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Background The association of evening chronotype with cardiometabolic disease has been well established. However, the extent to which circadian rhythm disturbances independently result in risk remains unclear. This study aimed to investigate the cross-sectional and prospective longitudinal associations between chronotype and cardiometabolic risk among Chinese young adults. Methods From April to May 2019, a total of 1 135 young adults were selected to complete the self-administered questionnaire, and 744 fasting blood samples were collected to quantify cardiometabolic parameters. From April to May 2021, 340 fasting blood samples were collected to quantify cardiometabolic parameters. The Morning and Evening Questionnaire 5 (MEQ-5) was used to assess chronotype. The cardiometabolic (CM)-risk score was the sum of standardized Z scores based on gender for the 5 indicators: waist circumference (WC), mean arterial pressure (MAP), triglyceride (TG), homeostasis model assessment for insulin resistance (HOMA-IR), and high-density lipoprotein cholesterol (HDL-C), where the HDL-C is multiplied by-1. The generalized linear model was used to determine the cross-sectional and prospective longitudinal associations between chronotype and each cardiometabolic parameter. Results Cross-sectional association analysis showed that lower MEQ-5 scores were correlated with higher fasting insulin ( β =-1.420, 95% CI : -2.386~-0.453), higher HOMA-IR ( β =-0.301, 95% CI : -0.507~-0.095), and higher CM risk score ( β =-0.063, 95% CI : -0.122~-0.003), even after adjustment for covariates. Prospective longitudinal association analysis also showed that lower MEQ-5 scores were associated with 2 years later higher fasting glucose ( β =-0.018, 95% CI : -0.034~-0.003), higher fasting insulin ( β =-0.384, 95% CI : -0.766~-0.003), higher HOMA-IR ( β =-0.089, 95% CI : -0.176~-0.002), and higher CM-risk score ( β =-0.109, 95% CI : -0.214~-0.003) after adjustment for covariates. Conclusions Evening chronotype was significantly correlated with higher CM risk among young adults. Our findings suggest that biologically and socially affected sleep timing misalignment is a contributing factor to cardiovascular disease risk.

FANCI is an essential component of Fanconi anemia pathway, which is responsible for the repair of DNA interstrand cross-links (ICLs). As an evolutionarily related partner of FANCD2, FANCI functions together with FANCD2 downstream of FA core complex. Currently, growing evidences showed that the essential role of FA pathway in male fertility. However, the underlying mechanisms for FANCI in regulating spermatogenesis remain unclear. In the present study, we found that the male Fanci −/− mice were sterile and exhibited abnormal spermatogenesis, including massive germ cell apoptosis in seminiferous tubules and dramatically decreased number of sperms in epididymis. Besides, FANCI deletion impaired maintenance of undifferentiated spermatogonia. Further investigation indicated that FANCI was essential for FANCD2 foci formation and regulated H3K4 and H3K9 methylation on meiotic sex chromosomes. These findings elucidate the role and mechanism of FANCI during spermatogenesis in mice and provide new insights into the etiology and molecular basis of nonobstructive azoospermia.

The transcription factor p63 guards genome integrity in the female germline, and its mutations have been reported in patients with premature ovarian insufficiency (POI). However, the precise contribution of the TP63 gene to the pathogenesis of POI needs to be further determined. Here, in 1,030 Chinese patients with POI, we identified 6 heterozygous mutations of the TP63 gene that impaired the C-terminal transactivation-inhibitory domain (TID) of the TAp63α protein and resulted in tetramer formation and constitutive activation of the mutant proteins. The mutant proteins induced cell apoptosis by increasing the expression of apoptosis-inducing factors in vitro. We next introduced a premature stop codon and selectively deleted the TID of TAp63α in mice and observed rapid depletion of the p63+/ΔTID mouse oocytes through apoptosis after birth. Finally, to further verify the pathogenicity of the mutation p.R647C in the TID that was present in 3 patients, we generated p63+/R647C mice and also found accelerated oocyte loss, but to a lesser degree than in the p63+/ΔTID mice. Together, these findings show that TID-related variants causing constitutive activation of TAp63α lead to POI by inducing oocyte apoptosis, which will facilitate the genetic diagnosis of POI in patients and provide a potential therapeutic target for extending female fertility.

Background Physical activity (PA) deficiency, outdoor time reduction during college have been associated with higher cumulative physiological burden as measured by allostatic load (AL). Therefore, the present research sought to analyze the independent and interaction effects of PA and outdoor time on AL in college students. Methods A cross-sectional survey was conducted in two universities from April to May 2019. Self-assessment questionnaire and International Physical Activity Questionnaire Short Version (IPAQ-SF) were used in the investigation, AL level was assessed according to the results of biochemical examination, blood pressure and human body morphological measurements. Binary Logistic Analysis was used to analyze the relationships between PA, outdoor time and AL. Results The prevalence of low PA, low outdoor time and high AL were 16.3%, 71.1% and 47.6%, respectively. Low PA ( OR =1.83, 95% CI : 1.20~2.78) and low outdoor time ( OR =1.90, 95% CI : 1.35~2.67) are independently associated with high AL ( P <0.05, for each). Interaction analysis indicated that low PA and low outdoor time were interactively associated with high AL ( OR =2.93, 95% CI : 1.73~4.94, P <0.05). Conclusions There were the significant independent and interaction effects between PA and outdoor time on AL. In the future, college students’ physical education can be arranged reasonably to reduce the health risks.

Objectives To investigate the rates of depressive symptoms in college students, explore the relationship between urinary phthalate metabolites and depressive symptoms and their gender differences, and further explore the moderating role of insomnia in this association. Methods A total of 1 179 college students were recruited from 2 universities in Hefei and Shangrao cities from April to May 2019. The depressive symptoms and insomnia of college students were investigated by the Patient Health Questionnaire 9 and Insomnia Severity Index. The high-performance liquid chromatography-tandem mass spectrometry was adapted to determine the concentration of urinary phthalate metabolites. The generalized linear model was used to analyze the relationship of phthalate metabolites with depressive symptoms. Moderating analysis was used to examine whether insomnia moderated the relationship of phthalate metabolites with depressive symptoms. Results The rates of mild depression, and moderate depression and above in college students were 31.9% and 9.2%, respectively. The phthalate metabolites exhibited a median and mean concentration spanning from 2.98 ∼ 156.55 ng/mL and 6.12 ∼ 205.53 ng/mL. The generalized linear model results showed that monobutyl phthalate (MBP) ( β  = 1.160, 95% CI : 0.423 ∼ 1.896) and low molecular weight phthalate (LMWP) ( β  = 1.230, 95% CI : 0.348 ∼ 2.113) were positively correlated with depressive symptoms, and MBP ( β  = 1.320, 95% CI : 0.453 ∼ 2.187) and LMWP ( β  = 1.396, 95% CI : 0.351 ∼ 2.440) were positively correlated with depressive symptoms only in female college students after stratified by gender. Furthermore, insomnia has a positive moderating role between MBP, LMWP, and depressive symptoms and has a sex-based difference. Conclusions This study suggests that there is a positive association of phthalate metabolites with depressive symptoms among Chinese college students, as well as insomnia plays a positive moderating role in this association.

Background: Oxidative stress contributes to adverse atrial remodeling in diabetes mellitus. This remodeling can be prevented by the PPAR-γ agonist pioglitazone via its antioxidant and anti-inflammatory effects. In this study, we examined the molecular mechanisms underlying the protective effects of pioglitazone on atrial remodeling in a rabbit model of diabetes. Methods: Rabbits were randomly divided into control, diabetic, and pioglitazone-treated diabetic groups. Echocardiographic, hemodynamic, and electrophysiological parameters were measured. Serum PPAR-γ levels, serum and tissue oxidative stress and inflammatory markers, mitochondrial morphology, reactive oxygen species (ROS) production rate, respiratory function, and mitochondrial membrane potential (MMP) levels were measured. Protein expression of the pro-fibrotic marker TGF-β1, the PPAR-γ coactivator-1α (PGC-1α), and the mitochondrial proteins (biogenesis-, fusion-, and fission-related proteins) was measured. HL-1 cells were transfected with PGC-1α small interfering RNA (siRNA) to determine the underlying mechanisms of pioglitazone improvement of mitochondrial function under oxidative stress. Results: The diabetic group demonstrated a larger left atrial diameter and fibrosis area than the controls, which were associated with a higher incidence of inducible atrial fibrillation (AF). The lower serum PPAR-γ level was associated with lower PGC-1α and higher NF-κB and TGF-β1 expression. Lower mitochondrial biogenesis (PGC-1α, NRF1, and TFAM)-, fusion (Opa1 and Mfn1)-, and fission (Drp1)-related proteins were detected. Mitochondrial swelling, higher mitochondrial ROS, lower respiratory control rate, and lower MMP were observed. The pioglitazone group showed a reversal of structural remodeling and a lower incidence of inducible AF, which were associated with higher PPAR-γ and PGC-1α. The pioglitazone group had lower NF-κB and TGF-β1 expression levels, whereas biogenesis-, fusion-, and fission-related protein expression was higher. Further, mitochondrial structure and function were improved. In HL-1 cells, PGC-1α siRNA transfection blunted the effect of pioglitazone on Mn-SOD protein expression and MMP collapse in H 2 O 2 -treated cells. Conclusion: Diabetes mellitus induces adverse atrial structural, electrophysiological remodeling, and mitochondrial damage and dysfunction. Pioglitazone prevented these abnormalities through the PPAR-γ/PGC-1α pathway.

Background Declining ovarian function in advance-aged women and in premature ovarian insufficiency (POI) patients seriously affects quality of life, and there is currently no effective treatment to rescue ovarian function in clinic. Stem cell transplantation is a promising therapeutic strategy for ovarian aging, but its clinical application is limited due to the low efficiency and unclear mechanism. Here, a novel combination of umbilical cord-mesenchymal stem cells (UC-MSCs) and autocrosslinked hyaluronic acid (HA) gel is explored to rescue ovarian reserve and fecundity in POI and naturally aging mice. Methods To investigate HA prolonged the survival after UC-MSCs transplantation, PCR and immunofluorescence were performed to track the cells on day 1, 3, 7 and 14 after transplantation. The effects of HA on UC-MSCs were analyzed by CCK8 assay, RNA-sequencing and 440 cytokine array. In vivo experiments were conducted to evaluate the therapeutic effects of UC-MSCs combined with HA transplantation in 4-vinylcyclohexene diepoxide (VCD)-induced POI mice and naturally aging mice model. Ovarian function was analyzed by ovarian morphology, follicle counts, estrous cycle, hormone levels and fertility ability. To investigate the mechanisms of stem cell therapy, conditioned medium was collected from UC-MSCs and fibroblast. Both in vitro ovarian culture model and 440 cytokine array were applied to assess the paracrine effect and determine the underlying mechanism. Hepatocyte growth factor (HGF) was identified as an effective factor and verified by HGF cytokine/neutralization antibody supplementation into ovarian culture system. Results HA not only prolongs the retention of UC-MSCs in the ovary, but also boosts their secretory function, and UC-MSCs promote follicular survival by activating the PI3K-AKT pathway through a paracrine mechanism both in vitro and in vivo. More importantly, HGF is identified as the key functional cytokine secreted by MSCs. Conclusions The results show that HA is an excellent cell scaffold to improve the treatment efficiency of UC-MSCs for ovarian aging under both physiological and pathological conditions, and the therapeutic mechanism is through activation of the PI3K-AKT pathway via HGF. These findings will facilitate the clinical application of MSCs transplantation for ovarian disorders.

Neuroinflammation plays an important role in the induction and maintenance of chronic pain. Orchestra of pattern-recognition receptor-induced pro-inflammatory and anti-inflammatory cytokines is critical for inflammation homeostasis. CD11b on macrophages could inhibit toll-like receptor (TLR) activation-induced inflammatory responses. However, the function of CD11b on microglia remains unknown. In the current study, we demonstrated that CD11b-deficient microglia cells produced more inflammatory cytokines, such as interleukin-6 and tumor necrosis factor alpha, while less anti-inflammatory cytokines. Signal transduction assay confirmed that nuclear factor-κB activation was increased in CD11b-deficient microglia cells, which resulted from decreased activation of Src. Inhibition of Src by PP1 increased inflammation in wild-type microglia cells significantly, but not in CD11b-deficient microglia cells. In vivo, CD11b-deficient mice were more susceptible to chronic constrictive injury-induced allodynia and hyperalgesia with significantly more inflammatory cytokines expression. All these results indicated that the regulatory function of CD11b-Src signal pathway on both inflammatory and anti-inflammatory cytokines in microglia cells is a potential target in neuropathic pain treatment.

Abstract This study aimed to investigate the brain grey matter volume (GMV) related to problematic mobile phone use (PMPU), and whether these regions of GMV play a potential moderating role in the relationship between PMPU and depressive symptoms. We recruited 266 students who underwent magnetic resonance imaging (MRI) scanning. PMPU and depressive symptoms were assessed by a self-rating questionnaire for adolescent PMPU and patient health questionnaire-9, respectively. A multiple regression model was performed to detect GMV and white matter (WM) integrity associated with PMPU by voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) methods, and the moderating analysis was conducted by PROCESS using SPSS software. VBM analysis found an inverse correlation between the GMV of the anterior cingulate gyrus (ACC) and right fusiform gyrus (FFG) with PMPU (PFDR < 0.05), and TBSS analysis revealed that fractional anisotropy (FA) in the body of the corpus callosum was negatively correlated with PMPU. The correlation between PMPU and depressive symptoms was moderated by the GMV of the ACC. These results suggest that the GMV of the ACC and right FFG, as well as FA in the body of the corpus callosum, was related to PMPU, and we further found that increased GMV of the ACC could reduce the relationship between PMPU and depressive symptoms in college students.

Inflammation is closely related to poor mental and physical health, including depressive symptoms and its specific symptoms. To reveal the linear and nonlinear relationships between depressive symptoms and chronic inflammation levels, and perform further analysis of the associations between symptom-specificity of depressive symptoms and inflammation among young adults by using a prospective design. In this longitudinal study, we examined college students recruited from two universities in China, who were examined at baseline and 2-years follow-up. Depressive symptoms were measured by applying the Patient Health Questionnaire 9 (PHQ-9) at baseline. Plasma levels of four inflammatory biomarkers, including interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and C reactive protein (CRP) were assayed at baseline and 2-year follow-up. In addition to the conventional generalized linear models, as well as restricted cubic splines were innovatively used to analyze the cross-sectional and longitudinal nonlinear relationships between depressive symptoms and inflammatory biomarkers. Generalized linear model analysis revealed that there were no statistical associations between depressive symptoms and any inflammatory biomarker levels. The results of the restricted cubic spline demonstrated a U-shaped nonlinear association between depressive symptoms and ΔIL-1β or ΔTNF-α (changes in baseline and 2-year follow-up), but these associations disappeared after adjusting the confounders. Symptom-specificity of depressive symptoms such as sleeping problems and suicidal ideation were associated with lower IL-1β at baseline or changes in IL-1β levels. Sleeping problems and psychomotor changes at baseline were associated with higher CRP at 2-year follow-up. Suicidal ideation at baseline was associated with changes in TNF-α levels. Our findings suggested that symptom-specificity of depressive symptoms was associated with inflammation during a 2-year follow-up at the transition to adulthood. Simultaneously, more research is warranted to seek the directionality of depressive symptoms and chronic inflammation.