small-cell BrM demonstrated an elevated risk of developing vision difficulties relative to males, whereas no significant sex difference observed in those under 76 years. Risk of most AEs decreased across all histological subtypes with receiving treatment after BrM diagnosis when compared to no treatment. This study underscores the existence of sex-specific differences in AEs among individuals aged 66 years and older diagnosed with LC-BrM. The AEs observed varied across histological subtypes, age cohorts, year of diagnosis, and treatment. Notably, receipt of treatment demonstrates consistent reduction in AE risk across all histological subgroups, underscoring the therapeutic benefit of treatment.

Sex-disaggregated analysis of central venous catheter-related bloodstream infections in patients with cancer.

Men are generally more susceptible to bacterial infections than women. Central venous catheters (CVCs), often used to administer systemic treatment in patients with cancer, are an important source of infection. However, little is known about sex-specific differences of CVC-related bloodstream infections (CRBSIs) in patients with cancer. This study aimed to compare CRBSIs in men vs. women in a large cohort of patients with cancer. Data were derived from the SECRECY registry including non-selected patients with centrally inserted non-tunneled internal jugular or subclavian vein CVCs in 10 hematology and oncology sites in Germany. Only CRBSIs classified as definite CRBSI (dCRBSI) or probable CRBSI were included, and the combination of both was summarized as dpCRBSI. CVCs were matched 1:1 for underlying disease, anatomic site of CVC insertion, type of CVC dressing, antimicrobial coated CVC, complicated CVC insertion and CVC in situ time by propensity score matching (PSM). Endpoints were CRBSI rates and incidences in CVCs inserted in men vs. women. A total of 5075 CVCs registered from March 2013 to March 2024 were included in the analysis, of which 3024 comprises the PSM cohort. 1512 (50.0%) CVCs were inserted in men. Underlying diseases mainly were hematological malignancies (96.4%). While there was no statistically significant difference between men and women in the dCRBSI rate (5.4% vs. 4.1%; p=0.12) and the dCRBSI incidence (3.8 vs. 2.9/1000 CVC days; p=0.11), the rate of dpCRBSI (9.9% vs. 6.7%; p=0.002) and the dpCRBSI incidence (7.0 vs. 4.7/1000 CVC days; p=0.002) were significantly higher in men vs. women. The proportion of coagulase-negative staphylococci as causative agent of both dCRBSI and dpCRBSI was higher in men than in women (58.8% vs. 41.2%; p=0.07, and 61.5% vs. 38.5%; p=0.002, respectively). A multivariable regression revealed neutropenia as an independent risk factor for dCRBSI and male sex as risk factor for dCRBSI and dpCRBSI. In patients with hematological malignancies, men have a higher risk of CRBSI than women. This finding may be attributed to the high number of jugular vein inserted CVCs which in men may be associated with higher rates of skin colonization than in women. Special preventive measures such as earlier removal of CVCs in men may be studied in future.

Sex differences in expression of CGRP family of receptors and ligands in the rat trigeminal system

BackgroundCalcitonin gene-related peptide (CGRP) is part of the calcitonin peptide family, which includes calcitonin (CT), amylin (AMY), and adrenomedullin (ADM). CGRP and its receptor are highly present in the trigeminovascular system (TVS). Recent research suggests that other members of the calcitonin family could be feasible therapeutic targets in the treatment of migraine. The present study aims to elucidate the distribution of ADM, AMY, CT, and their receptors in the rat TVS, and to explore potential sex differences in their expression.MethodsTrigeminal ganglia (TG) were dissected from male and female adult rats. Protein and gene expression were assessed through immunohistochemistry and RT-qPCR. Additionally, the dura mater was isolated for further investigation of protein expression and fiber localization using immunohistochemistry.ResultsQuantitative gene expression analysis revealed the presence of all genes in male and female TGs, except for calcitonin receptor (CTR). Notably, CGRP mRNA levels in TG were several folds higher than those of other genes. The receptor activity-modifying protein-1 (RAMP1) mRNA levels were significantly higher in female compared to male.No AMY or CT immunoreactivity was observed in the TVS. In contrast, immunoreactivity for ADM, CGRP, RAMP1, CTR, and calcitonin-like receptor (CLR) were observed in the cytoplasm of TG neurons. Immunoreactive Aδ-fibers storing RAMP1, ADM and CLR were also identified. RAMP2 and RAMP3 were expressed in nucleus of TG neurons and in satellite glial cells. Furthermore, RAMP1 and CLR were co-localized with CASPR in the nodes of Ranvier located in Aδ-fibers.ConclusionsThis study provides valuable insights into the distribution of the CGRP family of peptides and their receptors in the TVS. CGRP mRNA levels in the TG were markedly higher than those of other genes, demonstrating the key role of CGRP. The co-localization of CLR and RAMP1 on Aδ-fibers with CASPR suggests a potential role for this receptor in modulating trigeminal nerve function and neuronal excitability, with implications for migraine pathophysiology. Additionally, RAMP1 mRNA levels were significantly higher in female TG compared to males, indicating sex-specific differences in gene expression. These findings underscore the need for further research into the functional significance of gender-related variations.

Multi-organ gene expression analysis and network modeling reveal regulatory control cascades during the development of hypertension in female spontaneously hypertensive rat.

Hypertension is a multifactorial disease with stage-specific gene expression changes occurring in multiple organs over time. The temporal sequence and the extent of gene regulatory network changes occurring across organs during the development of hypertension remain unresolved. In this study, female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats were used to analyze expression patterns of 96 genes spanning inflammatory, metabolic, sympathetic, fibrotic, and renin-angiotensin (RAS) pathways in five organs, at five time points from the onset to established hypertension. We analyzed this multi-dimensional dataset containing ~15,000 data points and developed a data-driven dynamic network model that accounts for gene regulatory influences within and across visceral organs and multiple brainstem autonomic control regions. We integrated the data from female SHR and WKY with published multiorgan gene expression data from male SHR and WKY. In female SHR, catecholaminergic processes in the adrenal gland showed the earliest gene expression changes prior to inflammation-related gene expression changes in the kidney and liver. Hypertension pathogenesis in male SHR instead manifested early as catecholaminergic gene expression changes in brainstem and kidney, followed by an upregulation of inflammation-related genes in liver. RAS-related gene expression from the kidney-liver-lung axis was downregulated and intra-adrenal RAS was upregulated in female SHR, whereas the opposite pattern of gene regulation was observed in male SHR. We identified disease-specific and sex-specific differences in regulatory interactions within and across organs. The inferred multi-organ network model suggests a diminished influence of central autonomic neural circuits over multi-organ gene expression changes in female SHR. Our results point to the gene regulatory influence of the adrenal gland on spleen in female SHR, as compared to brainstem influence on kidney in male SHR. Our integrated molecular profiling and network modeling identified a stage-specific, sex-dependent, multi-organ cascade of gene regulation during the development of hypertension.

Antibiotic exposure and risk of overweight/obesity in children: a biomonitoring-based study from eastern Jiangsu, China

ObjectiveTo describe antibiotic exposure in children and explore its association with overweight/obesity.MethodsIn June 2022, 328 kindergarten and primary school children were selected from Nantong city in Jiangsu Province. Questionnaires were distributed, and morning urine samples were obtained. Total urinary concentrations of 41 antibiotics were measured using ultra-performance liquid chromatography and tandem mass spectrometry. The rates of antibiotic exposure were expressed as percentages (%), specific percentiles (P95 and P99), and the maximum values were used to describe the concentration of antibiotics. The association between urinary antibiotic creatinine-adjusted and overweight/obesity was analyzed using logistic regression.ResultsA total of 328 children were initially recruited, of which 295 aged 3–8 years met the inclusion criteria and were finally included in the study. The biomonitoring results revealed that 35 antibiotics were detected, with a total detection frequency of 98.31%. Among the included children, 24.75% were classified as overweight/obesity. Multinomial logistic regression analyses revealed significant associations between overweight/obese and exposure to veterinary antibiotics (VAs) and preferred veterinary antibiotics (PVAs). After adjusting for various overweight/obesity-relevant variables, higher exposure to sulfamethoxazole [OR = 2.35, 95% confidence interval (CI):1.17–4.70], norfloxacin (OR = 2.66, 95% CI: 1.01–7.08), and fluoroquinolones (OR = 1.97, 95% CI: 1.02–3.78) were significantly associated with overweight/obesity (p < 0.05). In addition, after stratification by sex and adjustment for confounding variables, sex-specific differences were observed in the association between antibiotic exposure and overweight/obesity. Notably, these associations were predominantly observed among boys.ConclusionChildren were extensively exposed to antibiotics. Exposure to certain types of veterinary antibiotics and preferred veterinary antibiotic exposure, mainly through food or drinking water, are associated with an increased risk of overweight/obesity in children.

Single-cell transcriptome unveils unique transcriptomic signatures of human organ-specific endothelial cells.

The heterogeneity of endothelial cells (ECs) across humantissues remains incompletely inventoried. We constructed an atlas of > 210,000 ECs derivedfrom 38 regions across 24 human tissues. Our analysis reveals significant differences in transcriptome, phenotype, metabolism and transcriptional regulationamong ECs from various tissues. Notably,arterial, venous, and lymphatic ECs shared more commonmarkers in multiple tissues than capillary ECs, which exhibited higher heterogeneity.This diversity in capillary ECs suggests their greater potential as targets for drug development. ECs from different tissues and vascular beds were found to be associated with specific diseases. Importantly,tissue specificity of EC senescence is moredetermined by somatic site than by tissue type (e.g. subcutaneus adipose tissue andvisceral adipose tissue). Additionally, sex-specific differences in brain EC senescencewere observed. Our EC atlas offers valuble resoursce for identifying EC subclusters in single-cell datasets from body tissues or organoids, facilitating thescreen oftissue-specific targeted therapies, and serving as a powerful tool for future discoveries.

Osteocytes contribute to sex-specific differences in osteoarthritic pain

Osteocytes contribute to sex-specific differences in osteoarthritic pain