The Functions and Application Prospects of Hepatocyte Growth Factor in Reproduction.

Hepatocyte growth factor (HGF) is expressed in multiple systems and mediates a variety of biological activities, such as mitosis, motility, and morphogenesis. A growing number of studies have revealed the expression patterns and functions of HGF in ovarian and testicular physiology from the prenatal to the adult stage. HGF regulates folliculogenesis and steroidogenesis by modulating the functions of theca cells and granulosa cells in the ovary. It also mediates somatic cell proliferation and steroidogenesis, thereby affecting spermatogenesis in males. In addition to its physiological effects on the reproductive system, HGF has shown advantages in preclinical studies over recent years for the treatment of male and female infertility, particularly in women with premature ovarian insufficiency. This review aims to summarize the pleiotropic functions of HGF in the reproductive system and to provide prospects for its clinical application.

Moderating effects of PER3 gene DNA methylation on the association between problematic mobile phone use and chronotype among Chinese young adults: Focus on gender differences.

Objective: To investigate the rates of problematic mobile phone use (PMPU) and chronotypes in young adults, and examine the associations of PMPU with chronotypes, as well as its gender differences. Furthermore, we explored the moderating role of PER3 gene DNA methylation on the associations. Methods: From April to May 2019, a total of 1,179 young adults were selected from 2 universities in Anhui and Jiangxi provinces. The Self-rating Questionnaire for Adolescent Problematic Mobile Phone Use (SQAPMPU) and reduced Morningness-Eveningness Questionnaire (rMEQ) were adopted to investigate PMPU and chronotypes in young adults, respectively. Moreover, 744 blood samples were collected to measure PER3 gene DNA methylation. Multivariate logistic regression models were established to analyze the associations between PMPU and chronotypes. Moderating analysis was used to determine whether PER3 gene DNA methylation moderated the relationships between PMPU and chronotypes. Results: The prevalence of PMPU, morning chronotypes (M-types), neutral chronotypes (N-types), and evening chronotypes (E-types) of young adults were 24.6%, 18.4%, 71.1%, and 10.5%, respectively. Multivariate logistic regression results indicated that PMPU was positively correlated with E-types (OR = 3.53, 95%CI: 2.08-6.00), and the association was observed only in females after stratified by gender (OR = 5.36, 95%CI: 2.70-10.67). Furthermore, PER3 gene DNA methylation has a negative moderating role between PMPU and chronotypes and has a sex-based difference. Conclusions: This study can provide valuable information for the prevention and control of circadian rhythm disturbance among young adults from the perspective of epidemiology and biological etiology.

Multifunctional magnetic tags with photocatalytic and enzyme-mimicking properties for constructing a sensitive dual-readout ELISA.

ELISA has become the gold standard for detecting harmful substances due to its specific antibody recognition and sensitive enzyme-catalyzed reactions. In this study, multifunctional magnetic Prussian blue nanolabels (MPBNs) were synthesized using a simple gentle two-step method to achieve a dual-readout mode. The MPBNs provide a sensitive colorimetric signal by efficiently catalyzing the oxidation of TMB and exhibit prominent photocatalytic degradation activity towards Rhodamine B (RhB). Supplemented by the quenching effect of oxTMB, the fluorescence was enabled to serve as a sensitive second signal. The magnetic property of the labels facilitates the separation and enrichment of the target, thereby improving sensitivity. Utilizing the versatile MPBNs, the visual limit of detection (vLOD) for Staphylococcus aureus is as low as 100 CFU/mL, with a quantitative analysis range of 102-108 CFU/mL. The introduction of photocatalytic reactions into immunoassay has opened up a new signal response system with strong momentum for development and application.

MCM8 interacts with DDX5 to promote R-loop resolution.

MCM8 has emerged as a core gene in reproductive aging and is crucial for meiotic homologous recombination repair. It also safeguards genome stability by coordinating the replication stress response during mitosis, but its function in mitotic germ cells remains elusive. Here we found that disabling MCM8 in mice resulted in proliferation defects of primordial germ cells (PGCs) and ultimately impaired fertility. We further demonstrated that MCM8 interacted with two known helicases DDX5 and DHX9, and loss of MCM8 led to R-loop accumulation by reducing the retention of these helicases at R-loops, thus inducing genome instability. Cells expressing premature ovarian insufficiency-causative mutants of MCM8 with decreased interaction with DDX5 displayed increased R-loop levels. These results show MCM8 interacts with R-loop-resolving factors to prevent R-loop-induced DNA damage, which may contribute to the maintenance of genome integrity of PGCs and reproductive reserve establishment. Our findings thus reveal an essential role for MCM8 in PGC development and improve our understanding of reproductive aging caused by genome instability in mitotic germ cells.

Prospective study of the association between chronotypes and depressive symptoms in Chinese university students: Moderating effects of PER1 gene DNA methylation.

Most studies have shown a link between chronotypes and mental health and have identified evening chronotypes (E-types) as a potential risk for depressive symptoms. However, the mechanisms behind this association remain unknown. Abnormal expression of the PER1 gene was not only associated with circadian rhythm disturbance, but also closely related to mental illness. Therefore, this study aimed to examine the association of chronotype with depressive symptoms, and further explore the moderating effects of the PER1 gene DNA methylation on chronotypes and depressive symptoms in Chinese university students. In a stratified cluster sampling design, chronotype and depressive symptoms were assessed in 1 042 university students from 2 universities in a two-year prospective survey from April 2019 to October 2020. The survey was conducted once every 6 months, corresponding to the time points in April 2019 (T0), October 2019 (T1), April 2020 (T2), and October 2020 (T3). At T0, the Morning and Evening Questionnaire 5 (MEQ-5) was adopted to assess chronotype. At T0-T3, the Patient Health Questionnaire 9 (PHQ-9) was adopted to investigate depressive symptoms. Meanwhile, at T0, participants were subjected to a health check-up trip in the hospital, and blood samples were taken from the students to measure the PER1 gene DNA methylation levels. Binary logistic regression was used to analyze the association of chronotypes with depressive symptoms. The depression/total depression group was coded as 1, while the remaining participants was defined as one group, and was coded as 0. The PROCESS plug-in of SPSS software was used to analyze the moderating effects of PER1 gene DNA methylation on the association of chronotype with depressive symptoms. After adjusting for covariates, the results indicated that T0 E-types were positively correlated with T0-T3 depression/total depression in female university students. Furthermore, the PER1 gene DNA methylation has negative moderating effects between T0 chronotype and T3 depressive symptoms and has a sex difference. This study can provide more favorable scientific value for the prevention and control of depression in university students.

Novel compound heterozygous variants in FANCI cause premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a common reproductive aging disorder due to a dramatic decline of ovarian function before 40 years of age. Accumulating evidence reveals that genetic defects, particularly those related to DNA damage response, are a crucial contributing factor to POI. We have demonstrated that the functional Fanconi anemia (FA) pathway maintains the rapid proliferation of primordial germ cells to establish a sufficient reproductive reserve by counteracting replication stress, but the clinical implications of this function in human ovarian function remain to be established. Here, we screened the FANCI gene, which encodes a key component for FA pathway activation, in our whole-exome sequencing database of 1030 patients with idiopathic POI, and identified two pairs of novel compound heterozygous variants, c.[97C > T];[1865C > T] and c.[158-2A > G];[c.959A > G], in two POI patients, respectively. The missense variants did not alter FANCI protein expression and nuclear localization, apart from the variant c.158-2A > G causing abnormal splicing and leading to a truncated mutant p.(S54Pfs*5). Furthermore, the four variants all diminished FANCD2 ubiquitination levels and increased DNA damage under replication stress, suggesting that the FANCI variants impaired FA pathway activation and replication stress response. This study first links replication stress response defects with the pathogenesis of human POI, providing a new insight into the essential roles of the FA genes in ovarian function.

Discovery of Novel 5,6-Dihydro-4H-pyrido[2,3,4-de]quinazoline Irreversible Inhibitors Targeting Both Wild-Type and A775_G776insYVMA Mutated HER2 Kinases.

HER2 mutations were seen in 4% of non-small-cell lung cancer (NSCLC) patients. Most of these mutations (90%) occur as an insertion mutation within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways. However, no targeted therapies have yet been approved worldwide. Here a novel series of highly potent HER2 inhibitors with a pyrido[2,3,4-de]quinazoline core were designed and developed. The derivatives with the pyrido[2,3,4-de]quinazoline core displayed superior efficacy of antiproliferation in BaF3 cells harboring HER2insYVMA mutation compared with afatinib and neratinib. Rat studies showed that 8a and 9a with the newly developed core have good pharmacokinetic properties with an oral bioavailability of 41.7 and 42.0%, respectively. Oral administration of 4a and 10e (30 mg/kg, QD) displayed significant antitumor efficacy in an in vivo xenograft model. We proposed promising strategies for the development of HER2insYVMA mutant inhibitors in this study.

Association of different sleep characteristics and cardiometabolic risk in college students / 中国学校卫生

Objective@#To describe the association of different sleep characteristics and cardiometabolic risk among college students, so as to provide reference for health promotion of college students.@*Methods@#By random cluster sampling method, a questionnaire survey and physical examination including blood pressure, waist circumference and blood lipid indicators, which were conducted in April and May of 2019 among a total of 1 179 college students from the first grade in two universities in Hefei City of Anhui Province and Shangrao City of Jiangxi Province. A total of 729 college students with valid questionnaires were included into analysis. The Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) were used to investigate sleep behavior, and the Morning And Evening Questionnaire-5 (MEQ-5) was used to investigate sleep characteristics. The cardiometabolic risk score was derived using the sum of the standardized sex specific Z scores of waist circumference, mean arterial pressure, HDL cholesterol (multiplied by -1), triglycerides, and insulin resistance index. The rank sum tests were used to compare differences in cardiometabolic risk scores across demographic characteristics. Generalized linear models were used to compare the association of different sleep characteristics with cardiometabolic risk scores among college students.@*Results@#The average cardiovascular metabolic risk score of college students was -0.32(-2.03, 1.58). There were statistically significant differences in cardiovascular metabolic risk scores among college students in variables such as smoking, health status, and physical activity levels ( t/F=-3.41, 12.88, 51.07, P <0.01). The results of the generalized linear model showed that nighttime preference ( B=1.89, 95%CI =1.02-3.49), insomnia symptoms ( B=3.25, 95%CI =1.79-5.90), and short or long sleep duration ( B=1.92, 95%CI =1.21-3.05) were positively correlated with the cardiovascular metabolic risk score of college students ( P <0.05).@*Conclusions@#Poor sleep patterns among college students are positively correlated with the risk of cardiovascular metabolism. The sleep behavior of college students should be actively changed to reduce the risk of cardiovascular disease.

Prospective study of the association between chronotype and cardiometabolic risk among Chinese young adults.

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 (ß=-1.420, 95%CI: -2.386~-0.453), higher HOMA-IR (ß=-0.301, 95%CI: -0.507~-0.095), and higher CM risk score (ß=-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 (ß=-0.018, 95%CI: -0.034~-0.003), higher fasting insulin (ß=-0.384, 95%CI: -0.766~-0.003), higher HOMA-IR (ß=-0.089, 95%CI: -0.176~-0.002), and higher CM-risk score (ß=-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.

[Association between changes in physical activity and comorbid symptoms of anxiety and depression in college students].

OBJECTIVE: To describe the prevalence of physical activity and comorbid symptoms of anxiety and depression in college students, and to explore the correlation strength between changes in physical activity and comorbid symptoms of anxiety and depression, so as to provide a reference for promoting college students' mental health. METHODS: From April to May 2019, 1179 freshmen majoring in public health, nursing, chemistry and physical education were randomly sampled from one university in Hefei City, Anhui Province, and Shangrao City, Jiangxi Province, respectively. A baseline questionnaire survey was conducted. A follow-up survey was conducted in May 2021, and a total of 1046 subjects were included, including 647 female and 399 male. The International Physical Activity Questionnaire-Short Form was used to evaluate the physical activity level of college students, and the Patient Health Questionnaire and Generalized Anxiety Disorder Scale were used to evaluate the anxiety and depression symptoms of college students during follow-up. Determining the coexistence of anxiety and depression symptoms in college students as anxiety-depression comorbid symptoms. RESULTS: In the follow-up survey, the detection rate of anxiety and depression comorbid symptoms of college students was 16.9%(n=177), and the detection rates of sufficient, decreased, increased, and insufficient physical activity changes were 72.5%(n=758), 13.8%(n=144), 9.2%(n=96), and 4.6%(n=48), respectively. The result of multiple Logistic regression model showed that, after controlling for confounding factors, compared with those with sustained high level of physical activity, i. e. , adequate physical activity, increased physical activity(OR=1.89, 95%CI 1.10-3.25), decreased physical activity(OR =2.80, 95% CI 1.72-4.57), and insufficient physical activity(OR = 3.66, 95% CI 1.85-7.23) increased the risk of anxiety-depression comorbidity symptoms of college students(P<0.05). However, there was no significant increase in the risk of anxiety or depressive symptoms in those who increased, decreased, or insufficient physical activity compared with those who were sufficient physical activity(P>0.05). CONCLUSION: The level of physical activity and its changes are related to mental health of college students. The continuous low level of physical activity is associated with the increased risk of comorbidity of anxiety and depression in college students.

Patterns of smartphone usage associated with depressive symptoms in nursing students.

Introduction: Rather than focusing on the activities that the smartphone has been used for, the existing literature frequently focuses on the association between problematic use of smartphone independent of the content of use (self-reported) and depressive symptoms in youth. This study aims to explore patterns of smartphone usage and the association with depressive symptoms in nursing students. Methods: This cross-sectional study of nursing freshmen (n = 1, 716) was conducted between October and November 2018. Participants were recruited from three Chinese public medical universities using stratified cluster sampling. Self-rated frequency of 12 different smartphone activities over the preceding week was evaluated. Depressive symptoms were assessed by using the Patient Health Questionnaire-9 (PHQ-9). Results: Of the 1,716 students recruited, 1,424 (83.0%) were girls, and the mean [SD] age was 18.90 [1.39] years. Using principal component analysis (PCA), two typical usage patterns were indicated. The "entertainment pattern" factor included a high frequency of streaming images or videos, searching for information, chatting online, online shopping, downloading, reading online, checking social media sites, taking pictures or videos, and playing games. The "communication pattern" had a high frequency of emailing, texting, and calling. Using logistic regression models, the association between smartphone usage patterns and depressive symptoms was tested. The "communication pattern" was significantly associated with a 53% increase in the odds of moderate and above depressive symptoms (AOR = 1.529; 95% CI = 1.286-1.818; p < 0.001), controlling for a set of socio-demographic and smartphone use covariates. Discussion: This study provides insights into how the patterns of smartphone usage are associated with the severity of depressive symptoms in nursing students. It indicates that it may primarily be how we use our smartphones rather than how much we use them that poses a risk for depression.

FAAP100 is required for the resolution of transcription-replication conflicts in primordial germ cells.

BACKGROUND: The maintenance of genome stability in primordial germ cells (PGCs) is crucial for the faithful transmission of genetic information and the establishment of reproductive reserve. Numerous studies in recent decades have linked the Fanconi anemia (FA) pathway with fertility, particularly PGC development. However, the role of FAAP100, an essential component of the FA core complex, in germ cell development is unexplored. RESULTS: We find that FAAP100 plays an essential role in R-loop resolution and replication fork protection to counteract transcription-replication conflicts (TRCs) during mouse PGC proliferation. FAAP100 deletion leads to FA pathway inactivation, increases TRCs as well as cotranscriptional R-loops, and contributes to the collapse of replication forks and the generation of DNA damage. Then, the activated p53 signaling pathway triggers PGC proliferation defects, ultimately resulting in insufficient establishment of reproductive reserve in both sexes of mice. CONCLUSIONS: Our findings suggest that FAAP100 is required for the resolution of TRCs in PGCs to safeguard their genome stability.

Does interpersonal self-support matter for freshman nursing students' professional identity? Evidence from mainland China.

Background: Many studies have focused on undergraduate nursing students' professional identity (PI), but freshman nursing students (FNSs) have been ignored, and the relationship between interpersonal self-support (ISS) and PI is unknown. This study was designed to determine the patterns of ISS and its association with PI among Chinese FNSs. Methods: A cross-sectional survey was conducted among 358 FNSs recruited from two nursing colleges in southeast China. Students completed the Sociodemographic Characteristics Questionnaire, the Interpersonal Self-Support Scale for Adolescent Students, and the Professional Identity Questionnaire for Nurse Students. Latent profile analysis (LPA) was used to determine the patterns of ISS among freshmen. The Bolck-Croon-Hagenaars method was used to examine the influencing role of ISS in PI. Results: LPA indicated that ISS could be classified into three subgroups: the ISS-Individualist group (7.54% of the total sample), ISS-Dependent group (63.13% of the total sample), and ISS-Extrovert group (29.33% of the total sample). Overall, these three profiles differed significantly in the five dimensions of ISS and PI (p < 0.05). The results of pairwise comparisons examined the positive role of the ISS-Extrovert group on the promotion of PI among FNSs. Conclusion: These findings emphasize the need for the promotion of PI and ISS among Chinese FNSs. Freshman students need more confidence and general communication knowledge to maintain harmonious social relationships with others. Parent-teacher association could be applied to nursing education to guide FNSs' positive development of ISS.

Organizing Uniform Phase Distribution in Methylammonium-Free 1.77 eV Wide-Bandgap Inverted Perovskite Solar Cells.

Disordered crystallization and poor phase stability of mixed halide perovskite films are still the main factors that compromise the performance of inverted wide bandgap (WBG; 1.77 eV) perovskite solar cells (PSCs). Great difficulties are evidenced due to the very different crystallization rates between I- and Br-based perovskite components through DMSO-alone assisted anti-solvent process. Here, a zwitterionic additive strategy is reported for finely regulating the crystal growth of Cs0.2 FA0.8 Pb(I0.6 Br0.4 )3 , thereby obtaining high-performance PSCs. The aminoethanesulfonic acid (AESA) is introduced to form hydrogen bonds and strong PbO bonds with perovskite precursors, realizing the complete coordination with both the organic (FAI) and inorganic (CsI, PbI2 , PbBr2 ) components, balancing their complexation effects, and realizing AESA-guided fast nucleation and retarded crystallization processes. This treatment substantially promotes homogeneous crystal growth of I- and Br-based perovskite components. Besides, this uniformly distributed AESA passivates the defects and inhibits the photo-induced halide segregation effectively. This strategy generates a record efficiency of 19.66%, with a Voc of 1.25 V and FF of 83.7% for an MA-free WBG p-i-n device at 1.77 eV. The unencapsulated devices display impressive humidity stability at 30 ± 5% RH for 1000 h and much improved continuous operation stability at MPP for 300 h.

Smartphone Use and Inflammation at 2-Year Follow-Up in College Students: The Mediating Role of Physical Activity.

Purpose: Smartphone use could lead to being physically inactive and a greater risk for health problems, such as inflammation. However, the associations between smartphone use, physical activity (PA), and systemic low-grade inflammation remained unclear. This study aimed to examine the potential mediating effect of PA on the association between smartphone use and inflammation. Patients and Methods: A two-year follow-up study was conducted between April 2019 and April 2021. Duration of smartphone use, smartphone dependence and PA were assessed by a self-administered questionnaire. Laboratory analysis of blood samples was performed to evaluate the levels of TNF-α, IL-6, IL-1ß, and CRP as biomarkers of systemic inflammation. The correlations between smartphone use, PA, and inflammation were analyzed using Pearson correlation. Structural equation modelling was used to analyze the potential mediating effect of PA on the associations between smartphone use and inflammation. Results: A total of 210 participants were included with a mean (standard deviation) age of 18.7 (1.0) years, 82 (39%) of whom were males. Smartphone dependence was negatively associated with the total PA level (r=-0.18, P<0.01). PA mediated the associations between the duration of smartphone use and smartphone dependence with inflammatory markers. Specifically, as PA decreased, the duration of smartphone use was more negatively associated with TNF-α (ab=-0.027; 95% CI: -0.052, -0.007) and more positively correlated to IL-6 (ab=0.020; 95% CI: 0.001, 0.046) and CRP (ab=0.038; 95% CI: 0.004, 0.086); smartphone dependency was more negatively associated with TNF-α (ab=-0.139; 95% CI: -0.288, -0.017) and more positively related to CRP (ab=0.206; 95% CI: 0.020, 0.421). Conclusion: Our study illustrates that there are no direct associations between smartphone use and systemic low-grade inflammation, however, PA level plays a weak but significant mediating effect on the associations between smartphone use and inflammation among college students.

Poor sleep pattern is associated with metabolic disorder during transition from adolescence to adulthood.

Objective: The purpose of this study was to investigate whether sleep pattern is associated with metabolic disorders among young adults. Methods: We measured sleep patterns using multiple sleep behaviors in an ongoing prospective cohort among college students (n = 1,151). At baseline, 729 college students provided fasting blood samples and human body morphological measurements for quantification of metabolic parameters. Then, 340 participants continued to take metabolic parameters measurements at a 2-year follow-up. Sleep patterns were defined by chronotype, sleep duration, insomnia, snoring, and daytime sleepiness. Metabolic scores were derived for four metabolic parameters including body mass index (BMI), waist circumference (WC), fasting blood sugar (FBG), and insulin. Multivariate linear regression model was applied to analyze the association between sleep pattern types and metabolic parameters and metabolic scores. Results: In the baseline survey, we found that a total of 41 (4.1%) participants had poor sleep patterns. Then, metabolic scores were significantly higher among college students with poor sleep patterns, compared with those who with healthy sleep patterns at baseline (1.00 ± 0.96 vs. 0.78 ± 0.72, p < 0.05) and 2-year follow-up (0.34 ± 0.65 vs. 1.50 ± 1.64, p < 0.05). After covariates were adjusted, poor sleep pattern (ß = 0.22, 95% CI: 0.06~2.53, p = 0.001) was associated with elevated metabolic scores at the 2-year follow-up. Conclusions: The elevated metabolic burden observed in college students with poor sleep patterns highlights the need to identify and address sleep problems in order to minimize the long-term impact on disease vulnerability.

TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.

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.

UBE2T resolves transcription-replication conflicts and protects common fragile sites in primordial germ cells.

The proper development of primordial germ cells (PGCs) is an essential prerequisite for gametogenesis and mammalian fertility. The Fanconi anemia (FA) pathway functions in maintaining the development of PGCs. FANCT/UBE2T serves as an E2 ubiquitin-conjugating enzyme that ubiquitylates the FANCD2-FANCI complex to activate the FA pathway, but its role in the development of PGCs is not clear. In this study, we found that Ube2t knockout mice showed defects in PGC proliferation, leading to severe loss of germ cells after birth. Deletion of UBE2T exacerbated DNA damage and triggered the activation of the p53 pathway. We further demonstrated that UBE2T counteracted transcription-replication conflicts by resolving R-loops and stabilizing replication forks, and also protected common fragile sites by resolving R-loops in large genes and promoting mitotic DNA synthesis to maintain the genome stability of PGCs. Overall, these results provide new insights into the function and regulatory mechanisms of the FA pathway ensuring normal development of PGCs.

Influence mechanism and impacting boundary of workplace isolation on the employee's negative behaviors.

Introduction: Based on social identity theory, by introducing organizational identification as mediating variable and identification orientation as moderating variable, this paper studies the influence mechanism and impacting boundary of workplace isolation on employee fatigue and turnover intention. Methods: Based on logic relationship, seven basic hypotheses are put forward to construct the theoretical model of the problem. Based on the 300 effective questionnaires being obtained from employees in Mainland China, the empirical investigation adopts the three-phase lag time design. By regression analysis and bootstrap test. Results: (1) Workplace isolation has a significant positive effect on employee's work fatigue; (2) Workplace isolation has a significant positive effect on employee's turnover intention; (3) Organizational identification plays a partial mediating role between workplace isolation and work fatigue; (4) Organizational identification plays a partial mediating role between workplace isolation and employee's turnover intention; (5) Employee identification orientation negatively moderates the relationship between workplace isolation and organizational identification, that is to say, the higher the degree of identification orientation, the more inhibited the negative impact of workplace isolation on organizational identification; (6) Employee identification orientation has a negative moderating effect, namely, compared with the low degree of employee identification orientation, the higher the employee identification orientation, the positive effect of workplace isolation on work fatigue and turnover intention through organizational identification become weaker. Discussion: Understanding these influencing mechanisms will have a great influence on guiding managers to mitigate the negative effects of "workplace isolation" in practice and improve the work efficiency of employees.

DNA repair protein FANCD2 has both ubiquitination-dependent and ubiquitination-independent functions during germ cell development.

When DNA interstrand crosslink lesions occur, a core complex of Fanconi anemia proteins promotes the ubiquitination of FANCD2 and FANCI, which recruit downstream factors to repair the lesion. However, FANCD2 maintains genome stability not only through its ubiquitination-dependent but also its ubiquitination-independent functions in various DNA damage response pathways. Increasing evidence suggests that FANCD2 is essential for fertility, but its ubiquitination-dependent and ubiquitination-independent roles during germ cell development are not well characterized. In this study, we analyzed germ cell development in Fancd2 KO and ubiquitination-deficient mutant (Fancd2K559R/K559R) mice. We showed that in the embryonic stage, both the ubiquitination-dependent and ubiquitination-independent functions of FANCD2 were required for the expansion of primordial germ cells and establishment of the reproductive reserve by reducing transcription-replication conflicts and thus maintaining genome stability in primordial germ cells. Furthermore, we found that during meiosis in spermatogenesis, FANCD2 promoted chromosome synapsis and regulated crossover formation independently of its ubiquitination, but that both ubiquitinated and nonubiquitinated FANCD2 functioned in programmed double strand break repair. Finally, we revealed that on meiotic XY chromosomes, H3K4me2 accumulation required ubiquitination-independent functionality of FANCD2, while the regulation of H3K9me2 and H3K9me3 depended on FANCD2 ubiquitination. Taken together, our findings suggest that FANCD2 has distinct functions that are both dependent on and independent of its ubiquitination during germ cell development.