Phase 1 Open-Label Dose Escalation Trial for the Development of a Human Bacillus Calmette-Guérin Challenge Model for Assessment of Tuberculosis Immunity In Vivo.

BACKGROUND: A controlled human infection model for assessing tuberculosis (TB) immunity can accelerate new vaccine development. METHODS: In this phase 1 dose escalation trial, 92 healthy adults received a single intradermal injection of 2 × 106 to 16 × 106 colony-forming units of Bacillus Calmette-Guérin (BCG). The primary endpoints were safety and BCG shedding as measured by quantitative polymerase chain reaction, colony-forming unit plating, and MGIT BACTEC culture. RESULTS: Doses up to 8 × 106 were safe, and there was evidence for increased BCG shedding with dose escalation. The MGIT time-to-positivity assay was the most consistent and precise measure of shedding. Power analyses indicated that 10% differences in MGIT time to positivity (area under the curve) could be detected in small cohorts (n = 30). Potential biomarkers of mycobacterial immunity were identified that correlated with shedding. Transcriptomic analysis uncovered dose- and time-dependent effects of BCG challenge and identified a putative transcriptional TB protective signature. Furthermore, we identified immunologic and transcriptomal differences that could represent an immune component underlying the observed higher rate of TB disease incidence in males. CONCLUSIONS: The safety, reactogenicity, and immunogenicity profiles indicate that this BCG human challenge model is feasible for assessing in vivo TB immunity and could facilitate the vaccine development process. CLINICAL TRIALS REGISTRATION: NCT01868464 (ClinicalTrials.gov).

Place Visitation Data Reveals the Geographic and Racial Disparities of COVID-19 Impact on HIV Service Utilization in the Deep South.

BACKGROUND: The COVID-19 pandemic has posed unprecedented pressure to health care systems, and interrupted health care delivery and access including HIV care in the United States' Deep South, which endures a double epidemic of HIV and COVID-19. Ryan White programs cover HIV care services for over half of PLWH in the Deep South. Given the important role of Ryan White programs, examining the visitation changes to Ryan White facilities during the pandemic offers insights into the impact of the pandemic on HIV healthcare utilization. OBJECTIVES: Analyze the geographic distribution of HIV facility visitors at the county level before and during the pandemic in the nine US states of Deep South (Alabama, Florida, Georgia, Louisiana, Mississippi, North Carolina, South Carolina, Tennessee, Texas) to reveal the geographic and racial disparity in visitation disruption caused by the pandemic. METHODS: We first extracted mobile device-based visitation data for Ryan White HIV facilities in the Deep South during 2019 and 2020. To quantify the disruption in visitations during 2020, we calculated the visitation reduction rate (VRR) for each county, using 2019 data as the baseline. Next, we conducted a spatial analysis of the VRR values to uncover geographical disparities in visitation interruptions. To investigate racial disparities, we performed spatial regression analyses with VRR as the dependent variable, and the percentages of Black, Hispanic, and Asian populations as the independent variables. In this analysis, we controlled for potential confounders. RESULTS: Geographic disparities in visitation reduction were observed, with all nine Deep South states experiencing significant drops. Georgia experienced the highest visitation loss (VRR = -0.58), followed by Texas (-0.47), Alabama (0.47), and Tennessee (-0.46), while South Carolina had the smallest reductions (-0.11). All the regression models consistently revealed racial disparities in visitation interruption. That is, counties with a higher proportion of Black population tended to have higher RW facility visitation reductions. CONCLUSIONS: Our analysis revealed distinct geographic disparities in visitation interruptions at Ryan White HIV facilities in the Deep South during the COVID-19 pandemic in 2020. Furthermore, we found that the Black/African American population experienced a greater disruption at the county level in the Deep South during this period.

Public Surveillance of Social Media for Suicide Using Advanced Deep Learning Models in Japan: Time Series Study From 2012 to 2022.

BACKGROUND: Social media platforms have been increasingly used to express suicidal thoughts, feelings, and acts, raising public concerns over time. A large body of literature has explored the suicide risks identified by people's expressions on social media. However, there is not enough evidence to conclude that social media provides public surveillance for suicide without aligning suicide risks detected on social media with actual suicidal behaviors. Corroborating this alignment is a crucial foundation for suicide prevention and intervention through social media and for estimating and predicting suicide in countries with no reliable suicide statistics. OBJECTIVE: This study aimed to corroborate whether the suicide risks identified on social media align with actual suicidal behaviors. This aim was achieved by tracking suicide risks detected by 62 million tweets posted in Japan over a 10-year period and assessing the locational and temporal alignment of such suicide risks with actual suicide behaviors recorded in national suicide statistics. METHODS: This study used a human-in-the-loop approach to identify suicide-risk tweets posted in Japan from January 2013 to December 2022. This approach involved keyword-filtered data mining, data scanning by human efforts, and data refinement via an advanced natural language processing model termed Bidirectional Encoder Representations from Transformers. The tweet-identified suicide risks were then compared with actual suicide records in both temporal and spatial dimensions to validate if they were statistically correlated. RESULTS: Twitter-identified suicide risks and actual suicide records were temporally correlated by month in the 10 years from 2013 to 2022 (correlation coefficient=0.533; P<.001); this correlation coefficient is higher at 0.652 when we advanced the Twitter-identified suicide risks 1 month earlier to compare with the actual suicide records. These 2 indicators were also spatially correlated by city with a correlation coefficient of 0.699 (P<.001) for the 10-year period. Among the 267 cities with the top quintile of suicide risks identified from both tweets and actual suicide records, 73.5% (n=196) of cities overlapped. In addition, Twitter-identified suicide risks were at a relatively lower level after midnight compared to a higher level in the afternoon, as well as a higher level on Sundays and Saturdays compared to weekdays. CONCLUSIONS: Social media platforms provide an anonymous space where people express their suicidal thoughts, ideation, and acts. Such expressions can serve as an alternative source to estimating and predicting suicide in countries without reliable suicide statistics. It can also provide real-time tracking of suicide risks, serving as an early warning for suicide. The identification of areas where suicide risks are highly concentrated is crucial for location-based mental health planning, enabling suicide prevention and intervention through social media in a spatially and temporally explicit manner.

Revealing geographic transmission pattern of COVID-19 using neighborhood-level simulation with human mobility data and SEIR model: A case study of South Carolina.

Direct human physical contact accelerates COVID-19 transmission. Smartphone mobility data has emerged as a valuable data source for revealing fine-grained human mobility, which can be used to estimate the intensity of physical contact surrounding different locations. Our study applied smartphone mobility data to simulate the second wave spreading of COVID-19 in January 2021 in three major metropolitan statistical areas (Columbia, Greenville, and Charleston) in South Carolina, United States. Based on the simulation, the number of historical county-level COVID-19 cases was allocated to neighborhoods (Census block groups) and points of interest (POIs), and the transmission rate of each allocated place was estimated. The result reveals that the COVID-19 infections during the study period mainly occurred in neighborhoods (86%), and the number is approximately proportional to the neighborhood's population. Restaurants and elementary and secondary schools contributed more COVID-19 infections than other POI categories. The simulation results for the coastal tourism Charleston area show high transmission rates in POIs related to travel and leisure activities. The results suggest that neighborhood-level infectious controlling measures are critical in reducing COVID-19 infections. We also found that households of lower socioeconomic status may be an umbrella against infection due to fewer visits to places such as malls and restaurants associated with their low financial status. Control measures should be tailored to different geographic locations since transmission rates and infection counts of POI categories vary among metropolitan areas.

Genome sequencing and functional annotation of Bacillus sp. strain BS-Z15 isolated from cotton rhizosphere soil having antagonistic activity against Verticillium dahliae.

In the present study, antagonistic activity of bacterial strain BS-Z15, was evaluated against Verticillium dahlia. The fermented broth of BS-Z15 inhibited the growth of Verticillium dahliae. The genome of strain BS-Z15 had a total size of 4,068,702 base pairs and contained 4318 genes, of which 4196 are coding sequences and 122 are non-coding RNA. Among these genes, nine genomic islands, 86 tRNAs, 13 sRNAs, and one prophage was determined. With the help of annotation databases, most unigene functions were identified. At the same time, genomic comparison between BS-Z15 and 12 Bacillus members showed that the genes of BS-Z15 were closely related to the Bacillus group, and were conserved between the two groups, including most of the genes associated with fungal antagonism. BS-Z15 contains genes involved in a variety of antagonistic mechanisms, including genes encoding or synthesizing mycosubtilin, chitinases (but not CHIA and CHIB), glycoside hydrolases, iron nutrients, and antibiosis. However, it only contained the complete mycosubtilin- and bacilibactin-related operators in the reported main antifungal gene cluster of B. subtilis. Mycosubtilin and bacilibactin may be the main active antifungal substance. Besides, some genes could encode products related to biofilm production, which may be related to the colonization ability of the strain in plant rhizospheres. The complete genome of B. subtilis BS-Z15 provided new insights into the potential metabolites it produces related to its biocontrol activity.

Monocyte chemotactic protein-induced protein 1 controls allergic airway inflammation by suppressing IL-5-producing TH2 cells through the Notch/Gata3 pathway.

BACKGROUND: Asthmatic and allergic inflammation is mediated by TH2 cytokines (IL-4, IL-5, and IL-13). Although we have learned much about how TH2 cells are differentiated, the TH2 checkpoint mechanisms remain elusive. OBJECTIVES: In this study we investigate how monocyte chemotactic protein-induced protein 1 (MCPIP1; encoded by the Zc3h12a gene) regulates IL-5-producing TH2 cell differentiation and TH2-mediated inflammation. METHODS: The functions of Zc3h12a-/- CD4 T cells were evaluated by checking the expression of TH2 cytokines and transcription factors in vivo and in vitro. Allergic airway inflammation of Zc3h12a-/- mice was examined with murine asthma models. In addition, antigen-specific CD4 T cells deficient in MCPIP1 were transferred to wild-type recipient mice, challenged with ovalbumin (OVA) or house dust mite (HDM), and accessed for TH2 inflammation. RESULTS: Zc3h12a-/- mice have spontaneous severe lung inflammation, with an increase in mainly IL-5- and IL-13-producing but not IL-4-producing TH2 cells in the lung. Mechanistically, differentiation of IL-5-producing Zc3h12a-/- TH2 cells is mediated through Notch signaling and Gata3 independent of IL-4. Gata3 mRNA is stabilized in Zc3h12a-/- TH2 cells. MCPIP1 promotes Gata3 mRNA decay through the RNase domain. Furthermore, deletion of MCPIP1 in OVA- or HDM-specific T cells leads to significantly increased TH2-mediated airway inflammation in OVA or HDM murine models of asthma. CONCLUSIONS: Our study reveals that MCPIP1 regulates the development and function of IL-5-producing TH2 cells through the Notch/Gata3 pathway. MCPIP1 represents a new and promising target for the treatment of asthma and other TH2-mediated diseases.

Suppression of IL-12 production by tristetraprolin through blocking NF-kcyB nuclear translocation.

Tristetraprolin (TTP), an mRNA-binding protein, plays a significant role in regulating the expression of adenylate-uridylate-rich elements containing mRNAs. Mice deficient of TTP (TTP(-/-)) develop a systemic autoimmune inflammatory syndrome characterized by cachexia, conjunctivitis, and dermatitis. IL-12 plays a crucial role in immune defense against infectious and malignant diseases. In this study, we found increased production of IL-12 during endotoxic shock and enhanced Th1 cells in TTP knockout mice. The levels of IL-12 p70 and p40 protein as well as p40 and p35 mRNA were also increased in activated macrophages deficient of TTP. In line with these findings, overexpression of TTP suppressed IL-12 p35 and p40 expression at the mRNA and promoter level, whereas it surprisingly had little effects on their mRNA stability. Our data showed that the inhibitory effects of TTP on p35 gene transcription were completely rescued by overexpression of NF-кB p65 and c-Rel but not by the p50 in activated macrophages. Our data further indicated that TTP acquired its inhibition on IL-12 expression through blocking nuclear translocation of NF-кB p65 and c-Rel while enhancing p50 upon stimulation. In summary, our study reveals a novel pathway through which TTP suppresses IL-12 production in macrophages, resulting in suppression of Th1 cell differentiation. This study may provide us with therapeutic targets for treatment of inflammatory and autoimmune disorders.

Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2.

Tumor cell-derived molecules such as cytokines and lipid mediators play a critical role in inducing chronic inflammation in the tumor microenvironment. We found that Th17 cells were increased in the peripheral blood, spleen, and tumor tissues of mammary gland tumor-bearing mice. The Th17 cell survival factor, IL-23, was also overexpressed in tumor tissues isolated from mice and human breast cancer patients. Soluble molecules secreted from breast tumor cells, but not normal breast epithelial cells, induced IL-23 protein secretion in dendritic cells via induction of p19 mRNA expression. Our data further indicate that tumor-secreted PGE2 through EP2 and EP4 receptors enhanced IL-23 p19 gene transcription through binding to the cAMP-response element in the p19 promoter. Blocking PGE2 synthesis by NS398, a COX2 inhibitor, abrogated the enhancement of p19 expression both in vitro and in vivo. Furthermore, blocking protein kinase A (PKA) by H89 completely abrogated the inductive effects of tumor-conditioned medium and PGE2 on p19 transcription, whereas the cAMP active analog, Forskolin, mimics the PGE2 effect. Taken together, our results indicate that tumor-secreted PGE2 induces IL-23, but not IL-12, production in the tumor microenvironment, leading to Th17 cell expansion. This inductive effect of PGE2 on IL-23 p19 transcription is mediated through cAMP/PKA signaling transduction pathway.

Understanding the bias of mobile location data across spatial scales and over time: A comprehensive analysis of SafeGraph data in the United States.

Mobile location data has emerged as a valuable data source for studying human mobility patterns in various contexts, including virus spreading, urban planning, and hazard evacuation. However, these data are often anonymized overviews derived from a panel of traced mobile devices, and the representativeness of these panels is not well documented. Without a clear understanding of the data representativeness, the interpretations of research based on mobile location data may be questionable. This article presents a comprehensive examination of the potential biases associated with mobile location data using SafeGraph Patterns data in the United States as a case study. The research rigorously scrutinizes and documents the bias from multiple dimensions, including spatial, temporal, urbanization, demographic, and socioeconomic, over a five-year period from 2018 to 2022 across diverse geographic levels, including state, county, census tract, and census block group. Our analysis of the SafeGraph Patterns dataset revealed an average sampling rate of 7.5% with notable temporal dynamics, geographic disparities, and urban-rural differences. The number of sampled devices was strongly correlated with the census population at the county level over the five years for both urban (r > 0.97) and rural counties (r > 0.91), but less so at the census tract and block group levels. We observed minor sampling biases among groups such as gender, age, and moderate-income, with biases typically ranging from -0.05 to +0.05. However, minority groups such as Hispanic populations, low-income households, and individuals with low levels of education generally exhibited higher levels of underrepresentation bias that varied over space, time, urbanization, and across geographic levels. These findings provide important insights for future studies that utilize SafeGraph data or other mobile location datasets, highlighting the need to thoroughly evaluate the spatiotemporal dynamics of the bias across spatial scales when employing such data sources.

Structural Racism and HIV Pre-exposure Prophylaxis Use in the Nationwide US: A County-Level Analysis.

BACKGROUND: Structural racism contributes to geographical inequalities in pre-exposure prophylaxis (PrEP) coverage in the United States (US). This study aims to investigate county-level variability in PrEP utilization across diverse dimensions of structural racism. METHODS: The 2013-2021 nationwide county-level PrEP rate and PrEP-to-need ratio (PNR) data were retrieved from AIDSVu. PrEP rate was defined as the number of PrEP users per 100,000 population, and PNR was defined as the ratio of PrEP users to new HIV diagnoses per calendar year. Linear mixed effect regression was employed to identify associations of county-level structural racism (e.g., structural racism in housing and socioeconomic status) with PrEP rate and PNR on a nationwide scale of the US. RESULTS: From 2013 to 2021, the mean PrEP rate and PNR increased from 3.62 to 71.10 and from 0.39 to 10.20, respectively. Counties with more structural racism in housing were more likely to have low PrEP rates (adjusted ß = - 5.80, 95% CI [- 8.84, - 2.75]). Higher PNR was found in counties with lower structural racism in socioeconomic status (adjusted ß = - 2.64, 95% CI [- 3.68, - 1.61]). Regionally, compared to the Midwest region, counties in the West region were more likely to have higher PrEP rate (adjusted ß = 30.99, 95% CI [22.19, 39.80]), and counties in the South had lower PNR (adjusted ß = - 1.87, 95% CI [- 2.57, - 1.17]). CONCLUSIONS: County-level structural racism plays a crucial role in understanding the challenges of scaling up PrEP coverage. The findings underscore the importance of tailored strategies across different regions and provide valuable insights for future interventions to optimize PrEP implementation.

Assessing the 2023 Canadian wildfire smoke impact in Northeastern US: Air quality, exposure and environmental justice.

The Canadian wildfires in June 2023 significantly impacted the northeastern United States, particularly in terms of worsened air pollution and environmental justice concerns. While advancements have been made in low-cost sensor deployments and satellite observations of atmospheric composition, integrating dynamic human mobility with wildfire PM2.5 exposure to fully understand the environmental justice implications remains underinvestigated. This study aims to enhance the accuracy of estimating ground-level fine particulate matter (PM2.5) concentrations by fusing chemical transport model outputs with empirical observations, estimating exposures using human mobility data, and evaluating the impact of environmental justice. Employing a novel data fusion technique, the study combines the Weather Research and Forecasting model with Chemistry (WRF-Chem) outputs and surface PM2.5 measurements, providing a more accurate estimation of PM2.5 distribution. The study addresses the gap in traditional exposure assessments by incorporating human mobility data and further investigates the spatial correlation of PM2.5 levels with various environmental and demographic factors from the US Environmental Protection Agency (EPA) Environmental Justice Screening and Mapping Tool (EJScreen). Results reveal that despite reduced mobility during high PM2.5 levels from wildfire smoke, exposure for both residents and individuals on the move remains high. Regions already burdened with high environmental pollution levels face amplified PM2.5 effects from wildfire smoke. Furthermore, we observed mixed correlations between PM2.5 concentrations and various demographic and socioeconomic factors, indicating complex exposure patterns across communities. Urban areas, in particular, experience persistent high exposure, while significant correlations in rural areas with EJScreen factors highlight the unique vulnerabilities of these populations to smoke exposure. These results advocate for a comprehensive approach to environmental health that leverages advanced models, integrates human mobility data, and addresses socio-demographic disparities, contributing to the development of equitable strategies against the growing threat of wildfires.

Tristetraprolin mediates immune evasion of mycobacterial infection in macrophages.

Immune evasion of Mycobacterium tuberculosis (Mtb) facilitates intracellular bacterial growth. The mechanisms of immune evasion, however, are still not fully understood. In this study, we reveal that tristetraprolin (TTP), one of the best characterized RNA-binding proteins controlling the stability of targeted mRNAs, mediates innate immune evasion of mycobacteria. We found that TTP knockout mice displayed reduced bacterial burden in the early stage after Mtb aerosol challenge. Macrophages deficient in TTP also showed an inhibition in intracellular mycobacterial growth. Live mycobacteria induced TTP protein expression in macrophages, which was blocked by the mTOR inhibitor rapamycin. Rapamycin and AZD8055 specifically blocked 4EBP1 phosphorylation in infected macrophages and suppressed intracellular BCG growth. Rapamycin promoted TTP protein degradation through the ubiquitination pathway, whereas the proteasome inhibitor MG-132 blocked rapamycin function and thus stabilized TTP protein. TTP induction suppressed the expression of iNOS/TNF-α/IL-12/IL-23, and weakened protective immune responses in macrophages, whereas rapamycin enhanced the bactericidal effects through TTP inhibition. Moreover, blocking TTP binding increased the expression of TNF-α and iNOS and suppressed intracellular mycobacterial growth. Overall, our study reveals a novel role for RNA-binding protein TTP in Mtb immune evasion mechanisms and provides a potential target for host-directed therapy against tuberculosis (TB).

Transcriptional suppression of IL-27 production by Mycobacterium tuberculosis-activated p38 MAPK via inhibition of AP-1 binding.

Mycobacterium tuberculosis remains a major global challenge to human health care, and the mechanisms of how M. tuberculosis evades host immune surveillance to favor its survival are still largely unknown. In this study, we found that bacillus Calmette-Guérin (BCG) and viable M. tuberculosis as well as M. tuberculosis lysates could activate IL-27 expression in human and mouse macrophages by induction of p28 subunit transcription. However, in parallel with these effects, BCG and M. tuberculosis lysate stimulation of macrophages induced activation of p38 MAPK signaling molecules MLK3/MKK3/MK2 to prevent maximal IL-27 production. M. tuberculosis lysate-induced p28 transcription was dependent on MyD88 signaling pathway. AP-1/c-Fos was shown to bind directly to the p28 promoter and induce p28 expression after M. tuberculosis lysate stimulation. Overexpression of p38α inhibited the binding of c-Fos to the p28 promoter but had no effect on c-Fos protein expression or phosphorylation in response to M. tuberculosis lysate stimulation. Furthermore, blockade of p38 by SB203580 enhanced M. tuberculosis-induced AP-1 binding to the p28 promoter. Importantly, we show that adding exogenous IL-27 to increase the levels produced by PBMCs stimulated with live mycobacteria enhanced the ability of BCG-expanded T cells to inhibit intracellular mycobacterial growth in human macrophages. Taken together, our data demonstrate that mycobacterial stimulation induces both IL-27 production and p38 MAPK activation. Strategies designed to tip the balance toward positive regulation of p28 induction by mycobacteria could lead to enhanced protective tuberculosis immunity.

Posttranscriptional regulation of IL-23 expression by IFN-gamma through tristetraprolin.

IL-23 plays an essential role in maintenance of IL-17-producing Th17 cells that are involved in the pathogenesis of several autoimmune diseases. Regulation of Th17 cells is tightly controlled by multiple factors such as IL-27 and IFN-γ. However, the detailed mechanisms responsible for IFN-γ-mediated Th17 cell inhibition are still largely unknown. In this study, we demonstrate that IFN-γ differentially regulates IL-12 and IL-23 production in both dendritic cells and macrophages. IFN-γ suppresses IL-23 expression by selectively targeting p19 mRNA stability through its 3'-untranslated region (3'UTR). Furthermore, IFN-γ enhances LPS-induced tristetraprolin (TTP) mRNA expression and protein production. Overexpression of TTP suppresses IL-23 p19 mRNA expression and p19 3'UTR-dependent luciferase activity. Additionally, deletion of TTP completely abolishes IFN-γ-mediated p19 mRNA degradation. We further demonstrate that IFN-γ suppresses LPS-induced p38 phosphorylation, and blockade of p38 MAPK signaling pathway with SB203580 inhibits IFN-γ- and LPS-induced p19 mRNA expression, whereas overexpression of p38 increases p19 mRNA expression via reducing TTP binding to the p19 3'UTR. Finally, inhibition of p38 phosphorylation by IFN-γ leads to TTP dephosphorylation that could result in stronger binding of the TTP to the adenosine/uridine-rich elements in the p19 3'UTR and p19 mRNA degradation. In summary, our results reveal a direct link among TTP, IFN-γ, and IL-23, indicating that IFN-γ-mediated Th17 cell suppression might act through TTP by increasing p19 mRNA degradation and therefore IL-23 inhibition.

Maternal lead exposure during lactation persistently impairs testicular development and steroidogenesis in male offspring.

Lead (Pb) is a testicular toxicant. In the present study, we investigated the effects of maternal Pb exposure during lactation on testicular development and steroidogenesis in male offspring. Maternal mice were exposed to different concentration of lead acetate (200 or 2000 ppm) through drinking water from postnatal day (PND) 0 to PND21. As expected, a high concentration of Pb was measured in the kidneys and liver of pups whose mothers were exposed to Pb during lactation. In addition, maternal Pb exposure during lactation elevated, to a less extent, Pb content in testes of weaning pups. Testis weight in weaning pups was significantly decreased when maternal mice were exposed to Pb during lactation. The level of serum and testicular T was reduced in Pb-exposed pups. The expression of P450scc, P450(17α) and 17ß-HSD, key enzymes for T synthesis, was down-regulated in testes of weaning pups whose mothers were exposed to Pb during lactation. Interestingly, the level of serum and testicular T remained decreased in adult offspring whose mothers were exposed to Pb during lactation. Importantly, the number of spermatozoa was significantly reduced in Pb-exposed male offspring. Taken together, these results suggest that Pb could be transported from dams to pups through milk. Maternal Pb exposure during lactation persistently disrupts testicular development and steroidogenesis in male offspring.

[Effects of bromopropane exposure on expression of DNA methyltransferases and level of histone acetylation in testis of male rats].

OBJECTIVE: To investigate the changes in the expression of DNA methyltransferases (DNMTs) and activities of histone acetyltransferase (HAT) and histone deacetylase (HDAC) in the testis of male rats exposed to bromopropanes (BPs). METHODS: Twenty-seven male rats were randomly divided into three groups to be intraperitoneally injected with 1-BP,2-BP, or corn oil (as a control) for two weeks. The sperm count and morphology in the epididymis were evaluated. The mRNA expression of DNMT1, DNMT3a, and DNMT3b and activities of HAT and HDAC in the testis were measured by quantitative real-time PCR and ELISA. RESULTS: Compared with the control group, the BP exposure groups showed significant decreased absolute and relative sperm counts; the proportion of tailless sperm increased in the 1-BP exposure group, while the proportion of sperm with abnormal heads increased in the 2-BP exposure group. The 2-BP exposure group had significantly lower mRNA expression of DNMT1, DNMT3a, and DNMT3b than the control group (P < 0.05). There were no significant differences in the activities of HAT and HDAC between the control group and 1-BP exposure group; the 2-BP exposure group showed significantly higher HAT activity than the control group (P < 0.05), but no significant difference was found in HDAC activity between them. CONCLUSION: Exposure to 2-BP might induce abnormal DNA methylation and histone acetylation, and epigenetic regulation might play an important role in the reproductive toxicity of 2-BP.

Association between immigrant concentration and mental health service utilization in the United States over time: A geospatial big data analysis.

Immigrants (foreign-born United States [US] citizens) generally have lower utilization of mental health services compared with US-born counterparts, but extant studies have not investigated the disparities in mental health service utilization within immigrant population nationwide over time. Leveraging mobile phone-based visitation data, we estimated the average mental health utilization in contiguous US census tracts in 2019, 2020, and 2021 by employing two novel outcomes: mental health service visits and visit-to-need ratio (i.e., visits per depression diagnosis). We then investigated the tract-level association between immigration concentration and mental health service utilization outcomes using mixed-effects linear regression models that accounted for spatial lag effects, time effects, and covariates. This study reveals spatial and temporal disparities in mental health service visits and visit-to-need ratio among different levels of immigrant concentration across the US, both before and during the pandemic. Tracts with higher concentrations of Latin American immigrants showed significantly lower mental health service utilization visits and visit-to-need ratio, particularly in the US West. Tracts with Asian and European immigrant concentrations experienced a more significant decline in mental health service utilization visits and visit-to-need ratio from 2019 to 2020 than those with Latin American concentrations. Meanwhile, in 2021, tracts with Latin American concentrations had the least recovery in mental health service utilization visits. The study highlights the potential of geospatial big data for mental health research and informs public health interventions.

Residential Segregation and County-Level COVID-19 Booster Coverage in the Deep South: Surveillance Report and Ecological Study.

BACKGROUND: COVID-19 had a greater impact in the Deep South compared with other regions in the United States. While vaccination remains a top priority for all eligible individuals, data regarding the progress of booster coverage in the Deep South and how the coverage varies by county and age are sparse. Despite existing evidence of racial and ethnic disparities in COVID-19 vaccinations at the individual level, there is an urgent need for evidence at the population level. Such information could highlight vulnerable communities and guide future health care policy-making and resource allocation. OBJECTIVE: We aimed to evaluate county-level COVID-19 booster coverage by age group in the Deep South and explore its association with residential segregation. METHODS: An ecological study was conducted at the population level by integrating COVID-19 vaccine surveillance data, residential segregation index, and county-level factors across the 418 counties of 5 Deep South states from December 15, 2021, to October 19, 2022. We analyzed the cumulative percentages of county-level COVID-19 booster uptake by age group (eg, 12 to 17 years, 18 to 64 years, and at least 65 years) by the end of the study period. The longitudinal relationships were examined between residential segregation, the interaction of time and residential segregation, and COVID-19 booster coverage using the Poisson model. RESULTS: As of October 19, 2022, among the 418 counties, the median of booster uptake was 40% (IQR 37.8%-43%). Compared with older adults (ie, at least 65 years; median 63.1%, IQR 59.5%-66.5%), youth (ie, 12 to 17 years; median 14.1%, IQR 11.3%-17.4%) and adults (ie, 18 to 64 years; median 33.4%, IQR 30.5%-36.5%) had lower percentages of booster uptake. There was geospatial heterogeneity in the county-level COVID-19 booster coverage. We found that higher segregated counties had lower percentages of booster coverage. Such relationships attenuated as time increased. The findings were consistent across the age groups. CONCLUSIONS: The progress of county-level COVID-19 booster coverage in the Deep South was slow and varied by age group. Residential segregation precluded the county-level COVID-19 booster coverage across age groups. Future efforts regarding vaccination strategies should focus on youth and adults. Health care facilities and resources are needed in racial and ethnic minority communities.

Effects of Bacillus subtilis BS-Z15 on Intestinal Microbiota Structure and Body Weight Gain in Mice.

In our previous study, we identified a metabolite of Bacillus subtilis BS-Z15 (a strain with probiotic characteristics) that could improve immunity in mice. In the present study, we examined the effects of B. subtilis BS-Z15 and its metabolites on body weight gain and the intestinal microbiota of mice. Sixty 25-day-old male Kunming white mice were selected and randomly divided into four groups: control group (A), daily saline gavage; B. subtilis-treated group (B), single gavage (1 × 109 CFU/time/animal/day); group D, 14 consecutive gavages (1 × 109 CFU/time/animal/day); and B. subtilis metabolite-treated group (E), 30 consecutive gavages (90 mg kg-1/time/animal/day). High-throughput sequencing technology was used to analyze intergroup differences in the mouse intestinal microbiota. The results showed that the three treated groups had significantly slower body weight gain compared with the control group, which lasted until the 45 days (P < 0.05), and the daily food intake of the treated mice was higher (P < 0.05). The intestinal microbiota structure of the mice in the treated groups was significantly altered compared with that in the control group, suggesting that B. subtilis BS-Z15 may regulate the weight gain of animals by affecting their intestinal bacterial composition. After stopping the gavage of B. subtilis BS-Z15, the abundance of this strain in the small intestine of the mice gradually decreased and its presence was undetectable at 45 days, indicating that B. subtilis BS-Z15 could not colonize the intestine of these mice. These findings suggest that B. subtilis BS-Z15 may regulate intestinal microbiota through its metabolites to reduce weight gain.

[Effects of rat maternal fenvalerate exposure on behavior development of rat pubertal female offspring].

OBJECTIVE: To explore the effects of rat maternal exposure to fenvalerate during lactation on behaviors development in rat pubertal female offspring. METHODS: Twelve ICR maternal mice were randomly divided into 7.5 and 30.0 mg/kg fenvalerate exposure groups and control group (four dams each group, ten pups each dam, half male half female, twenty female pups each group). The exposure groups were orally exposed to fenvalerate at the doses of 7.5 and 30 mg/kg a day from postnatal day 1 (PND1) to PND21. The control group was exposed to corn oil. The effects of maternal fenvalerate exposure during lactation on motor and species-typical behaviors in female offspring were observed on the PND 35. RESULTS: The peripheral time and standing frequency of 30.0 mg/kg exposure group were (263.4 ± 54.8) s and (47.3 ± 16.2) times, which were significantly higher than those [(203.4 ± 53.0) s and (30.9 ± 17.3) times] of control group (P < 0.05). The scores in 7.5 mg/kg and 30.0 mg/kg exposure groups were 56.50 ± 50.79 and 54.73 ± 53.91, respectively, which were significantly lower than that (114.53 ± 53.87) in control group (P < 0.05). However, no significant differences in beam walking scores, food hoarding quantity, food digging quantity, and nest construction scores between two exposure groups were found (P > 0.05). CONCLUSION: The rat maternal exposure to fenvalerate during lactation could decrease the ability of exploration and motor condition and increase the anxiety but not affect life habit in rat pubertal female offspring.