The capacity to adapt is essential for a population to avoid extinction in a changing world and is recognized as a global conservation priority. Adaptation requires additive (heritable) genetic variation for traits that influence survival and fecundity, but measuring this variation is difficult, particularly in species of conservation concern. Instead, molecular genetic diversity is often used to infer adaptive potential. However, previous research has cast doubt on the suitability of traditional molecular markers (allozymes and microsatellites) for this purpose given their weak relationship with heritability-a common measure of additive genetic variance. Advances in sequencing technology have since shifted focus toward nucleotide diversity and variation in functional regions, but their practicality for predicting adaptive potential remains debated. Furthermore, heritability itself is a poor proxy for adaptive potential because it depends on environmental variance. We collated 2,113 published estimates of evolvability-a measure of additive genetic variance that avoids environmental confounding-across 193 eukaryotic species, and evaluated how well evolvability is predicted by molecular diversity. We find that microsatellite and nucleotide diversity are not significantly correlated to each other, and neither predict evolvability. Nucleotide diversity explains 1.1% of interspecific differences in evolvability and doubling nucleotide diversity only corresponds to a 11.7% increase in evolvability. With theoretical work, we show that such weak associations are expected. Together, our results suggest that simple molecular measures of genetic variation are insufficient for predicting adaptive potential and reliance on these metrics risks misinforming conservation management.
Selective autophagy of the endoplasmic reticulum (reticulophagy) is driven by receptor-mediated ER remodeling. Reticulophagy receptors are essential for ER turnover. Productive cargo recognition during autophagosome-mediated reticulophagy depends on the interaction of the receptor with the COPII subunit Sfb3/Lst1 (SEC24C in mammals) as well as the phospholipid composition of the ER. We unexpectedly found that the conserved reticulophagy receptor Atg40 traffics to the vacuole/lysosome without cargo (ER membrane proteins) or Sfb3/Lst1 in neutral lipid-deficient mutant cells. Comprehensive lipidomic profiling of this lipid mutant revealed a shift in the phosphatidylethanolamine (PE)-to-phosphatidylcholine (PC) ratio, a compositional change predicted to alter biophysical properties of the ER, including membrane bendability. The discovery that membrane properties regulate receptor - cargo coupling efficiency at autophagic sites, as they do at secretory exit sites, extends current mechanistic models of reticulophagy and suggests membrane properties may also affect cargo selection on other types of selective autophagy pathways.
Febrile pediatric oncology patients with central lines are at high risk of sepsis. However, emerging evidence fails to support the historic 1-hour window for antibiotic administration in well-appearing patients, suggesting that providers may have more time to tailor antibiotic therapy in these patients. Before this quality improvement project, 92% of febrile oncology patients without severe neutropenia (absolute neutrophil count [ANC] ≥500) in our pediatric emergency department (ED) received empiric intravenous cefepime. The aim of this study was to decrease this percentage to 60% by June 30, 2025. A multidisciplinary team implemented interventions using Plan-Do-Study-Act (PDSA) methodology, including clinical pathways and order set updates, tips for communicating with families, and a risk stratification tool. The outcome measure was the percentage of febrile oncology patients without severe neutropenia who received cefepime. Process measures included order set use, percentage of antibiotics ordered before ANC results were obtained, and the time to ANC result. Balancing measures included readmission of patients within 7 days, admission to the intensive care unit within 24 hours of ED discharge, and percentage of patients with antibiotics administered >3 hours after arrival. There was an average of 7.9/month febrile oncology patients without severe neutropenia. Following the first PDSA cycle, cefepime use in patients without severe neutropenia decreased from 92% to 26.8%. Patients with antibiotics administered before ANC reporting decreased from 90% to 35.2%. Patients with IV antibiotics administered >3 hours from arrival increased from 2.3% to 29%. Remaining balancing measures did not statistically change. Implementation of a new clinical pathway with order sets, adoption of a risk stratification tool, and patient and family involvement safely improved antibiotic stewardship for febrile oncology patients.
As one of the critically important transcription factors, interferon regulatory factors (IRFs) modulate the host transcriptional program triggered by pathogen-associated molecular patterns in variety of marine invertebrates. Their activation is indispensable for initiating and modulating innate immune defenses across animal taxa. However, the functional characteristics and regulatory mechanisms of IRFs in echinoderms remain poorly understood. In this study, a newly identified IRF family member, Si-IRF1/2, was cloned and characterized in the sea urchin Strongylocentrotus intermedius. Si-IRF1/2 comprises a full-length ORF of 1668 bp, corresponding to a 555-amino-acid protein. Computational analysis identified a conserved IRF domain at the N-terminal region. This conserved signature was identified through integrated domain prediction and corroborated by multiple sequence alignment with orthologs from diverse species. Phylogenetic analysis showed that Si-IRF1/2 clusters closely with members of the vertebrate IRF1/2 proteins and molluscan IRF1/2 homologs. The tissue-specific expression profile of Si-IRF1/2 was assessed by qRT-PCR. Although transcripts were ubiquitously present, expression was markedly enriched in coelomocytes, indicating a specialized role in this immunologically relevant tissue. Moreover, expression of Si-IRF1/2 was upregulated when stimulated with lipopolysaccharide (LPS) and poly (I:C). Subcellular localization assays showed that Si-IRF1/2 is predominantly localized in the nucleus. The results of the RNAi experiment indicate that after Si-IRF1/2 was knocked down, the mRNA expressions of Si-strongylocins and Si-IL17s in coelomocytes changed significantly at 12 h after LPS stimulation. The transcriptional regulatory capacity of Si-IRF1/2 was further confirmed by dual-luciferase reporter assays, which demonstrated its ability to enhance the activity of promoters from multiple immune-related genes, including interleukin-6 (IL-6), Interferon-α/β (IFNα/β), Signal transducer and activator of transcription 3 (STAT3), activator protein-1 (AP-1), interferon-stimulated response element (ISRE), nuclear factor-κB (NF-κB), and tumor necrosis factor α (TNFα). Under LPS stimulation, overexpression of Si-IRF1/2 promoted activation of mitogen-activated protein kinase pathways, specifically c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2). Taken together, these findings provide new insights into the immune-regulatory role of Si-IRF1/2 to establish a conceptual framework for breeding sea urchin lines with improved resistance to disease, while simultaneously providing new knowledge of innate immune mechanisms mediated by IRFs in invertebrates.
The aging of salivary glands (SGs) leads to xerostomia, impaired oral defenses, and a compromised quality of life, yet the biology of human submandibular gland (SMG) aging remains poorly understood due to limited availability of human tissues and differences in anatomy and physiology between rodent and human SGs. The common marmoset (Callithrix jacchus) is a short-lived non-human primate (NHP) with SMG histology that closely resembles humans and has the potential to provide a translational model for investigating SG aging. In this study, we examined the age-associated structural and molecular alterations that occur in marmoset SMGs and evaluated whether chronic oral rapamycin treatment, a gerotherapeutic mTOR inhibitor, mitigates these age-related changes. Histological and immunofluorescence analyses revealed that there was a substantial decline in mucous and serous acinar units, expansion of ductal and collagen-rich stromal compartments, increased extracellular matrix remodeling, elevated dysregulation of lipid metabolism, and increased numbers of apoptotic and senescent cells in the SMG with aging. Rapamycin treatment was associated with partial preservation of acinar structure and a reduction in fibrosis, lipid accumulation, and number of apoptotic and senescent cells that resulted in an overall tissue phenotype that more closely resembled that of younger animals. These findings suggest that the aging marmoset SMG recapitulates key features of human SG aging and that rapamycin treatment was associated with an attenuation in the hallmarks of SG degeneration. The results suggest that the marmoset represents a valuable NHP model for studying SG aging biology and testing therapeutic strategies aimed at attenuating age-related structural degeneration associated with SG dysfunction.
This study establishes a label-free optical diffraction tomography (ODT)-based workflow for live-cell imaging and analysis to observe time-dependent morphological changes in macrophages. The method enables continuous recording of single-cell morphology and movement over extended periods under stable environmental conditions and allows extraction of quantitative parameters, including projected area, perimeter, and average migration speed. This workflow provides a practical approach for capturing dynamic cellular behaviors at the single-cell level without exogenous labeling. Using RAW264.7 macrophages as a model, time-lapse imaging was performed under lipopolysaccharide stimulation with baicalin pretreatment to capture dynamic cellular changes under different conditions. Representative cells were selected for tracking and quantitative analysis. The results show that this workflow supports stable long-term single-cell tracking and reflects temporal changes in cell morphology and motility. This approach provides a label-free method for observing dynamic cellular behaviors in response to different stimuli and can serve as a useful complement to conventional endpoint-based assays. It may also be applicable to other adherent cell types for studies of cell morphodynamics.
Preexposure prophylaxis (PrEP) is a key biomedical HIV prevention strategy that relies heavily on adherence for optimal effectiveness. In China, most PrEP users purchase their medication online, making it challenging to monitor and support adherence effectively. This protocol aims to describe a digital intervention developed to monitor and improve the medication adherence of real-world e-consumers of PrEP and an evaluation plan assessing its acceptability, feasibility, and effectiveness. The Real-Time Monitoring and Precision Intervention for HIV PrEP Adherence (REMOTE) trial is a parallel-group, open-label, online-delivered, active-controlled, and stratified randomized controlled trial conducted among 430 e-consumers of PrEP (320 event-driven regimen users and 110 daily regimen users) in China. People who have purchased PrEP online, have taken PrEP in the previous 3 months, and plan to continue for the next 6 months will be stratified by regimen type and randomized into control and intervention groups at a 1:1 ratio. A WeChat-based digital platform will deliver the REMOTE intervention. The monitoring module follows ecological momentary assessment principles. The intervention design is guided by the stages of change theory, tailoring strategies to different nonadherence risks based on monitoring results. Intervention components include low-risk (health education and an artificial intelligence chatbot), medium-risk (peer forum and admonitory education), and high-risk (customized reminders and physician counseling) strategies. The control group will use a simplified platform with only real-time monitoring. The primary outcome is the proportion of participants achieving optimal adherence for 6 months, assessed via real-time monitoring and validated via surveys at baseline and the 1-, 3-, and 6-month follow-ups. Secondary outcomes include PrEP adherence knowledge, self-efficacy, risk perception, adherence barriers, stigma, and social support, measured via surveys. Intention-to-treat analysis will be conducted. Funding for the study was approved in March 2024. Ethics approval for the study was granted in July 2024. The pilot trial was completed in November 2025. Baseline data collection commenced in January 2026. By February 5, 2026, recruitment and baseline data collection were completed, with 448 participants enrolled. The data have not been viewed by the research team. The intervention is currently ongoing, and the study is expected to conclude in August 2026. Results are anticipated to be published in early 2027. The REMOTE trial pioneers a real-time monitoring and precision intervention for e-consumers of PrEP. Leveraging technology and ecological momentary assessment, it delivers a personalized, real-time intervention that is crucial for adherence. The findings could significantly impact future HIV prevention strategies. Chinese Clinical Trial Registry ChiCTR2400088278; https://www.chictr.org.cn/showproj.html?proj=236414. DERR1-10.2196/92750.
We compared differentially expressed genes in Chinook Salmon Oncorhynchus tshawytscha with three divergent Ichthyophonus statuses (undetected, subclinical infections, or clinical disease; n = 100) to investigate associated transcriptomic responses. Disease associated with the fish parasite Ichthyophonus sp. was first diagnosed in adult Chinook Salmon from the Yukon River in the late 1980s and has subsequently been implicated in premature host mortality. Chinook Salmon tissue sample collections and Ichthyophonus infection data were leveraged from a multi-agency collaboration during summer 2022 at three locations along the main-stem Yukon River that spanned nearly 2,000 km of freshwater migration (lower, middle, and upper river). We sequenced the transcriptome and compared this to infection status based on routine diagnostic procedures. Among the 17,569 genes for which messenger RNA was detected, we identified a transcription signature in the skeletal muscle that was associated with Ichthyophonus infections and included 53 differentially expressed genes. The differentially expressed genes and their pathways included those known for involvement in immune functions, energy synthesis, cellular breakdown, and reproduction-all processes that are known to be influenced by senescence during spawning migrations. Results demonstrate a clear transcriptional difference between diseased fish (clinical disease group) and those in which Ichthyophonus was undetected, including identifying candidate markers for infection in this population. These results provide a foundation for development of nonlethal biomarkers to evaluate potential Ichthyophonus infections in Chinook Salmon based on gene transcription, protein products, or gene variants (e.g., polymorphisms). Yukon River Chinook Salmon have record low numbers and closed fishing, and a parasite (Ichthyophonus) is a mortality concern that can only be monitored via lethal sampling. This study explores the host response to the parasite in skeletal muscle as a possible nonlethal monitoring tool.
Black and minority ethnic communities are more likely to receive coercive mental health care, and involuntary admissions via crisis and criminal justice agencies. Lived experience informed interventions may be better able to address structural determinants, overcome resistance, and motivate innovations. The Synergia Collaborative Centre (SCC) sought to drive systems reform through insights from lived experience data, evidence syntheses, co-design and creative communications.We report a qualitative study of the SCC, applying a realist-informed secondary analysis method to interview data from an independent evaluation. Twenty-four stakeholders' transcripts were analysed alongside minutes of operational and advisory board meetings and project documents to discern how SCC was received by different stakeholders and how and whether it operated. Context-Mechanism-Outcome (CMO) configurations were generated drawing on ecological systems theory to enhance understanding of context, therefore, the findings were organised by eco-social levels. The programme successfully built confidence and leadership capacity, centring on lived experience, co-design and embedding local evidence-based actions through creative communications to motivate and engage partners. Power imbalances between established experts and new leaders risked disengagement of both; pessimism was born of historical failures of similar programmes and a lack of sustained resources; promoting policy makers and professional participants in the change process, alongside local community stakeholders were proposed for future traction. We distil facilitators and barriers to progressive change in community, health, and social systems as observed by stakeholders and as reported in their interviews as part of an evaluation of SCC.This research generated a refined programme theory exploring how the programme worked, to inform and generate recommendations for future programmes. We discuss strengths and limitations of using realist-informed secondary analysis methods for post-hoc assessment of complex programmes.
Traditional developmental science has often described child growth as a sequence of stages or linear progressions, yet many phenomena-abrupt spurts and regressions, idiosyncratic pathways, and widening individual differences-resist linear accounts. This article proposes chaos theory as a framework for quantifying developmental trajectories. Chaos theory, which addresses how complex patterns emerge from simple rules in deterministic yet unpredictable ways, aligns with observations of sensitive developmental periods, emergent behaviors, and divergent outcomes. I situate chaos theory alongside dynamic systems theory, neuroconstructivism, and developmental-cascade models and clarify how chaos might add mathematical precision to established insights: Bifurcation analysis identifies tipping points at which behaviors reorganize; Lyapunov exponents quantify stability and sensitivity to small perturbations; state-space methods reconstruct attractor landscapes from dense time series; and complexity metrics discriminate structured variability from noise. These tools convert powerful metaphors-soft assembly, attractors, cascades-into testable hypotheses about when and why qualitative change occurs. Such a framework also motivates microgenetic and high-density longitudinal designs, computational modeling of phase transitions, and interventions conceived as targeted perturbations delivered near sensitive windows. Finally, I discuss why adopting a chaos framework can be advantageous compared with (or in concert with) traditional linear models.
The Tinharé Archipelago (TA), located within an Environmental Protection Area (Bahia, Brazil), is a largely preserved mangrove area. Despite this, it is subject to frequent anthropogenic activities, notably the 2019 oil spill that impacted the Brazilian coastline. This study assessed the concentration of Polycyclic Aromatic Hydrocarbons (PAHs) in sediments collected from three estuaries within the TA islands (Boipeba, Garapuá, and Morro de São Paulo) and evaluated temporal changes in contamination levels. Surface sediments were collected at seven points within each estuary in August 2021 and August 2023. Samples were extracted using organic solvents via an Accelerated Solvent Extraction system. Quantification of the 16 priority PAHs was performed using gas chromatography coupled with mass spectrometry. Total PAHs concentrations ranged from 33.5 to 5746 ng g-1. Garapuá exhibited moderate to high concentrations, while contamination levels in the other areas ranged from low to moderate. Diagnostic ratios suggested shifts in contamination sources, although their interpretation is subject to limitations in weathered sediments. Garapuá (2023) exhibited signatures consistent with petrogenic inputs, possibly associated with weathered oil residues, whereas Boipeba (2021) and Morro de São Paulo (2023) may be contaminated by petroleum combustion sources. Pyrogenic signals from biomass burning were more prevalent Morro de São Paulo (2021) and Boipeba (2023), suggesting local human activities. Despite regional conservation efforts, the persistence of oil-derived PAHs underscores the lasting environmental impact of oil spills. These findings indicate the persistence of petroleum-related contamination in tropical mangrove systems, although the specific contribution of the 2019 oil spill cannot be unequivocally established using PAHs data alone. Continued monitoring is essential to understand contaminant dynamics and guide protection strategies.
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Nutrient and water supply are decisive limiting factors for trees and their productivity. Yet, the consequences of fertilization for drought responses, especially during the sensitive nursery stage, remain poorly understood. In this study, we exposed potted saplings of Pinus sylvestris, Fagus sylvatica, and Quercus robur to two levels of fertilization and three water regimes. The effects of fertilization, drought, and their interaction on gas exchange, hydraulic traits, and growth were examined. Fertilization generally promoted gas exchange, hydraulic conductance, and biomass accumulation but responses were species-specific and did not always persist under and after drought. While fertilized Q. robur maintained or even increased its biomass and physiological performance under drought, the benefits of fertilization for P. sylvestris and F. sylvatica diminished under increasing drought intensity. No consistent changes in drought resistance traits (e.g., turgor loss point, embolism resistance) were observed across species in response to fertilization, which may indicate limited plasticity or acclimation potential of saplings. Our findings highlight the species-specific fertilization effects on drought responses and post-drought performance of saplings, emphasizing the need to consider both factors in silvicultural practices under future climate scenarios.
The relationships among circadian rhythm syndrome, physical function, and muscle strength remain unclear. This study aimed to demonstrate the separate and combined deleterious effects of solid fuel use and circadian rhythm syndrome on physical function and muscle strength. We used data from the China Health and Retirement Longitudinal Study cohort. The study population consisted of participants who underwent comprehensive assessments of metabolism, circadian rhythm, indoor air pollution, physical function, and muscle strength at the initial evaluation. Muscle strength was assessed using repeated grip strength measurements, and physical function was assessed using a composite score of muscle strength, physical performance, and balance. Circadian rhythm syndrome was derived from the 5 diagnostic components of metabolic syndrome combined with sleep duration and depression. Logistic regression and linear mixed models were used to assess the relationships among solid fuel use, circadian rhythm syndrome, physical function, and muscle strength. Furthermore, we analyzed the mediating role of circadian rhythm syndrome and its combined effect with solid fuel use on physical function and muscle strength. A total of 7934 participants were included in the study, most of whom used solid fuels. Solid fuel use was positively associated with circadian rhythm syndrome (odds ratio [OR] 1.078, 95% CI 1.031-1.125; P<.05). Circadian rhythm syndrome was found to be a significant risk factor for impairment of physical function (β=-0.475; P<.05) and muscle strength (β=-0.304; P<.05). Participants who used solid fuels and had circadian rhythm syndrome needed to pay more attention to changes in physical function (β=-0.698; P<.05) and muscle strength (β=-0.332; P<.05). A significant interaction was observed between solid fuel use and circadian rhythm syndrome on physical function (Pinteraction=.03) and muscle strength (Pinteraction=.02). Circadian rhythm syndrome partially mediated the association between solid fuel use and physical function, accounting for 2.51% of the total effect. Circadian rhythm syndrome exacerbates the adverse effects of solid fuel use on physical function and muscle strength. Fuel cleanliness and regular work and rest habits are crucial for the health of middle-aged and older adults.
The ability to dynamically adjust a behavioral response to a stimulus depending on context is of critical importance for animals. To investigate the neural basis supporting context-dependent sensory processing, we developed a behavioral task in which mice changed their response to a single whisker deflection according to a continuously present contextual cue. Through unbiased optogenetic inactivation mapping, we found that neuronal activity in sensory and motor cortices contributed to task execution and, interestingly, we uncovered an unexpected role of the retrosplenial cortex (RSC) for contextual integration. Widefield calcium imaging revealed that the RSC was the first dorsal cortical area to show context discrimination in response to whisker stimulation, followed by the whisker motor cortex. Finally, we combined optogenetic inactivation with calcium imaging to define causal context-dependent changes in sensorimotor processing. Our cortex-wide mapping experiments thus begin to define key cortical nodes for context-dependent sensorimotor transformation and highlight an important contribution of RSC.
In individuals with schizophrenia receiving either clozapine or olanzapine, this study examined changes in 1) body weight and other cardiometabolic measures and microbiota biodiversity and composition between commencement and completion of 24-week semaglutide intervention; 2) body weight between commencement and 76-week follow-up. 24-week intervention (16-weeks full-dose (1.0 mg/week) after 8-weeks' titration) of open-label nurse-administered semaglutide in a public mental health setting, with one-year post-intervention follow-up (76-week trial-completion). people with schizophrenia without diabetes receiving clozapine or olanzapine with BMI > 27 kg/m2. %body weight change at 24-weeks, and 76-weeks. Secondary endpoints: %change in waist circumference, HbA1c at 24-weeks and 76-weeks, body composition at 24-weeks. Gut microbiota changes were compared at baseline, 10-weeks and 24-weeks intervention completion. Mean age: 41.5 years (range 18-61), 65.4% female. Intervention completed by 65.4% (n = 17/26). 24-week intervention: intention-to-treat body weight reduction: -9.8% (95% CI: [-12.7%, -6.8%], p < 0.001) or - 10.1 kg (95% CI [-13.6, -6.6]); waist circumference reduction: -7.3% (95% CI: [-10.1%, -4.4%], p < 0.001); HbA1c non-significant reduction: -5.3% (95% CI [-10.4%, 0.1%], p = 0.055). Microbial alpha diversity decreased as time on semaglutide increased, with enrichment of Parasutterella excrementihominis. Trial completion: 88.2% (n = 15/17). Average body weight change baseline-76-weeks: -5.1% (95% CI: [-8.3%, -1.9%], p = 0.001) or - 5.3 kg (95% CI: [-8.9, -1.7]). Semaglutide was associated with significant weight loss in overweight/obese people with schizophrenia. These benefits attenuated following semaglutide discontinuation. Gut microbial compositional differences consistent with improvement in health outcomes may occur in semaglutide-treated people living with schizophrenia.
Abnormal cognitive aging is characterized by memory decline beyond normal age-related physiological changes. Nevertheless, the intrinsic mechanisms driving individual memory heterogeneity during aging remain poorly elucidated. Given the critical roles of brain interstitial fluid (ISF) dynamics and extracellular space (ECS) transport in maintaining neural homeostasis, the present study aimed to explore whether ECS compartmentalization and ISF drainage disturbance contribute to interindividual variations in memory performance during aging. Aged rats were stratified according to their memory performance. A multi-modal strategy combining behavioral assessment, microdialysis, metabolomics, and electrophysiological recording was applied to detect structural and functional deficits in ECS barrier integrity and ISF drainage, with the assistance of MRI-based tracer imaging, fluorescence imaging, and ultrastructural observation. The results demonstrated that memory-impaired aged rats exhibited region-specific neurotransmitter imbalance in the caudate nucleus and thalamus, which was closely associated with age-related ECS barrier dysfunction. Such barrier dysfunction induced ISF drainage disturbance, thereby reducing local neurotransmitter concentrations in the caudate nucleus and impairing thalamocortical oscillations during non-rapid eye movement sleep, and ultimately disturbing memory consolidation. Further tracer imaging and electron microscopy examinations confirmed that compromised myelin integrity in the internal capsule served as the structural basis for age-related ISF drainage disturbance. Collectively, these findings reveal that ISF drainage disturbance induced by age-related ECS barrier alterations acts as a non-degenerative mechanism underlying memory heterogeneity in cognitive aging. This work highlights ECS compartment integrity as a promising biomarker and therapeutic target for intervening age-related cognitive decline.
This study investigated the color-related compounds of Salvia miltiorrhiza after sweating. Stereomicroscopy and Electronic eye system were employed to characterize color variation. UPLC-Q-Orbitrap-MS and HPLC identified differential compounds. Furthermore, μ-FTIR and MALDI-MSI visualized the spatial distribution of compounds, and the compounds distribution was confirmed via HPLC. Result showed that after sweating, the appearance characteristics of Salvia miltiorrhiza changed significantly, exhibiting a reddish-brown epidermis and purple-brown inner tissue. Among 49 significantly altered compounds, tanshinones accounted for 58%. HPLC further indicated that the content of tanshinones showed a significant increase. Integrated μ-FTIR and MALDI-MSI demonstrated tanshinones increased after sweating and accumulated in the epidermis. Further confirmation of the increase in tanshinones was achieved by HPLC analysis of epidermis and cortex isolated. These results reveal tanshinones as the color-related compounds and clarify their spatial distribution, providing insights into the chemical changes during the traditional sweating process of Salvia miltiorrhiza.
Safety studies of the COVID-19 vaccine have identified some adverse events. Yet newer variant-updated formulations, along with increased hybrid immunity, may change these risks. Early-era safety data may not reflect experience with updated formulations in more immune-experienced populations. To evaluate 90-day risks for adverse events after coadministration of COVID-19 and influenza vaccines compared with influenza vaccination alone, across bivalent, XBB-adapted, and KP-adapted COVID-19 vaccine periods. Target trial emulation using electronic health care data. U.S. Department of Veterans Affairs. Participants receiving both COVID-19 and seasonal influenza vaccines (n = 705 124) and those receiving only an influenza vaccine (n = 1 813 205) between 1 September 2022 and 26 August 2025. Receipt of both COVID-19 and seasonal influenza vaccines versus receipt of only an influenza vaccine. 90-day risks for 46 prespecified individual adverse events grouped into 3 composite outcomes (tier 1, serious or life-threatening; tier 2, clinically significant; tier 3, less severe or self-limiting), using weighted discrete-time survival models. For all 3 composite outcomes, risks were similar between groups: tier 1 (risk ratio [RR], 1.03 [95% CI, 0.99 to 1.09]), tier 2 (RR, 0.99 [CI, 0.96 to 1.03]), and tier 3 (RR, 0.99 [CI, 0.96 to 1.02]). Of the 46 individual adverse events, 2 tier-3 risks had nominal statistical significance: syncope (RR, 1.09 [CI, 1.02 to 1.17]) and tinnitus (RR, 0.95 [CI, 0.92 to 0.99]); no risks were statistically significant after correcting for multiple comparisons. For all risks in tier 1 or tier 2, confidence bounds included 1.0 (no effect). In period-stratified analyses, neither composite (tier) nor individual event estimates supported differences in risks between groups. Generalizability and potential unmeasured confounding. Same-day coadministration of COVID-19 and influenza vaccines was not associated with an increased risk for adverse events in 3 updated-formulation periods. These findings support the short-term safety of coadministration. U.S. Department of Veterans Affairs.
We assessed the risk of perfluorooctanoic acid (PFOA) to ovarian function by integrating in vivo mouse data with physiologically based toxicokinetic (PBTK) modeling and population-level analysis. Adult mice received PFOA (0.06, 1.15, 22 mg/kg bw/day; 14 days), followed by analysis of ovarian histology and whole-ovary transcriptomics. Effect doses were converted to human equivalent doses (HEDs) and propagated through a PBTK model to estimate ovarian bioactive concentrations (OBCs) in human ovaries. Median histology HEDs were 41 and 501 mg/week, whereas transcriptomic HED was 322 mg/week values above PFOA levels inferred from follicular fluid (FF) (∼0.002-0.0069 μg/mL). Lowest histology OBC was 25.6 μg/mL, and the fifth percentile transcriptomic OBC was 21.3 μg/mL, both exceeding PFOA FF levels. A subset of 21 ovarian genes had OBCs within 100-fold of PFOA FF levels. Clinical conditions such as cirrhosis Child-Pugh (CP) class C (CP-C), end-stage renal disease (ESRD), and morbid obesity double the risk for PFOA-induced ovarian dysfunction. Weibull distributions to gene-level OBCs across clinical populations and extrapolation to low percentiles (p = 0.05-10-4) showed that cirrhosis CP-C, ESRD, and morbid obesity demonstrated progressively smaller OBC percentiles compared with healthy as p decreased. Other populations showed modest changes or slight increases at the lowest percentiles. Overall, predicted PFOA OBCs remain above currently reported human PFOA FF levels, supporting a population-level margin of safety under current exposure. The gene-level and vulnerable population analyses identify sensitive molecular targets and subgroups in which this margin is reduced, warranting prioritization in future biomonitoring and reproductive risk assessment.