A missing jigsaw within the hygiene hypothesis: Low-dose bisphenol A exposure attenuates lipopolysaccharide-induced asthma protection.

The rising occurrence of allergic asthma in early life across industrialized countries suggests that environmental factors play a crucial role in determining asthma susceptibility and severity. While prior exposure to microbial lipopolysaccharides (LPSs) has been found to offer protection against allergic asthma, infants residing in urban environments are increasingly exposed to environmental pollutants. Utilizing limulus lysate test screens and virtual screening models, we identified pollutants that can modulate LPS bioactivity. This investigation revealed that bisphenol A (BPA), a chemical commonly used in numerous household items and previously implicated in obesity and cancer, effectively neutralizes LPS. In-depth mechanistic analyses showed that BPA specifically binds to the lipid A component of LPS, leading to inactivation. This interaction eliminates the immunostimulatory activity of LPS, making mice more susceptible to house dust mite (HDM)-induced allergic asthma. BPA reactivates lung epithelial cells, consequently amplifying type 2 responses to HDMs in dendritic cells. This chemical interplay provides new insights into the pathophysiology of asthma in relation to human exposure. Understanding the intricate relationships between environmental chemicals and microbial antigens, as well as their impacts on innate immunity, is critical for the development of intervention strategies to address immune disorders resulting from urbanization.

Current status and influencing factors of policy identification in health impact assessment: a case study of Zhejiang Province.

BACKGROUND: Health impact assessment (HIA) is a procedure, method and tool for evaluating the potential health impacts of policies, plans and construction projects, as well as the distribution of these impacts on population. Majority of international studies on health impact assessment have focussed on conceptual papers or case evaluations, neglecting participants' views on policies. METHODS: A semi-structured interview with 30 health impact assessment experts was employed in this study, and the Nvivo software was utilized to analyse factors that influence policy identification. Subsequently, a multi-stage stratified random sampling method was adopted to survey 655 pilot staff members involved in health impact assessment in Zhejiang Province. Descriptive statistics were used to describe the current status and identify the factors influencing policy identification. In addition, hierarchical linear regression analysis and structural equation modelling were employed to determine the relationship between policy identification and influencing factors. RESULTS: Statistically significant differences were found among participants in the level of identification of policies across three dimensions. The policy sentiment dimension had the highest score (4.137 ± 0.664), followed by policy cognition (4.075 ± 0.632) and policy evaluation (3.631 ± 0.797) dimensions. Subject trust had a positive impact on policy cognition (ß = 0.503, P < 0.001), policy sentiment (ß = 0.504, P < 0.001) and policy evaluation (ß = 0.465, P < 0.001). Procedural justice had a positive impact on policy sentiment (ß = 0.085, P < 0.01) and policy evaluation (ß = 0.084, P < 0.05), but not policy cognition (ß = 0.056, P > 0.05). Policy identification is influenced by age and average monthly salary among other factors. CONCLUSION: These results highlight the importance of subjective trust and procedural justice in policy identification of health impact assessment. They provide valuable insights to developing interventions to overcome barriers to the implementation and enhancement of global identification of policies. Going forward, cross-sectoral synergies, enhanced international communication and training to increase participants' trust in the policy should be optimized to improve health impact assessment. Additional measures should be taken, such as ensuring seamless communication channels, embedding health impact assessment in administrative mechanisms, and establishing strong oversight and grievance mechanisms to improve fairness and transparency in the implementation and results of health impact assessment.

A Roadmap for a Consensus Human Skin Cell Atlas and Single-Cell Data Standardization.

Single-cell technologies have become essential to driving discovery in both basic and translational investigative dermatology. Despite the multitude of available datasets, a central reference atlas of normal human skin, which can serve as a reference resource for skin cell types, cell states, and their molecular signatures, is still lacking. For any such atlas to receive broad acceptance, participation by many investigators during atlas construction is an essential prerequisite. As part of the Human Cell Atlas project, we have assembled a Skin Biological Network to build a consensus Human Skin Cell Atlas and outline a roadmap toward that goal. We define the drivers of skin diversity to be considered when selecting sequencing datasets for the atlas and list practical hurdles during skin sampling that can result in data gaps and impede comprehensive representation and technical considerations for tissue processing and computational analysis, the accounting for which should minimize biases in cell type enrichments and exclusions and decrease batch effects. By outlining our goals for Atlas 1.0, we discuss how it will uncover new aspects of skin biology.

Effects of Social Networks on Job Performance of Individuals among the Hypertension Management Teams in Rural China.

BACKGROUND: Limited studies have explored the relationship among cross-organizational and multidisciplinary medical staff. AIM: The present study conducted an in-depth examination and validation of the influence of complex cross-organization and multidisciplinary social networks on the job performance of team members. METHOD: Multi-level hierarchical regression analysis was used to assess the impact of the centrality and the characteristics of structural holes in social networks (i.e., advice network, information network, friendship network, and trust network) on job performance. RESULTS: The in-closeness centrality of the advice network (ß = 0.176, p < 0.05) and the betweenness centrality of the trust network (ß = 0.126, p < 0.05) had positive effects on task performance. The in-closeness centrality of the advice network (ß = 0.226, p < 0.05; ß = 0.213, p < 0.05) and the CI (1 - constraint index) of the friendship network (ß = 0.130, p < 0.05; ß = 0.132, p < 0.05) had positive effects on contextual performance and overall job performance. Meanwhile, the out-closeness centrality of the information network (ß = -0.368, p < 0.01; ß = -0.334, p < 0.05) had a negative effect on contextual performance and overall job performance. CONCLUSIONS: This study investigates the relationship between healthcare professionals' job performance and their social networks, taking into account the perspectives of cross-organizational and multidisciplinary teams. The study contributes to the effort of breaking down barriers between different disciplines and organizations, and ultimately, improving the quality of healthcare delivery.

Signalling by senescent melanocytes hyperactivates hair growth.

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

Bifurcation analysis in a Holling-Tanner predator-prey model with strong Allee effect.

In this paper, we analyze the bifurcation of a Holling-Tanner predator-prey model with strong Allee effect. We confirm that the degenerate equilibrium of system can be a cusp of codimension 2 or 3. As the values of parameters vary, we show that some bifurcations will appear in system. By calculating the Lyapunov number, the system undergoes a subcritical Hopf bifurcation, supercritical Hopf bifurcation or degenerate Hopf bifurcation. We show that there exists bistable phenomena and two limit cycles. By verifying the transversality condition, we also prove that the system undergoes a Bogdanov-Takens bifurcation of codimension 2 or 3. The main conclusions of this paper complement and improve the previous paper [30]. Moreover, numerical simulations are given to verify the theoretical results.

Delivery of spike-RBD by bacterial type three secretion system for SARS-CoV-2 vaccine development.

COVID-19 pandemic continues to spread throughout the world with an urgent demand for a safe and protective vaccine to effectuate herd protection and control the spread of SARS-CoV-2. Here, we report the development of a bacterial vector COVID-19 vaccine (aPA-RBD) that carries the gene for the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Live-attenuated strains of Pseudomonas aeruginosa (aPA) were constructed which express the recombinant RBD and effectively deliver RBD protein into various antigen presenting cells through bacterial type 3 secretion system (T3SS) in vitro. In mice, two-dose of intranasal aPA-RBD vaccinations elicited the development of RBD-specific serum IgG and IgM. Importantly, the sera from the immunized mice were able to neutralize host cell infections by SARS-CoV-2 pseudovirus as well as the authentic virus variants potently. T-cell responses of immunized mice were assessed by enzyme-linked immunospot (ELISPOT) and intracellular cytokine staining (ICS) assays. aPA-RBD vaccinations can elicit RBD-specific CD4+and CD8+T cell responses. T3SS-based RBD intracellular delivery heightens the efficiency of antigen presentation and enables the aPA-RBD vaccine to elicit CD8+T cell response. Thus, aPA vector has the potential as an inexpensive, readily manufactured, and respiratory tract vaccination route vaccine platform for other pathogens.

Dimethylation of histone H3 lysine 36 (H3K36me2) as a potential biomarker for glioma diagnosis, grading, and prognosis.

Abnormal histone methylation plays a key role in glioma development but the clinical value of specific alterations is still unclear. Here, the potential significance of histone H3 lysine 36 dimethylation (H3K36me2) was investigated as a biomarker for glioma. Seventy-three glioma patients were included in the study and the level of H3K36me2 in the tumor tissues was determined by immunohistochemistry. The χ2 test was used to explore the influence of clinical and pathological characteristics on H3K36me2 levels. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS). COX regression was used to explore the relationship between H3K36me2 levels and glioma prognosis. The results indicated that the H3K36me2 level increases with glioma grade. The proportion of high H3K36me2 levels was lower in glioma patients under the age of 52 years. H3K36me2 levels were negatively correlated with IDH1 mutation and MGMT promoter methylation, and positively correlated with p53 expression. Thus, high H3K36me2 levels positively correlated with poor prognosis of gliomas. In conclusion, H3K36me2 may be considered as a potential biomarker for glioma diagnosis, grading, and prognosis, but the overall clinical value of H3K36me2 determination deserves further investigation. These results may have important implications for accurate diagnosis and future precision treatment of gliomas.

The associations of APP, PSEN1, and PSEN2 genes with Alzheimer's disease: A large case-control study in Chinese population.

AIM: The associations of non-pathogenic variants of APP, PSEN1, and PSEN2 with Alzheimer's disease (AD) remain unclear. This study is aimed at determining the role of these variants in AD. METHODS: Our study recruited 1154 AD patients and 2403 controls. APP, PSEN1, PSEN2, and APOE were sequenced using a targeted panel. Variants were classified into common or rare variants with the minor allele frequencies (MAF) cutoff of 0.01. Common variant (MAF≥0.01)-based association test was performed by PLINK 1.9, and gene-based (MAF <0.01) association analysis was conducted using Sequence Kernel Association Test-Optimal (SKAT-O test). Additionally, using PLINK 1.9, we performed AD endophenotypes association studies. RESULTS: A common variant, PSEN2 rs11405, was suggestively associated with AD risk (p = 1.08 × 10-2 ). The gene-based association analysis revealed that the APP gene exhibited a significant association with AD (p = 1.43 × 10-2 ). In the AD endophenotypes association studies, APP rs459543 was nominally correlated with CSF Aß42 level (p = 7.91 × 10-3 ). CONCLUSION: Our study indicated that non-pathogenic variants in PSEN2 and APP may be involved in AD pathogenesis in the Chinese population.

Engineering Immunomodulatory Biomaterials to Drive Skin Wounds toward Regenerative Healing.

The healing of human skin wounds is designed for a rapid fibroproliferative response at the expense of tissue complexity and is therefore prone to scar formation. Moreover, wound healing often goes awry when excessive inflammation leads to chronic nonhealing wounds or when excessive repair results in uncontrolled tissue fibrosis. The immune system plays a central role in orchestrating wound healing, and, thus, controlling immune cell activities holds great potential for reducing scars and enhancing regeneration. Biomaterial dressings directly interact with immune cells in the wound and have been shown to improve the repair process. A few studies have even shown that biomaterials can induce complete regeneration through mechanisms involving immune cells. Here, we review the role of the immune system in skin repair and regeneration and describe how advances in biomaterial research may uncover immunomodulatory elements to enhance fully functional skin regeneration.

Significance of differential expression of OLFM4 in the development of endometrial adenocarcinoma.

The incidence of endometrial adenocarcinoma (EA) has increased worldwide in recent years due to the widespread use of estrogen therapy and the overall increase in life expectancy. However, we know of no sensitive molecular index that can be used to predict the onset of EA, evaluate the therapeutic effects of treatment agents, or provide prognostic benefit in post-treatment follow-up. To explore the correlation between human olfactomedin 4 (OLFM4) and the clinicopathologic parameters of EA, and to determine the precise involvement of OLFM4 as a related factor in the occurrence and development of EA. We enrolled 61 gynecologic patients for a retrospective study at the Tai'an Central Hospital of Shandong Province from January 1, 2016, to June 30, 2022. We determined the expression levels of estrogen receptor α (ERα), progesterone receptor (PR), and OLFM4 proteins in endometrial tissue with the immunohistochemical S-P staining method, and analyzed the correlations among ERα, PR, and OLFM4 protein expression levels and with the pathologic stage, histologic grade, myometrial invasiveness, and lymphatic metastasis of EA. The expression levels of OLFM4 in EA were higher than in normal endometrium (P = .036). The expression level of OLFM4 protein in stage II-III patients was higher than that in stage I patients (P = .034), and the expression levels of ERα and PR proteins in EA were lower than those in normal endometrial tissue (P = .014 and P = .0005). While we observed no correlation in endometrial tissues of disparate pathologic types between OLFM4 and the expression levels of ERα and PR proteins, we noted a positive correlation between the expression levels of ERα and PR protein. The expression level of OLFM4 protein increased with the malignant degree of endometrial lesions and OLFM4 protein expression was related to the FIGO stage of EA. And OLFM4 protein can be used as 1 of the potential diagnostic factors for endometrial lesions, which is worthy of further study.

Clinical characteristics and genotype-phenotype correlation analysis of familial Alzheimer's disease patients with pathogenic/likely pathogenic amyloid protein precursor mutations.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with aging, environmental, and genetic factors. Amyloid protein precursor (APP) is a known pathogenic gene for familial Alzheimer's disease (FAD), and now more than 70 APP mutations have been reported, but the genotype-phenotype correlation remains unclear. In this study, we collected clinical data from patients carrying APP mutations defined as pathogenic/likely pathogenic according to the American college of medical genetics and genomics (ACMG) guidelines. Then, we reanalyzed the clinical characteristics and identified genotype-phenotype correlations in APP mutations. Our results indicated that the clinical phenotypes of APP mutations are generally consistent with typical AD despite the fact that they show more non-demented symptoms and neurological symptoms. We also performed genotype-phenotype analysis according to the difference in APP processing caused by the mutations, and we found that there were indeed differences in onset age, behavioral and psychological disorders of dementia (BPSD) and myoclonus.

CYLD variants identified in Alzheimer's disease and frontotemporal dementia patients.

OBJECTIVES: CYLD was a novel causative gene for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Given the clinical and pathological overlap of FTD and Alzheimer's disease (AD), it is necessary to screen CYLD in AD patients and FTD patients in the Chinese population. METHODS: In our study, using a targeted sequencing panel, we sequenced the CYLD gene in a large cohort of 2485 participants in the Chinese population, including 1008 AD patients, 105 FTD patients, and 1372 controls. RESULTS: In the present study, the average onset age of AD and FTD patients was 66.84 ± 30.42 years old and 60 ± 10.00 years old, respectively. Our study reported three novel CYLD variants: p.Phe288Leu (patient No. 1, AD), p.Tyr485Phe (patients No. 6-9, all AD) and p.Thr951Ala (patient No. 10, AD), plus a previously reported variant: p.Arg397Ser (patient No. 2-5, AD and No. 11, FTD). These variants were absent in our in-house controls and predicted to be deleterious according to the MutationTaster. The variant carriers were composed of 10 AD patients and one FTD patient, and the average onset age was 61.2 ± 10.9 years. The frequency of CYLD variants in AD was similar to that in FTD, which was 0.99% (10/1008) and 0.95% (1/105), respectively. INTERPRETATION: Our finding extended the genotype and phenotype of the CYLD gene and demonstrated that CYLD rare damaging variants may be implicated in AD and FTD pathogenesis.

Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state.

Hair follicle stem cells are regulated by dermal papilla fibroblasts, their principal signaling niche. Overactivation of Hedgehog signaling in the niche dramatically accelerates hair growth and induces follicle multiplication in mice. On single-cell RNA sequencing, dermal papilla fibroblasts increase heterogeneity to include new Wnt5ahigh states. Transcriptionally, mutant fibroblasts activate regulatory networks for Gli1, Alx3, Ebf1, Hoxc8, Sox18, and Zfp239. These networks jointly upregulate secreted factors for multiple hair morphogenesis and hair-growth-related pathways. Among these is non-conventional TGF-ß ligand Scube3. We show that in normal mouse skin, Scube3 is expressed only in dermal papillae of growing, but not in resting follicles. SCUBE3 protein microinjection is sufficient to induce new hair growth, and pharmacological TGF-ß inhibition rescues mutant hair hyper-activation phenotype. Moreover, dermal-papilla-enriched expression of SCUBE3 and its growth-activating effect are partially conserved in human scalp hair follicles. Thus, Hedgehog regulates mesenchymal niche function in the hair follicle via SCUBE3/TGF-ß mechanism.

Genetics of progressive supranuclear palsy in a Chinese population.

BACKGROUND: Genetics plays an important role in progressive supranuclear palsy (PSP) and remains poorly understood. A detailed literature search identified 19 PSP-associated genes: MAPT, LRRK2, LRP10, DCTN1, GRN, NPC1, PARK, TARDBP, TBK1, BSN, GBA, STX6, EIF2AK3, MOBP, DUSP10, SLCO1A2, RUNX2, CXCR4, and APOE. To date, genetic studies on PSP have focused on Caucasian population. The gaps in PSP genetic study on East Asian populations need to be filled. METHODS: Exon and flanking regions of the PSP-associated genes were sequenced in 104 patients with PSP and 488 healthy controls. Common variant-based association analysis and gene-based association tests of rare variants were performed using PLINK 1.9 and the sequence kernel association test-optimal, respectively. Additionally, the association of APOE and MAPT genotypes with PSP was evaluated. The above association analyses were repeated among probable PSP patients. Finally, PLINK 1.9 was used to test variants associated with the onset age of PSP. RESULTS: A rare non-pathogenic variant of MAPT (c.425C > T,p.A142V) was detected in a PSP patient. No common variants were significantly associated with PSP. In both the rare-variant and the rare-damaging-variant groups, the combined effect for GBA reached statistical significance (p = 1.43 × 10-3, p = 4.98 × 10-4). The result between APOE, MAPT genotypes and PSP risk were inconsistent across all PSP group and probably PSP group. CONCLUSIONS: The pathogenic variant in MAPT were uncommon in PSP patients. Moreover, GBA gene was likely to increase the risk of PSP, and GBA-associated diseases were beyond α-synucleinopathies. The association between APOE, MAPT and PSP is still unclear among the non-Caucasian population.

Single-cell analysis of human basal cell carcinoma reveals novel regulators of tumor growth and the tumor microenvironment.

How basal cell carcinoma (BCC) interacts with its tumor microenvironment to promote growth is unclear. We use singe-cell RNA sequencing to define the human BCC ecosystem and discriminate between normal and malignant epithelial cells. We identify spatial biomarkers of tumors and their surrounding stroma that reinforce the heterogeneity of each tissue type. Combining pseudotime, RNA velocity-PAGA, cellular entropy, and regulon analysis in stromal cells reveals a cancer-specific rewiring of fibroblasts, where STAT1, TGF-ß, and inflammatory signals induce a noncanonical WNT5A program that maintains the stromal inflammatory state. Cell-cell communication modeling suggests that tumors respond to the sudden burst of fibroblast-specific inflammatory signaling pathways by producing heat shock proteins, whose expression we validated in situ. Last, dose-dependent treatment with an HSP70 inhibitor suppresses in vitro vismodegib-resistant BCC cell growth, Hedgehog signaling, and in vivo tumor growth in a BCC mouse model, validating HSP70's essential role in tumor growth and reinforcing the critical nature of tumor microenvironment cross-talk in BCC progression.

Anesthetic management for cesarean section in parturient with an uncorrected single ventricle: A case report and literature review.

RATIONALE: Patients with a single ventricle, who have not undergone surgery, reportedly have a lower survival rate. Furthermore, multiple pregnancies are rare among these females. We reported a case of anesthesia management of cesarean section in an uncorrected single-ventricular multi-pregnancy woman and review the anesthesia management of the published similar cases. PATIENT CONCERNS: An uncorrected single ventricular pregnant woman with a cardiac function of New York Heart Association class II, who had experienced one spontaneous abortion and three vaginal deliveries, was scheduled for cesarean section at 37+6 weeks of gestation. DIAGNOSES: : Echocardiography revealed a complex congenital heart disease in the mother: a single ventricle (the left ventricle is dominant), atrioventricular valve ectopic, double-inlet left ventricle, abnormal location of the great arteries, probably pulmonary stenosis, atrial septal defect, and left-to-right shunt. The fetus was in breech presentation with umbilical cord around the neck. INTERVENTIONS: Cesarean section was successfully performed under the combined spinal epidural anesthesia with careful monitoring. OUTCOMES: : Both mother and newborn recovered good and were discharged from the hospital 5 days after surgery without any adverse reactions. LESSONS: Single ventricular pregnant woman with a cardiac function of New York Heart Association class I-II could tolerate pregnancy and delivery well. Both general and regional anesthesia are applicable to cesarean section in these patients. The principle of anesthesia management is to maintain the appropriate balance between systemic vascular resistance and pulmonary vascular resistance, as well as to maintain preload and cardiac output.

Variants in the Niemann-pick type C genes are not associated with Alzheimer's disease: a large case-control study in the Chinese population.

Despite the similar clinical and pathological features between Niemann-Pick type C (NPC) disease and Alzheimer's disease (AD), few studies have investigated the role of NPC genes in AD. To elucidate the role of NPC genes in AD, we sequenced NPC1 and NPC2 in 1192 AD patients and 2412 controls. Variants were divided into common variants and rare variants according to minor allele frequency (MAF). Common variant (MAF≥0.01) based association analysis was conducted by PLINK 1.9. Gene-based aggregation testing of rare variants was performed by Sequence Kernel Association Test-Optimal (SKAT-O test), respectively. Age at onset (AAO) and mini-mental state examination (MMSE) association studies were also performed with PLINK 1.9. Six common variants were identified and exhibited no association with AD. Gene-based aggregation testing revealed that both NPC1 and NPC2 were not associated with AD risk. Additionally, AAO and MMSE association studies revealed that no common variants were linked with AD endophenotypes. Taken together, our study indicated that NPC1 and NPC2 may not be implicated in AD pathogenesis in the Chinese population.