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Poultry Science Apr 2024Magang geese are typical short-day breeders whose reproductive behaviors are significantly influenced by photoperiod. Exposure to a long-day photoperiod results in...
Magang geese are typical short-day breeders whose reproductive behaviors are significantly influenced by photoperiod. Exposure to a long-day photoperiod results in testicular regression and spermatogenesis arrest in Magang geese. To investigate the epigenetic influence of DNA methylation on the seasonal testicular regression in Magang geese, we conducted whole-genome bisulfite sequencing and transcriptome sequencing of testes across 3 reproductive phases during a long-day photoperiod. A total of 250,326 differentially methylated regions (DMR) were identified among the 3 comparison groups, with a significant number showing hypermethylation, especially in intronic regions of the genome. Integrating bisulfite sequencing with transcriptome sequencing data revealed that DMR-associated genes tend to be differentially expressed in the testes, highlighting a potential regulatory role for DNA methylation in gene expression. Furthermore, there was a significant negative correlation between changes in the methylation of CG DMRs and changes in the expression of their associated genes in the testes. A total of 3,359 DMR-associated differentially expressed genes (DEG) were identified; functional enrichment analyses revealed that motor proteins, MAPK signaling pathway, ECM-receptor interaction, phagosome, TGF-beta signaling pathway, and calcium signaling might contribute to the testicular regression process. GSEA revealed that the significantly enriched activated hallmark gene set was associated with apoptosis and estrogen response during testicular regression, while the repressed hallmark gene set was involved in spermatogenesis. Our study also revealed that methylation changes significantly impacted the expression level of vitamin A metabolism-related genes during testicular degeneration, with hypermethylation of STRA6 and increased calmodulin levels indicating vitamin A efflux during the testicular regression. These findings were corroborated by pyrosequencing and real-time qPCR, which revealed that the vitamin A metabolic pathway plays a pivotal role in testicular degeneration under long-day conditions. Additionally, metabolomics analysis revealed an insufficiency of vitamin A and an abnormally high level of oxysterols accumulated in the testes during testicular regression. In conclusion, our study demonstrated that testicular degeneration in Magang geese induced by a long-day photoperiod is linked to vitamin A homeostasis disruption, which manifests as the hypermethylation status of STRA6, vitamin A efflux, and a high level of oxysterol accumulation. These findings offer new insights into the effects of DNA methylation on the seasonal testicular regression that occurs during long-day photoperiods in Magang geese.
PubMed: 38917605
DOI: 10.1016/j.psj.2024.103769 -
Communications Medicine Jun 2024While potential risk factors for multiple sclerosis (MS) have been extensively researched, it remains unclear how persons with MS theorize about their MS. Such theories...
BACKGROUND
While potential risk factors for multiple sclerosis (MS) have been extensively researched, it remains unclear how persons with MS theorize about their MS. Such theories may affect mental health and treatment adherence. Using natural language processing techniques, we investigated large-scale text data about theories that persons with MS have about the causes of their disease. We examined the topics into which their theories could be grouped and the prevalence of each theory topic.
METHODS
A total of 486 participants of the Swiss MS Registry longitudinal citizen science project provided text data on their theories about the etiology of MS. We used the transformer-based BERTopic Python library for topic modeling to identify underlying topics. We then conducted an in-depth characterization of the topics and assessed their prevalence.
RESULTS
The topic modeling analysis identifies 19 distinct topics that participants theorize as causal for their MS. The topics most frequently cited are Mental Distress (31.5%), Stress (Exhaustion, Work) (29.8%), Heredity/Familial Aggregation (27.4%), and Diet, Obesity (16.0%). The 19 theory topics can be grouped into four high-level categories: physical health (mentioned by 56.2% of all participants), mental health (mentioned by 53.7%), risk factors established in the scientific literature (genetics, Epstein-Barr virus, smoking, vitamin D deficiency/low sunlight exposure; mentioned by 47.7%), and fate/coincidence (mentioned by 3.1%). Our study highlights the importance of mental health issues for theories participants have about the causes of their MS.
CONCLUSIONS
Our findings emphasize the importance of communication between healthcare professionals and persons with MS about the pathogenesis of MS, the scientific evidence base and mental health.
PubMed: 38914643
DOI: 10.1038/s43856-024-00546-3 -
Frontiers in Nutrition 2024Vitamin D plays a major role in the musculoskeletal and immune system. Understanding the comprehensive mechanism of vitamin D receptors and the enzyme of vitamin D...
INTRODUCTION
Vitamin D plays a major role in the musculoskeletal and immune system. Understanding the comprehensive mechanism of vitamin D receptors and the enzyme of vitamin D induction (CYP2R1) and inhibition (CYP24A1) in its metabolism is interesting. This study aims to understand vitamin D metabolism in Indonesian pediatrics, specifically in Jakarta, which has abundant sun exposure.
METHODOLOGY
A cross-sectional study with comparative, correlative, and multivariate analysis on vitamin D, vitamin D receptor, CYP2R1, and CYP24A1 levels was conducted on 46 children with no known morbidity.
RESULT
Subjects were mostly male (52.2%), age group of 2-6 years (34.8%), and had sufficient vitamin D status (43.5%, median 27.55 ng/mL). Age was found to have a negative correlation with vitamin D levels ( < 0.001; = -0.625) and CYP2R1 ( = 0.035; = -0.311). Significant positive associations were found between CYP24A1 and CYP2R1 ( = 0.046; = 0.296). Participants aged 0-2 are more likely to have a higher level of vitamin D status compared to those aged >2 years (OR 42.092, 95% CI [4.532-390.914], = 0.001). VDR levels were significantly lower in insufficient vitamin D levels than in the sufficient group ( = 0.018). VDR and vitamin D status had a positive relation (OR 7.023, 95% CI [1.864-26.453], = 0.004).
CONCLUSION
Vitamin D levels decrease with the increase in age. Vitamin D receptor level has an inline-level progression with vitamin D level. CYP2R1 and CYP24A1 suggest a directly proportional relationship. Vitamin D screening and supplementation in children older than 2 years old are suggested.
PubMed: 38912300
DOI: 10.3389/fnut.2024.1394367 -
Blood Science (Baltimore, Md.) Jul 2024Ivosidenib, an isocitrate dehydrogenase 1 () inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with -mutated (m) acute myeloid...
Ivosidenib, an isocitrate dehydrogenase 1 () inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with -mutated (m) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) m AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration ( ) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%-53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R m AML patients were also consistent with results from pivotal study.
PubMed: 38911469
DOI: 10.1097/BS9.0000000000000196 -
Environment International Jun 2024There has been an increased concern on indoor air quality (IAQ) in residences since the majority of individuals' time is mainly spent indoors. We inspected and measured...
There has been an increased concern on indoor air quality (IAQ) in residences since the majority of individuals' time is mainly spent indoors. We inspected and measured indoor environmental parameters in 399 homes in northeast China in order to study IAQ. We systematically measured multilevel environmental parameters (physical, chemical, and biological) in children's bedrooms during all seasons. The results indicated that the median values for indoor temperature, relative humidity, total volatile organic compounds (TVOC), and formaldehyde concentrations throughout the year were within the Chinese national standards. However, the median carbon dioxide concentrations exceeded 1000 ppm during spring, autumn, and winter. In the same seasons, the air change rate (ACR) was below the minimum required level of 0.5 h. Di-2-ethylhexyl phthalate (DEHP), di-n-butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP) were predominantly detected in settled dust, displaying median concentrations of 126.9, 41.5, and 16.3 μg/g, respectively. Notably, phthalate concentrations were significantly higher in urban houses as compared to rural houses. Furthermore, median concentrations of Dermatophagoides farinae (Der f) and endotoxin were 689.4 ng/g and 3689.1 EU/g, respectively, trending higher in winter than summer. There was a negative correlation between ACR and chemical pollutants (TVOC, formaldehyde, and DiBP). In conclusion, northeast Chinese homes had poor indoor air quality with ubiquitous exposure to modern chemical compounds and insufficient ventilation.
PubMed: 38908271
DOI: 10.1016/j.envint.2024.108825 -
Food Chemistry Jun 2024Shark meat consumption may pose a significant risk to human health as high levels of toxic pollutants bioaccumulate in muscular tissue. Commercial harvest of...
Shark meat consumption may pose a significant risk to human health as high levels of toxic pollutants bioaccumulate in muscular tissue. Commercial harvest of Carcharhinus brachyurus meat in South Africa is estimated at 100-300 filleted tons per annum. Muscle tissue samples from 41 sharks were collected from the southern and eastern coastlines of South Africa in 2022 and analysed for 10 trace elements and 8 polychlorinated biphenyl congeners. All trace elements were found to be lower than the regulatory maximum limits for human consumption in most samples irrespective of shark length, sex, and sampling region. However, the estimated daily intake for Mercury and Arsenic exceeded the oral reference dose set by international agencies. The meat from this shark may be consumed due to its low toxic potential for human health, however long-term exposure to C. brachyurus meat should be avoided as it could pose detrimental health risks to consumers.
PubMed: 38908246
DOI: 10.1016/j.foodchem.2024.140081 -
Ecotoxicology and Environmental Safety Jun 2024The objectives of this study were to measure the mediation effect of plasma proteins and to clarify their mediating role in the relationship between stroke risk and...
The objectives of this study were to measure the mediation effect of plasma proteins and to clarify their mediating role in the relationship between stroke risk and particulate matter 2.5 (PM) exposure. The possible mediating role of plasma proteins on the causative link between PM exposure and stroke incidence were examined using a two-step Mendelian randomization (MR) approach based on two-sample Mendelian randomization (TSMR). The findings revealed a significant positive causal relationship between PM exposure and stroke, with an inverse variance weighted odds ratio of 1.219 (95 % CI: 1.002 - 1.482, P < 0.05). Additionally, a positive causal association was identified between PM exposure and several plasma proteins, including FAM134B, SAP, ITGB7, Elafin, and DCLK3. Among these, FAM134B, ITGB7, Elafin, and DCLK3 also demonstrated a positive causal association with stroke, whereas only SAP was found to be negatively causally associated with stroke. Remarkably, four plasma proteins, namely DCLK3, FAM134B, Elafin, and ITGB7, were identified as mediators, accounting for substantial proportions (14.5 %, 13.6 %, 11.1 %, and 9.9 %) of the causal association between PM and stroke. These results remained robust across various sensitivity analyses. Consequently, the study highlights the significant and independent impact of PM on stroke risk and identifies specific plasma proteins as potential targets for preventive interventions against PM-induced stroke.
PubMed: 38908058
DOI: 10.1016/j.ecoenv.2024.116624 -
Ecotoxicology and Environmental Safety Jun 2024Exposure to carbon disulfide (CS) is a recognized risk factor in the pathogenesis of Parkinson's disease, yet the underlying mechanisms of deleterious effects on...
Exposure to carbon disulfide (CS) is a recognized risk factor in the pathogenesis of Parkinson's disease, yet the underlying mechanisms of deleterious effects on mitochondrial integrity have remained elusive. Here, through establishing CS exposure models in rat and SH-SY5Y cells, we demonstrated that highly expressed α-synuclein (α-Syn) is transferred to mitochondria via membrane proteins such as Tom20 and leads to mitochondrial dysfunction and mitochondrial oxidative stress, which ultimately causes neuronal injury. We first found significant mitochondrial damage and oxidative stress in CS-exposed rat midbrain and SH-SY5Y cells and showed that mitochondrial oxidative stress was the main factor of mitochondrial damage by Mitoquinone intervention. Further experiments revealed that CS exposure led to the accumulation of α-Syn in mitochondria and that α-Syn co-immunoprecipitated with mitochondrial membrane proteins. Finally, the use of an α-Syn inhibitor (ELN484228) and small interfering RNA (siRNA) effectively mitigated the accumulation of α-Syn in neurons, as well as the inhibition of mitochondrial membrane potential, caused by CS exposure. In conclusion, our study identifies the translocation of α-Syn to mitochondria and the impairment of mitochondrial function, which has important implications for the broader understanding and treatment of neurodegenerative diseases associated with environmental toxins.
PubMed: 38908057
DOI: 10.1016/j.ecoenv.2024.116613 -
NanoImpact Jun 2024Micro- and nanoplastics have emerged as critical pollutants in various ecosystems, posing potential environmental and human health risks. Washing of polyester textiles...
Micro- and nanoplastics have emerged as critical pollutants in various ecosystems, posing potential environmental and human health risks. Washing of polyester textiles has been identified as one of the sources of nanoplastics. However, other stages of the textile life cycle may also release nanoparticles. This study aimed to examine nanoparticle release during UV degradation of polyester textiles under controlled and real-world conditions. Fleece polyester textiles were weathered under simulated sunlight for up to two months, either in air or submerged in water. We conducted bi-weekly SEM image analyses and quantified released nanoparticles using nanoparticle tracking analysis (NTA). At week 0, the fiber surface appeared smooth after prewashing. In the air group, nanoparticles appeared on the fiber surface after UV-exposure. In the group of textiles submerged in water, the surfaces developed more pits over time. The cumulative nanoparticle emission from the weathered textiles ranged from 1.4 × 10 to 4.0 × 10 particles per gram of fabric in the air group and from 1.6 × 10 to 4.4 × 10 particles per gram of fabric in the water group over two months. The predominant particle size fell into the 100 to 200 nm range. The estimated mass of the released nanoparticles was 0.06-0.26 g per gram of fabric, which is lower than the amount released during the washing of new textiles. Additionally, Scanning Transmission X-ray Microscopy (STXM) images indicated that the weathered nanoparticles underwent oxidation. Overall, the research offers valuable insights into nanoparticle formation and release from polyester textiles during UV degradation.
PubMed: 38906250
DOI: 10.1016/j.impact.2024.100520 -
European Journal of Pharmaceutical... Jun 2024Tacrolimus (FK506) is a cornerstone of GVHD-prophylaxis treatment in paediatrics undergoing haematopoietic stem cell transplantation (HSCT). However, due to concerns...
Tacrolimus (FK506) is a cornerstone of GVHD-prophylaxis treatment in paediatrics undergoing haematopoietic stem cell transplantation (HSCT). However, due to concerns about highly inter/intra-individual variability, precision dosing of FK506 is crucial. Cytochrome P450(CYP) 3A4 and 3A5 are considered important sources of FK506 pharmacokinetic variability. Nevertheless, the impact of age-related maturation in hepatic and intestinal CYP3A4/3A5 enzymes remains unknown in paediatric HSCT patients. Physiologically-based pharmacokinetic (PBPK) models were developed and verified in adult volunteers and adult HSCT patients using GastroPlus (version 9.0), and then extrapolated to paediatric HSCT patients, taking into account the maturation of CYP3A4 and CYP3A5. Default CYP3A4 and CYP3A5 ontogeny profiles were updated based on the latest reports. The paediatric PBPK model was evaluated with independent data collected from Sun Yat-sen Memorial Hospital (86 paediatric HSCT patients, 1 to 16 -year-old). Simulations were performed to evaluate a reported FK506 dosing regimen in infants and children with different CYP3A5 genotypes. Extensive PBPK model validation indicated good predictability, with the predicted/observed (P/O) ratios within the range of 0.80-fold to 1.25-fold. Blood tacrolimus concentration-time curves were comparable between the real and virtual patients. Simulations showed that the higher levels of tacrolimus in 9-month-old to 3-year-old infants were mainly attributed to the CYP3A4/3A5 ontogeny profiles, which resulted in lower clearance and higher exposure relative to dose. The oral dosage of 0.1 mg/kg/day (q12 h) is considered appropriate for paediatric HSCT patients 9 months to 15 years of age with CYP3A5 *1/*1 genotypes. Lower doses were required for paediatric HSCT patients with CYP3A5 *1/*3 (0.08 mg/kg/day, q12h) or CYP3A5 *3/*3 genotypes (0.07 mg/kg/day, q12h), and analyses demonstrated 12.5%-20% decreases in ≤3-year-old patients. The study highlights the feasibility of PBPK modelling to explore age-related enzyme maturation in infants and children(≤3-year-old) undergoing HSCT and emphasizes the need to include hepatic and gut CYP3A4/3A5 maturation parameters.
PubMed: 38906231
DOI: 10.1016/j.ejps.2024.106839