Immunocompetent mouse models revealed that S100A4+ monocytes/macrophages facilitate long-term Zika virus infection in the testes.

During its global epidemic, Zika virus (ZIKV) attracted widespread attention due to its link with various severe neurological symptoms and potential harm to male fertility. However, the understanding of how ZIKV invades and persists in the male reproductive system is limited due to the lack of immunocompetent small animal models. In this study, immunocompetent murine models were generated by using anti-IFNAR antibody blocked C57BL/6 male mice and human STAT2 (hSTAT2) knock in (KI) male mice. After infection, viral RNA could persist in the testes even after the disappearance of viremia. We also found a population of ZIKV-susceptible S100A4+ monocytes/macrophages that were recruited into testes from peripheral blood and played a crucial role for ZIKV infection in the testis. By using single-cell RNA sequencing, we also proved that S100A4+ monocytes/macrophages had a great impact on the microenvironment of ZIKV-infected testes, thus promoting ZIKV-induced testicular lesions. In conclusion, this study proposed a novel mechanism of long-term ZIKV infection in the male reproductive system.

Mice with type I interferon signaling deficiency are prone to epilepsy upon HSV-1 infection.

Viral encephalitis continues to be a significant public health concern. In our previous study, we discovered a lower expression of antiviral factors, such as IFN-ß, STING and IFI16, in the brain tissues of patients with Rasmussen's encephalitis (RE), a rare chronic neurological disorder often occurred in children, characterized by unihemispheric brain atrophy. Furthermore, a higher cumulative viral score of human herpes viruses (HHVs) was also found to have a significant positive correlation with the unihemispheric atrophy in RE. Type I IFNs (IFN-I) signaling is essential for innate anti-infection response by binding to IFN-α/ß receptor (IFNAR). In this study, we infected WT mice and IFNAR-deficient A6 mice with herpes simplex virus 1 (HSV-1) via periocular injection to investigate the relationship between IFN-I signaling and HHVs-induced brain lesions. While all mice exhibited typical viral encephalitis lesions in their brains, HSV-induced epilepsy was only observed in A6 mice. The gene expression matrix, functional enrichment analysis and protein-protein interaction network revealed four gene models that were positively related with HSV-induced epilepsy. Additionally, ten key genes with the highest scores were identified. Taken together, these findings indicate that intact IFN-I signaling can effectively limit HHVs induced neural symptoms and brain lesions, thereby confirming the positive correlation between IFN-I signaling repression and brain atrophy in RE and other HHVs encephalitis.

Single-cell RNA sequencing to understand host-virus interactions.

Single-cell RNA sequencing (scRNA-seq) has allowed for the profiling of host and virus transcripts and host-virus interactions at single-cell resolution. This review summarizes the existing scRNA-seq technologies together with their strengths and weaknesses. The applications of scRNA-seq in various virological studies are discussed in depth, which broaden the understanding of the immune atlas, host-virus interactions, and immune repertoire. scRNA-seq can be widely used for virology in the near future to better understand the pathogenic mechanisms and discover more effective therapeutic strategies.

Decomposing the change in the cognitive function gap between older men and women over time in China: The Chinese Longitudinal Healthy Longevity Survey.

Background: This study explored how modifiable social determinants of cognitive function can influence these gender gaps. Methods: We utilized six waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), including 56,127 individuals aged 65+. The Kitagawa-Oaxaca-Blinder decomposition approach was used for the analysis. Results: Older women consistently had lower average levels of cognitive function than men in each period, but the gap is narrowing. From 2002 to 2018, the gender gap in cognitive function decreased by 1.45 (95% confidence interval (CI) = -1.843, -1.097) points. The coefficients for the endowment effects decreased from 0.387 (95% CI = -0.563, -0.211) to 1.789 (95% CI = -2.471, -1.107) from 2005 to 2018. Lifestyle changes, social participation, and physical health factors significantly contributed to explaining the changes in gender gaps in cognitive function. Conclusions: Among these contributing factors, lifestyle, social participation, and physical health have emerged as pivotal elements in reducing the gender gap in cognitive function. Targeted interventions for these variables are essential among older women to narrow the cognitive gender gaps effectively.

Zika virus infection leads to hormone deficiencies of the hypothalamic-pituitary-gonadal axis and diminished fertility in mice.

IMPORTANCE: Zika virus (ZIKV) infection in pregnant women during the third trimester can cause neurodevelopmental delays and cryptorchidism in children without microcephaly. However, the consequences of congenital ZIKV infection on fertility in these children remain unclear. Here, using an immunocompetent mouse model, we reveal that congenital ZIKV infection can cause hormonal disorders of the hypothalamic-pituitary-gonadal axis, leading to reduced fertility and decreased sexual preference. Our study has for the first time linked the hypothalamus to the reproductive system and social behaviors after ZIKV infection. Although the extent to which these observations in mice translate to humans remains unclear, these findings did suggest that the reproductive health and hormone levels of ZIKV-exposed children should receive more attention to improve their living quality.

Neutrophil infiltration leads to fetal growth restriction by impairing the placental vasculature in DENV-infected pregnant mice.

BACKGROUND: Dengue virus (DENV) infection during pregnancy increases the risk of adverse fetal outcomes, which has become a new clinical challenge. However, the underlying mechanism remains unknown. METHODS: The effect of DENV-2 infection on fetuses was investigated using pregnant interferon α/ß receptor-deficient (Ifnar1-/-) mice. The histopathological changes in the placentas were analyzed by morphological techniques. A mouse inflammation array was used to detect the cytokine and chemokine profiles in the serum and placenta. The infiltration characteristics of inflammatory cells in the placentas were evaluated by single-cell RNA sequencing. FINDINGS: Fetal growth restriction observed in DENV-2 infection was mainly caused by the destruction of the placental vasculature rather than direct damage from the virus in our mouse model. After infection, neutrophil infiltration into the placenta disrupts the expression profile of matrix metalloproteinases, which leads to placental dysvascularization and insufficiency. Notably, similar histopathological changes were observed in the placentas from DENV-infected puerperae. INTERPRETATION: Neutrophils play key roles in placental histopathological damage during DENV infection, which indicates that interfering with aberrant neutrophil infiltration into the placenta may be an important therapeutic target for adverse pregnancy outcomes in DENV infection. FUNDING: The National Key Research and Development Plans of China (2021YFC2300200-02 to J.A., 2019YFC0121905 to Q.Z.C.), the National Natural Science Foundation of China (NSFC) (U1902210 and 81972979 to J. A., 81902048 to Z. Y. S., and 82172266 to P.G.W.), and the Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan, China (IDHT20190510 to J. A.).

Single-cell RNA sequencing reveals the fragility of male spermatogenic cells to Zika virus-induced complement activation.

Zika virus (ZIKV) is a potential threat to male reproductive health but the mechanisms underlying its influence on testes during ZIKV infection remain obscure. To address this question, we perform single-cell RNA sequencing using testes from ZIKV-infected mice. The results reveal the fragility of spermatogenic cells, especially spermatogonia, to ZIKV infection and show that the genes of the complement system are significantly upregulated mainly in infiltrated S100A4 + monocytes/macrophages. Complement activation and its contribution to testicular damage are validated by ELISA, RT‒qPCR and IFA and further verify in ZIKV-infected northern pigtailed macaques by RNA genome sequencing and IFA, suggesting that this might be the common response to ZIKV infection in primates. On this basis, we test the complement inhibitor C1INH and S100A4 inhibitors sulindac and niclosamide for their effects on testis protection. C1INH alleviates the pathological change in the testis but deteriorates ZIKV infection in general. In contrast, niclosamide effectively reduces S100A4 + monocyte/macrophage infiltration, inhibits complement activation, alleviates testicular damage, and rescues the fertility of male mice from ZIKV infection. This discovery therefore encourages male reproductive health protection during the next ZIKV epidemic.

Mice 3D testicular organoid system as a novel tool to study Zika virus pathogenesis.

Zika virus (ZIKV) poses a serious threat to global public health due to its close relationship with neurological and male reproductive damage. However, deficiency of human testicular samples hinders the in-depth research on ZIKV-induced male reproductive system injury. Organoids are relatively simple in vitro models, which could mimic the pathological changes of corresponding organs. In this study, we constructed a 3D testicular organoid model using primary testicular cells from adult BALB/c mice. Similar to the testis, this organoid system has a blood-testis barrier (BTB)-like structure and could synthesize testosterone. ZIKV tropism of testicular cells and ZIKV-induced pathological changes in testicular organoid was also similar to that in mammalian testis. Therefore, our results provide a simple and reproducible in vitro testicular model for the investigations of ZIKV-induced testicular injury.

Gender disparity in disability among Chinese oldest-old: Age and cohort trends.

This study aimed at exploring gender disparity in disability and identifying related disablement process factors among Chinese oldest-old. Data came from eight waves of the Chinese Longitudinal Healthy Longevity Study (CLHLS). A hierarchical logistic Age-Period-Cohort (A-P-C) model was used to estimate the trend of gender disparity, and related disablement process factors were further decomposed by the Oaxaca-Blinder decomposition. Our results found that women had higher disabilities than men. The age-based trend of gender disparity in Instrumental Activities of Daily Living (IADL) continued to decline; that in Functional Limitation (FL) increased at first and then declined. The cohort-based trend of gender disparity in IADL showed a decreasing trend with each subsequent cohort; that in FL showed an increasing trend. Among the disablement process factors, health behaviors and social supports were the most important contributors to gender disparity in disability. The disability was higher for women than men, and the gender differences were attenuated at very old ages. To reduce gender disparities in disability, more attention should be paid to relevant factors of gender disparity in disability.

Adverse Childhood Experiences, Family Support, and Depression: Evidence from Internal Migrants in China.

Previous studies have linked poor family support and adverse childhood experiences (ACEs) to increased risk of depression; however, little is known about the interplay between the two when it comes to their effects on depression. Therefore, the current study examined if family support moderated the cumulative effect of ACEs on depression. Based on data from a migrant survey in Shiyan, Hubei Province, in 2019 (N = 1,326), this study used the ordinary least squares method to analyze the effect of ACEs on depression and evaluate whether family support moderated this effect. Higher exposure to ACEs and lower scores of family support were associated with higher depression levels in adulthood. The moderation model indicated that family support significantly moderated the relationship between ACEs and depression. Appropriate interventions to reduce depression should target internal migrants with history of ACEs. Community nurses should consider ACEs as an integral part of psychosocial assessment. Negative effects of ACEs can be reduced through teaching skills that increase effective family interaction and maintain supportive family networks. [Journal of Psychosocial Nursing and Mental Health Services, 61(3), 19-25.].

Investigating the paradox of increasing obesity and declining heart disease mortality in the United States: Age-period-cohort model.

Background: Obesity as a risk factor of heart disease (HD) is confirmed through observational, laboratory, and intervention studies. However, it cannot explain why HD declines, but obesity increases in the United States in recent decades. This study attempted to understand this paradox. Methods: Annual data of national HD mortality (1999-2018) were derived from Wide-Ranging Online Data for Epidemiologic Research, biannual obesity data (1999-2016) from the National Health and Nutrition Examination Survey, and smoking data (1965-1990) were from the National Health Interview Survey. Age-period-cohort method was used to decompose HD mortality into age, period, and cohort effects, and to estimate age-cohort adjusted mortality rates. To explain the paradox, age-cohort adjusted rates were associated with obesity rates to verify the positive obesity-HD relationship, while smoking rates were associated with cohort effects to explain the current declines in HD mortality. Results: During 1999-2018, the prevalence of obesity increased while the crude HD mortality rate declined for both sex and all races. After controlling for the curvilinear age effect and consistent declining cohort effect, the age-cohort adjusted HD mortality sustained stable in 1999-2007 and increased thereafter. The age-cohort adjusted rate in 1999-2018 (per 100,000) increased from 189.31 to 238.56 for males, 67.23 to 90.28 for females, 115.54 to 157.39 for White, 246.40 to 292.59 for Black, 79.79 to 101.40 for Hispanics, and 49.95 to 62.86 for Asian. The age-cohort adjusted HD mortality rates were positively associated with obesity rates (r = 0.68 for males, 0.91 for females, 0.89 for White, and 0.69 for Hispanic, p < 0.05), but not significant for Black and Asian. Further, during 1965-1990, the estimated cohort effect showed a decline in HD risk and was positively associated with smoking rates (r = 0.98 for both sex, 0.99 for White, and 0.98 for Black, p < 0.01). Conclusion: Study findings reveal potential increase of HD risk and support the positive relationship between obesity and HD risk. Declines in HD mortality in the past two decades are primarily due to tobacco use reduction and this protective effect was entangled in the mortality rates as cohort effect.

The relationship between childhood abuse and depression among adolescents: The mediating role of school connectedness and psychological resilience.

BACKGROUND: Adolescent depression is a major public health concern worldwide, and depressive symptoms among adolescents in Chinese secondary school increase with grade. Although numerous studies noted that childhood abuse was associated with the development of depression in adolescents, the underlying mediators involved in this pathway remain unclear. Therefore, our study aims to explore whether psychological resilience and school connectedness mediate the association between childhood abuse and depression among Chinese adolescents. METHODS: A cross-sectional survey was carried out among 1607 adolescents at four high schools located in Henan Province, Central China. Structural equation modeling was performed to determine whether psychological resilience and school connectedness mediate the influence of childhood abuse on depression. RESULTS: Findings revealed that childhood abuse was directly (ß = 0.410, p < 0.001) and indirectly (ß = 0.141, p < 0.001) related to depression. Specifically, psychological resilience (ß = 0.018, p = 0.009), school connectedness (ß = 0.087, p < 0.001), and school connectedness together with psychological resilience (ß = 0.036, p < 0.001) partially mediated the relationship between childhood abuse and depression. CONCLUSIONS: The detrimental impact of childhood abuse on adolescents' depression may be reduced by fostering psychological resilience and school connectedness.

Growth hormone attenuates the brain damage caused by ZIKV infection in mice.

As a member of vector-borne viruses, Zika virus (ZIKV) can cause microcephaly and various neurological symptoms in newborns. Previously, we found that ZIKV could infect hypothalamus, causing a decrease in growth hormone (GH) secretion, growth delay and deficits in learning and memory in suckling mice. Early administration of GH can improve the cognitive function of the mice. Therefore, in this study we further investigated the mechanism underlying the protective role of GH in ZIKV infection in suckling mice. Our results showed that GH could effectively reduce brain damage caused by ZIKV infection via reducing cell apoptosis and inflammatory response rather than inhibiting viral replication. Our results provide important evidences not only for understanding the mechanism underlying ZIKV-associated neurological symptoms but also for the treatment of ZIKV infection.

Rasmussen's encephalitis is characterized by relatively lower production of IFN-ß and activated cytotoxic T cell upon herpes viruses infection.

BACKGROUND: The etiology of Rasmussen's encephalitis (RE), a rare chronic neurological disorder characterized by CD8+ T cell infiltration and unihemispheric brain atrophy, is still unknown. Various human herpes viruses (HHVs) have been detected in RE brain, but their contribution to RE pathogenesis is unclear. METHODS: HHVs infection and relevant immune response were compared among brain tissues from RE, temporal lobe epilepsy (TLE) and traumatic brain injury (TBI) patients. Viral antigen or genome, CD8+ T cells, microglia and innate immunity molecules were analyzed by immunohistochemical staining, DNA dot blot assay or immunofluorescence double staining. Cytokines were measured by multiplex flow cytometry. Cell apoptosis was visualized by TUNEL staining. Viral infection, immune response and the severity of unihemispheric atrophy were subjected to correlation analysis. RESULTS: Antigens of various HHVs were prevalent in RE and TLE brains, and the cumulative viral score of HHVs positively correlated with the unihemispheric atrophy in RE patients. CD8+ T cells infiltration were observed in both RE and TLE brains and showed co-localization with HHV antigens, but their activation, as revealed by Granzyme B (GZMB) release and apoptosis, was found only in RE. In comparison to TLE, RE brain tissues contained higher level of inflammatory cytokines, but the interferon-ß level, which was negatively correlated with cumulative viral score, was relatively lower. In line with this, the DNA sensor STING and IFI16, rather than other innate immunity signaling molecules, were insufficiently activated in RE. CONCLUSIONS: Compared with TBI, both RE and TLE had prevalently HHV infection and immune response in brain tissues. However, in comparison to TLE, RE showed insufficient activation of antiviral innate immunity but overactivation of cytotoxic T cells. Our results show the relatively lower level of antiviral innate immunity and overactivation of cytotoxic T cells in RE cases upon HHV infection, the overactivated T cells might be a compensate to the innate immunity but the causative evidence is lack in our study and need more investigation in the future.

How workplace violence correlates turnover intention among Chinese health care workers in COVID-19 context: The mediating role of perceived social support and mental health.

AIM: To elucidate the effects of workplace violence on turnover intention among Chinese health care workers, and to identify the potential mediators in this relationship. BACKGROUND: Workplace violence has emerged as a crucial determinant of turnover intention for health care workers. METHODS: A cross-sectional survey was conducted among Chinese health care workers (N = 1,063) between 13 and 20 February 2020. Mediation effects were tested using structural equation modelling with weighted least squares mean and variance adjusted (WLSMV) estimator. RESULTS: Workplace violence had both direct and indirect effects on turnover intention among Chinese health care workers. Specifically, perceived social support, mental health and perceived social support together with mental health partially mediated the relationship between workplace violence and turnover intention. CONCLUSIONS: Chinese health care workers experiencing violence during the COVID-19 outbreak were more likely to report turnover intention. Enhancing social support and reducing mental health problems would be beneficial in decreasing the detrimental effects of workplace violence on turnover intention. IMPLICATIONS FOR NURSING MANAGEMENT: Ensuring health care workers' health and safety is vital in reducing turnover intention, which in turn ascertains continuity of health care delivery. Health care managers should develop targeted interventions to improve social support and prevent post-violence mental health problems.

How does health literacy affect the utilization of basic public health services in Chinese migrants?

Previous studies have focused on the determinants of basic public health services utilization, such as socioeconomic status and mobility characteristics, rather than on health literacy. Thus, this study aimed to estimate the effect of health literacy on the utilization of basic public health services among Chinese migrants. Based on the 2016 China Migrants Dynamic Survey data (N = 2335), this study used propensity score matching approach to estimate the effect of health literacy on the utilization of basic public health services, including the establishment of health records and receipt of health education, and to explore heterogeneity in this effect based on educational attainment and urban-rural status. The findings show that high levels of health literacy increased the probability of establishing health records and receiving more health education. Also, high levels of health literacy had a positive effect on the utilization of basic public health services among Chinese migrants, especially those with less education or living in urban areas. Policy makers should more carefully consider the actual situation and needs of migrants who are living in urban areas or have less education, constructing more targeted service programs.

Epidemiological and clinical characteristics of the chikungunya outbreak in Ruili City, Yunnan Province, China.

Chikungunya fever is an acute infectious disease caused by the chikungunya virus (CHIKV) that is characterized by fever, rash, and joint pain. CHIKV has infected millions of people in Africa, Asia, America, and Europe since it re-emerged in the Indian Ocean region in 2004. Here, we report an outbreak of Chikungunya fever that occurred in Ruili of Yunnan Province, a city located on the border between China and Myanmar, in September 2019. The outbreak lasted for three months from September to December. Overall, 112 cases were confirmed by a real-time reverse-transcription polymerase chain reaction in the Ruili People's Hospital, and they showed apparent temporal, spatial, and population aggregation. Among them, 91 were local cases distributed in 19 communities of Ruili City, and 21 were imported cases. The number of female patients was higher than that of male patients, and most patients were between 20 and 60 years old. The main clinical manifestations included joint pain (91.96%), fever (86.61%), fatigue (58.04%), chills (57.14%), rash (48.21%), headache (39.29%), and so forth. Biochemical indexes revealed increased C-reactive protein (63.39%), lymphopenia (57.17%), increased hemoglobin (33.04%), neutrophilia (28.57%), and thrombocytopenia (16.07%). Phylogenetic analysis of the complete sequences indicated that the CHIKV strains in this outbreak belonged to the Indian Ocean clade of the East/Central/South African genotype. We speculated that this chikungunya outbreak might be caused by CHIKV-infected persons returning from Myanmar, and provided a reference for the formulation of effective treatment and prevention measures.

Zika Virus Infection in the Ovary Induces a Continuously Elevated Progesterone Level and Compromises Conception in Interferon Alpha/Beta Receptor-Deficient Mice.

Zika virus (ZIKV) belongs to mosquito-borne flaviviruses. Unlike other members in the family, ZIKV can be sexually transmitted, and the female genital tracts are susceptible to ZIKV. However, the impact of ZIKV infection on nonpregnant female reproductive health is not understood. In this study, we investigated the effects of ZIKV infection on the ovary by using nonpregnant female interferon α/ß receptor-deficient (Ifnar1-/-) mice. The results showed that the ovary supported ZIKV replication, and the granulosa and theca cells of antral follicles were susceptible. ZIKV replication in situ significantly reduced the numbers of antral follicles, aggravated follicular atresia, and disrupted folliculogenesis. Notably, ZIKV replication in the ovary caused disordered ovarian steroidogenesis manifested by decreased expression of key enzymes linked to sex hormone synthesis, including the cytochrome P450 17A1 (CYP17A1) and aromatase (CYP19A1). Further, we observed that ZIKV infection disrupted the estrous cycle and thus prolonged the time to conceive. More importantly, although ZIKV RNA could not be detected at 3 months postinfection, damaged ovarian structure and dysfunction were also observed. Taken together, our study demonstrates that ZIKV infection in nonpregnant female mice cause ovarian damage and dysfunction, even long after ZIKV clearance. These data provide important information to understand the effects of ZIKV infection in female reproductive tissues and basic evidence for further studies. IMPORTANCE Zika virus (ZIKV), a flavivirus, is primarily transmitted by mosquito bites. But it can also be transmitted vertically and sexually. Although ZIKV-associated Guillain-Barré syndrome and microcephaly have drawn great attention, there have been few studies on the potential effects of ZIKV on the genital tract of nonpregnant females. This study investigated the effects of ZIKV on the ovaries in mice. We found that ZIKV replicated in the ovary and the granulosa and theca cells of antral follicles were susceptible. ZIKV replication in situ significantly damaged ovarian structure and function and disrupted folliculogenesis. Notably, ZIKV infection further disrupted the estrous cycle and prolonged the time to conceive in mice by causing disordered ovarian steroidogenesis. These effects were observed in both the acute phase and the recovery phase after viral elimination. Overall, the new findings provide important additions to make out the potential adverse impacts of ZIKV on reproductive health in females.

Genetic Factors in Rasmussen's Encephalitis Characterized by Whole-Exome Sequencing.

Rasmussen's encephalitis (RE) is a rare chronic neurological disorder characterized by unihemispheric brain atrophy and epileptic seizures. The mechanisms of RE are complex. Adaptive immunity, innate immunity and viral infection are all involved in the development of RE. However, there are few studies on the role of genetic factors in the mechanisms of RE. Thus, the objective of this study was to reveal the genetic factors in the mechanisms of RE. Whole-exome sequencing (WES) was performed in 15 RE patients. Ten patients with temporal lobe epilepsy (TLE), which is a common and frequently intractable seizure disorder, were used as the controls. Thirty-one non-silent single nucleotide variants (SNVs) affecting 16 genes were identified in the RE cases. The functions of the genes with SNVs were associated with antigen presentation, antiviral infection, epilepsy, schizophrenia and nerve cell regeneration. Genetic factors of RE were found first in this study. These results suggest that RE patients have congenital abnormalities in adaptive immunity and are susceptible to some harmful factors, which lead to polygenic abnormal disease.