PLoS ONE最新文献

Aim: The underlying mechanisms contributing to cholestatic liver injury remain unclear. The pro-inflammatory leukocyte-restricted cytokine interleukin-17A (IL-17A) has been implicated in human cholestatic liver injury. However, mechanistic insights are lacking and require further exploration in preclinical models. Herein, we examined the effect of IL-17A genetic ablation in a mouse model of cholestatic liver injury.

Method: Age and gender-matched littermate wild type (WT) and Il-17a-/- C57BL/6 mice were fed an intermittent 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 21 days to induce cholestatic liver injury or a control diet.

Results: As compared to WT littermates, Il-17a-/- mice displayed more abundant desmin-positive myofibroblasts and increased fibrosis. NanoString analysis of intrahepatic leukocyte populations using a fibrosis-related gene panel identified upregulation of Tnfsf14 (encoding the protein LIGHT) in the DDC-fed Il-17a-/- mice. Although mass cytometry identified an increase in myeloid cells in both genotypes of the DDC-fed mice, we could not identify LIGHT expression in this cell lineage. Instead, the upregulation of LIGHT expression was largely restricted to a CD4+ T cell population as assessed by flow cytometry. Enhanced LIGHT expression was observed in a Th1+ CD4+ T cell population. LIGHT activated primary human hepatic stellate cells in vitro, suggesting that LIGHT stimulation of hepatic fibrogenesis may be direct.

Conclusion: Taken together, these data suggest that IL-17A restrains expression of the profibrogenic cytokine, LIGHT, by Th1-polarized CD4+ T cells, and implicate a role for LIGHT in cholestatic fibrogenesis in DDC-fed mice; a finding which requires validation in additional models.

Traditional herbal extracts are attracting attention in the context of animal disease control because of their low side effects, diverse bioactive compounds, and low antimicrobial resistance risk. However, the underlying mechanisms remain inadequately understood. To characterize the multifaceted biological activities that underlie their therapeutic potential, this study systematically evaluated the antiviral and complex immunomodulatory properties of three distinct herbal combinations (designated Extracts A, B, and C) in vitro. The antiviral activities of the extracts were tested against bovine rotavirus and bovine coronavirus, two major pathogens of neonatal calf diarrhea, and their regulation of inflammatory mediators was assessed in a murine macrophage model (RAW 264.7 cells) stimulated with lipopolysaccharide from Escherichia coli by measuring nitric oxide production and the gene expression of inflammation related enzymes. Immunomodulatory effects were investigated by analyzing the gene expression of T helper cell-associated cytokines in both RAW 264.7 cells and bovine peripheral blood mononuclear cells (PBMCs). All three extracts exhibited inhibitory activity against both viruses and reduced the expression of specific inflammatory mediators. Furthermore, the extracts demonstrated complex immunomodulatory effects in bovine PBMCs, with Extract C promoting T helper 1 and T helper 17 responses while suppressing the regulatory T-cell transcription factor Forkhead Box P3. In conclusion, this in vitro study demonstrates that these herbal extracts possess antiviral and immunomodulatory potential, providing a basis for future studies to determine their relevance in viral infections associated with calf diarrhea.

Purpose: There is extensive research on sound localization performance of blind individuals in laboratory settings. However, less is known about their spatial hearing experiences in more complex everyday environments. This study aims to assess the perceived sound localization abilities in blind individuals in common everyday tasks, which is a critical determinant of confidence and engagement in such tasks (e.g., independent travel).

Method: Fifty-eight adults with total or near-total blindness, including 28 with self-reported normal hearing and 30 with self-reported hard of hearing participated in this study. They completed the Dual Sensory Spatial Localization Questionnaire (DS-SLQ), a recently developed instrument that evaluates perceived difficulty in everyday localization tasks using vision and hearing. Properties of the DS-SLQ for blind individuals, including whether its items measure a single attribute (i.e., unidimensionality) and whether item difficulties match blind individuals' perceived abilities (i.e., targeting), were validated using Rasch analysis. Multivariable regression models and correlation analysis evaluated the impacts of the onset of blindness, residual vision, hearing status, onset of hearing loss, use of hearing aids, and echolocation skills on perceived sound localization abilities.

Results: The DS-SLQ showed excellent targeting and good unidimentionality for blind individuals. Individuals with later onset of blindness reported significantly lower perceived sound localization abilities. The presence of hearing loss, particularly early onset, was associated with further reductions in perceived sound localization ability. Those who reported higher echolocation skills also reported better perceived sound localization abilities, regardless of their hearing status. Residual vision and use of hearing aids were not associated with perceived sound localization abilities.

Conclusion: Beyond frequently studied vision factors, hearing loss and its onset further affect perceived sound localization abilities and the likelihood of an individual being an echolocator. It is critical to consider hearing status in the rehabilitation of blind individuals for maintaining and enhancing spatial localization skills.

Research on carbon storage is crucial for guiding regional sustainable development. However, Sichuan Province lacks long-term systematic analyses of carbon storage, and the driving mechanisms behind its changes remain unclear. This study systematically examines the spatiotemporal evolution of LUCC(land use/cover change) and carbon storage in Sichuan from 1980 to 2020, analyzes driving factors of carbon storage changes, and simulates future carbon storage distribution under different scenarios, based on LUCC data and 13 driving factors. Key findings include: (1) Over the 40-year period, land use was dominated by grassland, forest land, and farmland, maintaining a stable "grassland/forest land in the west, farmland in the east" pattern, with notable farmland and water body shrinkage alongside grassland and construction land expansion. (2) Total carbon storage showed minor fluctuations (9,201.53-9,209.52 Tg) but exhibited significant spatial heterogeneity, persistently displaying a "high in the west and low in the east" distribution. Water body-to-grassland and farmland-to-forest land conversions substantially increased carbon storage, while forest land-to-grassland and farmland-to-construction land transitions decreased it. (3) Spatial autocorrelation analysis revealed a negative correlation between carbon storage and land use intensity, with pronounced spatial clustering-High-High clusters concentrated in western regions and Low-Low clusters distributed peripherally. (4) Temperature and Digital Elevation Model emerged as dominant factors, while transportation accessibility and precipitation showed minimal influence. Human activities demonstrated moderate regulatory effects, with factor interactions significantly enhancing explanatory power, indicating multi-factor driven changes. (5) Multi-scenario projections (2030-2050) maintained the "high in the west and low in the east" pattern. Compared to 2020, SSP1-1.9 (Shared Socioeconomic Pathway 1-1.9) showed minimal change (10,711.94 ~ 10,712.16 Tg), SSP2-4.5 (Shared Socioeconomic Pathway 2-4.5) exhibited the largest decline (9,243.73 ~ 9,202.01 Tg), and SSP5-8.5 (Shared Socioeconomic Pathway 5-8.5) also decreased notably (9,015.01 ~ 8,980.07 Tg). This study provides a scientific basis for future land use optimization and carbon sink management in Sichuan Province.

Southern Indiana has intensive livestock production, yet species-resolved fecal pathogen and pathogen associated gene profiles are limited. At 10 sites in southern Indiana (April-June 2024), we collected 128 fecal specimens from 10 hosts: pigs (n = 12), horses (12), cats (12), chickens (12), dogs (22), white-tailed deer (12), sheep (12), goats (12), cows (12), and humans (10). We extracted and assayed total nucleic acids using a custom 43-target TaqMan Array Card (RT-qPCR). Flotation microscopy was performed on pig and dog stools for helminth ova. In-silico specificity checks were conducted for selected targets due to potential for cross reactivity between pathogen species. Most samples (60%, 75/126) were positive for ≥1 target, including enteropathogenic Escherichia coli (eae) 16% and shiga toxin genes (stx1 10%, stx2 6.3%). Higher prevalence of genes associated with specific pathogens and gut microbes in specific animals was common, including E. coli O157:H7 in pigs (42%) and sheep (8.3%); Campylobacter coli in chickens (36%) and Klebsiella pneumoniae in humans (60%) and dogs (9.1%). We found the protozoa Giardia in 15% of samples (notably dogs 32%, cows 33%) and Cryptosporidium in 14% (cats 55%, cows 25%, chickens 27%). Most (55%) chicken samples were positive for Plasmodium, which aligned with evidence of locally circulating avian haemosporidians. The Ascaris lumbricoides assay was positive only in pigs (17%), and we identified Ascaris type eggs in 92% of pig samples via microscopy, suggesting our Ascaris lumbricoides assay cross reacted with Ascaris suum supporting detection of the swine lineage (A. suum). We detected the class 1 integron-integrase gene (intI1) in 43% of stools, concentrated in chickens, pigs, and horses. These findings suggest animal feces poses a public health hazard in Southern Indiana and indicate the need for targeted One Health studies to better understand the public health risks of specific exposures and animal feces management practices (e.g., farm storage capacity, land application timing, soil incorporation/injection, tile-drain proximity).

Until the beginning of this century, neurons of the supraoptic nucleus (SON) were repeatedly shown to express tyrosine hydroxylase (TH) in salt loaded rats. However, its role remains unsolved due to methodological problems. Given that these issues can now be solved using transgenic mice and more advanced methods, the aim of this study was to reproduce the salt loading models used in rats, in C57BL/6 mice and transgenic mice expressing the green fluorescent protein gene under the TH promoter. Our study also attempted to identify a model that would most significantly increase TH synthesis in vasopressinergic neurons. This was assessed with immunocytochemistry by measuring the number of TH-immunoreactive neurons in the SON and the intraneuronal content of TH-immunoreactive material in individual neurons. In the first model, when using 3% NaCl as drinking water, the highest number of TH-immnopositive neurons was detected on the 3rd day, while the intraneuronal TH content did not change. In the second model, 10 hours after the intraperitoneal administration of 8.5% NaCl (experiment) or 0.9% NaCl (control), the number of TH-immunopositive neurons was significantly higher than in the first model. Moreover, the intraneuronal content of TH increased. Additional PCR analysis showed in the second model an increase in the expression of the TH gene and genes of some transcription factors (Sp1, Atf4, c-Fos, c-Jun) that initiate the TH gene expression in SON. Thus, we developed and characterized a salt loading model in mice with the highest level of TH synthesis, which will be used in the future to assess the functional significance of this protein.

The development of Bovine Respiratory Disease (BRD) in beef cattle is associated with stressful events, including auction and transport. In addition to the effects of commingling on pathogen exposure, stress also impacts immune function and has classically been associated with an immunosuppressed state. Much of the research on cattle immunity in stress has focused on peripheral blood immune functionality rather than mucosal immune responses. To characterize immunity at the primary site of pathogen colonization in BRD, we evaluated stress responses in lung cells from beef stocker cattle to understand mucosal immune changes. Stocker calves were sampled via bronchoalveolar lavage fluid (BALF) collection within 24 hours of auction and transport to a new facility (Stressed, n = 12), or allowed to acclimate for 2 months at the new facility before sampling (Acclimated, n = 7). Lavage cellular RNA was extracted and sequenced for bulk RNA-seq gene expression. Differential gene expression analysis of RNA sequencing data demonstrated a profound upregulation of inflammatory genes in Stressed calves compared to Acclimated calves, including expression of CXCL8, CSF3R, IL1B, and CCL22. Top pathway upregulation in Stressed calves involved neutrophil migration and chemotaxis, and cytokine signaling. To predict cellular population proportions from the data, CIBERSORTx was used to deconvolute bulk RNA-seq gene counts. This analysis showed that Stressed calves had significantly increased BALF neutrophils compared to Acclimated calves (p = 0.003). Neutrophilic infiltration occurred in the absence of pathogen colonization of the lungs in most calves, as demonstrated by a multi-pathogen respiratory qPCR screen. As such, the stress induced an inflammatory response in lungs not explained by pathogen exposure. This study provides strong evidence that shipping stress in beef stocker calves can trigger increased inflammatory pulmonary mucosal immune responses, which has important implications for the pathogenesis of BRD.

Background: Type-2-diabetes-mellitus (T2DM), often linked to obesity, raises risk of microvascular and macrovascular complications. International guidelines recommend triple-therapy to reach haemoglobin A1c (HbA1c) targets when dual therapy fails to adequately control blood glucose levels. Sitagliptin, enhances glycaemic control by prolonging incretin action, boosting insulin secretion, and lowering glucagon levels. When combined with glimepiride and metformin this triple-therapy targets multiple mechanisms. This study evaluated the effectiveness and safety of this combination for improved T2DM management in Indian patients.

Method: This real-world, multicentre, observational chart review evaluated the efficacy and safety of a triple fixed-dose combination therapy in 1235 adult patients with T2DM across 194 clinical sites in India. Data were retrospectively extracted from patient records over a 12-week period. Descriptive and analytical statistics was applied for the study endpoints using SPSS ver. 29.0.1.0(171) and Microsoft Excel 2019.

Result: The study population had a mean age of 56.89 ± 10.29 years, with 64.70% reporting a family history of type 2 diabetes mellitus (T2DM). Smoking was identified as a prominent risk factor, affecting 38.65% of participants. Significant improvements were observed in glycemic parameters over 12 weeks: HbA1c levels decreased from 8.20 ± 0.60% to 7.08 ± 0.77% (p < 0.0001), fasting blood glucose (FBG) from 188.54 ± 47.59 mg/dL to 146.01 ± 41.53 mg/dL (p < 0.0001), and 2-hour postprandial plasma glucose (PPG) from 234.74 ± 50.40 mg/dL to 179.40 ± 42.51 mg/dL (p < 0.0001). Additionally, body weight significantly reduced from 75.99 ± 8.67 kg to 74.76 ± 9.07 kg (p < 0.0001). No significant safety concerns identified during the treatment period.

Conclusion: The triple-combination therapy (sitagliptin, glimepiride, and metformin) demonstrated superior efficacy in achieving glycemic control, as evidenced by significant reductions in HbA1c, fasting blood glucose (FBG), and postprandial plasma glucose (PPG). Furthermore, the therapy facilitated meaningful weight reduction, highlighting its clinical utility as a comprehensive therapeutic option for managing glycemic parameters in both T2DM with overweight and normal-weight patients.

This qualitative exploratory study aimed to learn clinicians' perspectives on Pre-exposure Prophylaxis (PrEP) initiation, the HIV risk assessment process, perceived barriers to PrEP implementation, and how a potential electronic health record (EHR)-based PrEP clinical decision support tool can help improve their practices. Using purposive sampling, we recruited 15 clinicians with experience in PrEP practices for the three remote focus groups held between October 2021 and November 2021 using a semi-structured discussion guide. The focus groups were audio-recorded, transcribed, and analyzed in NVivo using thematic analysis. Five themes emerged from the qualitative analysis: (1) PrEP initiation is a joint effort between patients and clinicians; (2) Patient-clinician conversations are key for identifying PrEP candidates; (3) EHRs are helpful but insufficient for identifying PrEP candidates; (4) Patient, clinician, and system-level barriers deter PrEP implementation; and (5) Adopting technological innovations in health care can improve PrEP prescribing. Our analysis suggests that implementing effective communication strategies and behavioral interventions can improve PrEP awareness and reduce barriers in patient-clinician discussions of sexual history and substance use.