Search Results (126)

Background: Somatic symptom disorder (SSD) in children may be influenced by stress reactivity and psychosocial factors. The glucocorticoid receptor (GR), encoded by NR3C1, is a key mediator of stress responses. However, the relationship between NR3C1 methylation and SSD remains unclear. Methods: We analyzed NR3C1 exon 1F methylation in cell-free DNA from saliva in 34 children with SSD and 29 age- and sex-matched controls using bisulfite amplicon sequencing. Psychological assessments included the Beck Depression Inventory-II (BDI-II) and KINDL questionnaires to evaluate associations with methylation patterns. Results: Methylation levels showed age-related differences. In children under 13, CpG sites displayed mixed methylation, and specific sites correlated with KINDL and BDI-II scores. KINDL physical and total well-being scores negatively correlated with CpG30 and positively with CpG35; BDI-II scores negatively correlated with CpG32 and CpG35. In children aged 13 or older, CpG sites showed uniformly high methylation with no correlation to psychological measures. The SSD group showed significantly higher average methylation across the exon 1F region than controls in the older age group. These children also had more cases of orthostatic dysregulation and longer illness duration. Conclusions: This study suggests age-dependent epigenetic regulation of NR3C1 in SSD. While younger children showed CpG-specific correlations with psychological symptoms, older children demonstrated uniformly high methylation and potentially reduced gene expression, potentially reflecting cumulative stress, autonomic dysfunction, and internalizing disorders such as anxiety and depression. Full article

Background: DNA damage response (DDR) pathway alterations contribute to genomic instability and malignant progression in several cancers. Methods: We retrospectively reviewed molecular profiles from 5309 sarcoma patient samples, including 746 from pediatric/adolescent and young adults (ped/AYA), encompassing 38 histologic subtypes. The gene expression profiles were further analyzed for immunotherapy-related biomarker associations, including analysis of the T cell-inflamed score. Results: Pathogenic/likely pathogenic DDR alterations were detected in 15.9% (N = 842) of samples overall and 9.25% (N = 69) of Ped/AYA tumors, with mutations occurring most frequently in ATRX (10.1%). Shorter overall survival was observed for patients with DDR-alterations compared to those with DDR-wildtype tumors (Hazard Ratio = 1.172, 95% CI: 1.068–1.287; p < 0.001). In many subtypes, DDR-mutated tumors were found to have increased rates of immune markers, including PD-L1+, dMMR/MSI-high, and TMB. Conclusions: Our study of somatic DDR-pathway mutations provides a better understanding of the molecular associations across sarcoma subtypes that may aid in developing future prognostic and therapeutic options for these rare cancers. Full article

Mastitis significantly impacts both the yield and quality of milk. The somatic cell count (SCC) and differential somatic cell count (DSCC), which are related to immune cells, are primary indicators for assessing mammary gland health. In this study, eight previously established mid-infrared spectroscopy models were utilized to predict the content of milk protein fractions (αs1-CN, β-CN, κ-CN, total CN, α-LA, β-LG, IgG, and LF) in milk samples from 21,388 lactating cows across 33 herds. Four linear mixed models were applied to analyze the secretion patterns of milk protein fractions by days in milk (DIM) and parity, their variations under different mastitis conditions, and their associations with the somatic cell score (SCS), DSCC, and immune cell counts (PMN + LYM score (PMN + LYMS) and MAC score (MACS)). The primary findings of the investigation comprised the following: (1) IgG was higher in early lactation, decreased with advancing lactation days, and slightly increased in late lactation, while seven other protein factions decreased from early to peak lactation and increased during mid-to-late lactation. Parity influenced all milk protein fractions except αs1-CN, with total CN, β-CN, and α-LA decreasing and κ-CN, β-LG, IgG, and LF increasing as parity increased (p < 0.05). (2) Mastitis significantly reduced the milk yield, fat percentage, protein percentage, and the contents of total CN, β-CN, κ-CN, and α-LA while increasing β-LG, IgG, and LF. (3) The SCS was negatively correlated with milk yield and α-LA but positively correlated with the fat percentage, protein percentage, κ-CN, β-LG, IgG, and LF. (4) When the DSCC increased to 50%, the milk yield decreased, while the milk protein percentage and κ-CN content significantly increased (p < 0.05). When the DSCC exceeded 50%, the fat percentage, protein percentage, total casein, αs1-CN, β-CN, κ-CN, β-LG, IgG, and LF decreased, while the α-LA content increased (p < 0.05). (5) When the PMN + LYMS increased, the milk yield and α-LA content rose, while the milk fat percentage, the milk protein percentage, and the contents of αs1-CN, β-CN, κ-CN, total CN, β-LG, IgG, and LF decreased (p < 0.05). Conversely, when the MACS increased, the milk yield and α-LA content declined, whereas the milk fat percentage, the milk protein percentage, and the contents of αs1-CN, β-CN, κ-CN, total CN, β-LG, IgG, and LF increased (p < 0.05). This study offers valuable insights into enhancing milk product quality, advancing the early diagnosis and mechanistic research of bovine mastitis, and the sustainable development of the dairy farming industry. Full article

Nuclear receptor coactivator 6 is a gene that produces a protein that regulates transcriptional activity. It is also involved in many processes like cell survival, metabolism, homeostasis, and embryonic development. This study focused on studying the genetic influence of single-nucleotide polymorphisms (SNPs) within the NCOA6 gene on lactation performance characteristics. The objective of this study was to determine the genetic impact of SNPs of the NCOA6 gene on milk production traits. After the random selection of twenty cows, PCR amplification and sequencing were performed from their blood samples to find the SNPs present in the bovine NCOA6 gene. As a result, two SNPs, g.71544C > T and g.87310A > G, were found. Then, the genotyping of the cows (n = 985) was conducted using a Sequenom MassARRAY based on previously identified SNP information. The least-square method was applied to study the links between lactation traits, somatic cell score (SSC), and 305-day milk output. The results indicated that the SNP g.87310A > G was strongly associated with g.71544C > T in linkage disequilibrium. The single-nucleotide polymorphism g.87310A > G showed a very strong association with daily milk yield and 305-day milk production. Individuals with the AA genotype exhibited a notable increase in daily milk production by 1.64 kg, and their 305-day milk yield was approximately 500 kg higher. This variation demonstrated a significant genetic effect on milk output. In brief, the pleiotropic influence of the cattle NCOA6 gene on lactation traits was revealed in this study. However, additional research will provide a basis for further exploring the underlying correlation and theoretical framework of the molecular genetics of milk composition and the production attributes of Holstein cows. Full article

Mastitis is an important disease limiting milk production in dairy cows. Somatic cell score is commonly used as one of the main ways to gauge the level of mastitis in dairy cows, with higher somatic cell scores usually indicating possible mastitis. However, the main molecular markers affecting somatic cell scores remain unknown. The aim of this study was to investigate the association between single nucleotide polymorphisms in the SLC11A1 gene and somatic cell score in Chinese Holstein cows. In this study, 210 Chinese Holstein cows were genotyped and potential SNPs were detected by DNA sequencing, PCR-SSCP and PCR-RFLP analysis. Our results revealed two SNPs were identified in the CDS region of SLC11A1: c.723C>T and c.1144C>G. For the c.723C>T polymorphic site, two genotypes (AA, AB) were found and the genotype frequencies were 0.790 and 0.210, respectively. The results of the association analysis showed that the mean somatic cell score of the AA genotypes were significantly lower than those of the AB genotypes, suggesting that the A allele is a potential marker for improving mastitis resistance in Chinese Holstein cows. For the c.1144C>G polymorphic site, three genotypes (CC, CD, and DD) were found and the genotype frequencies were 0.629, 0.352 and 0.019, respectively. The association analysis revealed that the mean somatic cell score of CC genotypes was lower than that of CD and DD genotypes, however, no significant differences were observed among the various genotype groups when subjected to pair-wise comparisons. The bioinformatic analysis showed that these mutations affected the secondary and tertiary structure of SLC11A1 mRNA, suggesting that they may affect gene expression or protein translation and function. Finally, we predicted the SLC11A1 protein interaction network and found that SPI1, NOD2, TLR2 and S100A12 interacted with SLC11A1 and were reported as candidate genes associated with mastitis resistance. The results indicated that the SNP (c.723C>T) could be potential molecular marker for improving mastitis resistance traits in Chinese Holstein cows. We recommend further validation of this SNP in larger populations and its potential integration into breeding programs to enhance mastitis resistance in dairy cows. Full article

Background/Objectives: The resistance to occult mastitis in dairy cows is a multifaceted trait influenced by a variety of genetic and environmental factors, posing significant challenges to its prevention and treatment. Methods: In this study, a cohort of 389 Holstein dairy cows was selected for investigation. The genes NOD2, CXCR1, SPP1 and LF, which are implicated in resistance to occult mastitis, were genotyped utilizing the efficient and cost-effective Kompetitive Allele-Specific PCR (KASP) technology. Additionally, the study analyzed the association between various single nucleotide polymorphisms (SNPs) and the somatic cell score in Holstein dairy cows. Multi-locus penetrance variance analysis (MPVA) analysis was also conducted to assess the resistance of different genotypic combinations to recessive mastitis in dairy cows. A genotyping kit for occult mastitis resistance was developed. Subsequently, 300 Holstein cows were randomly selected to evaluate the accuracy of the kit’s classification and resistance detection. Results: The findings revealed that the most effective genotype combination was SPP1(AA)-CXCR1(CC)-NOD2(CA)-LF(GA). Upon verification, the genotyping kit for recessive mastitis resistance in dairy cows exhibited an accuracy rate of 100% for individual genotyping and 95.90% for resistance detection. Conclusions: From the perspective of disease resistance genetics, this study lays a foundation for the precise management of dairy cow herds. It enables the early identification and removal of individuals susceptible to subclinical mastitis, thereby improving the overall quality of the cattle population. Full article

Background/Objectives: Cellular senescence plays a critical role in tumorigenesis, immune cell infiltration, and treatment response. Adrenocortical carcinoma (ACC) is a malignant tumor that lacks effective therapies. This study aimed to construct and validate a senescence-related gene signature as an independent prognostic predictor for ACC and explore its impact on the tumor microenvironment, immunotherapy, and chemotherapy response. Methods: Data were collected from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Using Kaplan–Meier survival analysis, LASSO penalized Cox regression and multivariable Cox regression, we identified a prognostic model with four senescence-related genes (HJURP, CDK1, FOXM1, and CHEK1). The model’s prognostic value was validated through survival analysis, risk score curves, and receiver operating characteristic (ROC) curves. Tumor mutation burden was assessed with maftools, and the tumor microenvironment was analyzed using CIBERSORT and ESTIMATE. Immune and chemotherapeutic responses were assessed through Tumor Immune Dysfunction and Exclusion (TIDE) and OncoPredict. Results: The risk score derived from our model showed a strong association with overall survival (OS) in ACC patients (p < 0.001, HR = 2.478). Higher risk scores were correlated with more advanced tumor stages and a greater frequency of somatic mutations. Differentially expressed genes (DEGs) that were downregulated in the high-risk group were significantly enriched in immune-related pathways. Furthermore, high-risk patients were predicted to have reduced sensitivity to immunotherapy (p = 0.02). Bioinformatics analysis identified potential chemotherapeutic agents, including BI-2536 and MIM1, as more effective treatment options for high-risk patients. Conclusions: Our findings indicate that this prognostic model may serve as a valuable tool for predicting overall survival (OS) and treatment responses in ACC patients, including those receiving chemotherapy and immunotherapy. Full article

Glioblastoma (GBM) is the most aggressive primary brain cancer, with poor prognosis due to its aggressive behavior and high heterogeneity. This study aimed to identify cellular senescence (CS) and lipid metabolism (LM)-related prognostic genes to improve GBM prognosis and treatment. Transcriptome and scRNA-seq data, CS-associated genes (CSAGs), and LM-related genes (LMRGs) were acquired from public databases. Prognostic genes were identified by intersecting CSAGs, LMRGs, and differentially expressed genes (DEGs), followed by WGCNA and univariate Cox regression. A risk model and nomogram were constructed. Analyses covered clinicopathological features, immune microenvironment, somatic mutations, and drug sensitivity. GBM scRNA-seq data identified key cells and prognostic gene expression. SOCS1 and PHB2 were identified as prognostic markers, contributing to the construction of a robust risk model with excellent predictive ability. High-risk group (HRG) patients had poorer survival, higher immune and stromal scores, and distinct somatic mutation profiles. Drug sensitivity analysis revealed significant differences in IC50 values. In microglia differentiation, SOCS1 and PHB2 showed dynamic expression patterns. These findings provide new strategies for GBM prognosis and treatment. Full article

Protein phosphorylation is a dynamic and reversible modification involved in almost all cellular processes. Numerous investigations have shown that protein phosphorylation modification enzymes (PPMEs) that regulate protein phosphorylation play an important role in the occurrence and treatment of tumors. However, there is still a lack of effective insights into the value of PPMEs in the classification and treatment of patients with lung adenocarcinoma (LUAD). Here, four topological algorithms identified 15 hub PPMEs from a protein–protein interaction (PPI) network. This PPI network was constructed using 124 PPMEs significantly correlated with 35 cancer hallmark-related pathways. Our study illustrates that these hub PPMEs can affect the survival of patients with LUAD in the form of somatic mutation or expression perturbation. Consistency clustering based on hub PPMEs recognized two phosphorylation modification subtypes (namely cluster1 and cluster2) from LUAD. Compared with patients in cluster1, the survival prognosis of patients in cluster2 is worse. This disparity is probably attributed to the higher tumor mutation burden, the higher male proportion, and the more significant expression disturbance in patients in cluster2. Moreover, phosphorylation modification subtypes also have different characteristics in terms of immune activity, immune infiltration level, immunotherapy response, and drug sensitivity. We constructed a PSig scoring system by using a principal component analysis algorithm to estimate the level of phosphorylation modification in individual LUAD patients. Patients in the high and low PSig score groups demonstrated different characteristics in terms of survival rate, tumor mutation burden, somatic gene mutation rate, immune cell abundance, and sensitivity to immunotherapy and drug treatment. This work reveals that phosphorylation plays a non-negligible role in the tumor microenvironment and immunotherapy of LUAD. Evaluating the phosphorylation status of individual LUAD patients by the PSig score can contribute to enhancing our cognition of the tumor microenvironment and guiding the formulation of more effective personalized treatment strategies. Full article

Glutathione (GSH), widely present in plant and animal cells and crucial for combating oxidative stress and inflammation, has not been evaluated in dairy cows. This study aims to evaluate the effects of rumen-protected glutathione (RPGSH) supplementation on lactation, nutrient metabolism, oxidative stress, inflammation, and health in transition dairy cows. Forty Holstein dairy cows (2.65 ± 0.78 of parity, 2.81 ± 0.24 of body condition score, 9207.56 ± 1139.18 kg of previous 305-day milk yield, 657.53 ± 55.52 kg of body weight, mean ± SD) were selected from a large cohort of 3215 cows on day 21 before expected calving (day −21 ± 3 d). Cows were randomly stratified into four dietary treatment groups (n = 10 per group): control (basal diet + 0 g/d RPGSH); T1 (basal diet + 1.5 g/d RPGSH); T2 (basal diet + 2 g/d RPGSH); and T3 (basal diet + 3 g/d RPGSH). Supplementation commenced approximately 21 days (±3) prepartum and continued through 21 days postpartum. Blood samples were collected at −21 ± 3, −14 ± 3, −7 ± 3, 0, 7, 14, and 21 d for analysis of serum metabolic parameters related to oxidative stress and inflammation. Milk composition was analyzed from samples collected on days 3, 7, 14, and 21 postpartum. Compared with the control group, supplementation with 2 g/d of RPGSH reduced somatic cell count (p < 0.05) and the incidence of postpartum diseases in dairy cows. No differences were observed among the groups in milk yield, milk fat, protein, lactose, total solids, dry matter intake, or energy-corrected milk. However, fat-corrected milk and feed efficiency were higher in the T2 group compared to the control (p < 0.05). Calcium and phosphorus levels did not differ among the groups. Compared to the control group, cows supplemented with 2 g/d RPGSH had lower β-hydroxybutyrate levels and higher glucose levels on days 14 and 21 postpartum (p < 0.05). From days 14 to 21 postpartum, RPGSH supplementation increased blood GSH, serum catalase, and total antioxidant capacity while reducing malondialdehyde, reactive oxygen species, haptoglobin, cortisol, C-reactive protein, and interleukin−6 levels compared with the control group (p < 0.05). The supplementation of 2 g/d RPGSH showed relatively better effects. RPGSH supplementation at 2 g/d improved lactation performance, nutrient metabolism, oxidative stress, and inflammation status in dairy cows, playing a crucial role in maintaining their health. To our knowledge, this is the first report on the effects of supplementing RPGSH additive in Holstein cows. Full article

Adopting a new milking system at a dairy farm causes various changes. This study examined the impact on udder health when changing from a conventional milking system to an automatic milking system. For this purpose, quarter milk samples were taken six times from 138 cows at one conventional dairy farm in Northern Germany over a five-week period around the time of the milking system changeover. To assess udder health, the absolute number of new intramammary infections and the causative pathogen genera and species were analysed for each individual study time point. Pathogen species were detected using matrix-assisted laser desorption ionisation time-of-flight, and the infection dynamics were analysed using two Poisson regression models. In addition, the prevalence and incidence of new intramammary infections and the infection dynamics of the four most frequently isolated pathogen species were calculated. Mixed models were used to determine the development of the new infection rate, the somatic cell count, the teat-end condition, and the udder hygiene between the individual study time points and to compare the new infection rate before and after the changeover of the milking system. After the automatic milking system had been installed, a significant increase in the quarter-level somatic cell count occurred (p < 0.001). Two days before the installation of the automatic milking system, the mean quarter-level somatic cell count was 11,940 cells/mL milk; one sampling date later, 8 days after the changeover, a mean quarter-level somatic cell count of 60,117 cells/mL milk was measured. The significant increase in somatic cell count was probably caused by the time between the last milking and the quarter milk sampling. Additionally, significantly more udders were scored as clean 8 days (95%) and 15 days (96%) after the changeover of the milking system compared to at the last sampling date (88%). Also, significantly more teat ends were classified as free of hyperkeratosis 15 days (80%) compared to 22 days (67%) after the changeover of the milking system. The highest number of absolute new intramammary infections was detected 8 days before the transition of the milking system (28.6%). The lowest number of absolute new intramammary infections occurred 8 days after the change to the automatic milking system (11.0%). Minor mastitis pathogens, such as non-aureus staphylococci and coryneform bacteria, were mainly responsible for the development of new intramammary infections. The most frequently isolated pathogen species were Staphylococcus sciuri, Staphylococcus chromogenes, Staphylococcus haemolyticus, and Corynebacterium amycolatum, with a prevalence of up to 23.9, 10.7, 8.4, and 5.3%, respectively. By comparing the new infection rate before and after the changeover of the milking system, it was possible to establish that the changeover to the automatic milking system had no significant influence on the new intramammary infection rate (p = 0.988). Therefore, this trial confirmed that the changeover from a conventional milking system to an automatic milking system had no negative influence on udder health. Full article

Clonal hematopoiesis (CH) is associated with an increased risk of developing myeloid neoplasms (MNs) such as myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). In general, CH comprises clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). It is an age-related phenomenon characterized by the presence of somatic mutations in hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) that acquire a fitness advantage under selection pressure. Individuals with CHIP have an absolute risk of 0.5–1.0% per year for progressing to MDS or AML. Inflammation, smoking, cytotoxic therapy, and radiation can promote the process of clonal expansion and leukemic transformation. Of note, exposure to chemotherapy or radiation for patients with solid tumors or lymphomas can increase the risk of therapy-related MN. Beyond hematological malignancies, CH also serves as an independent risk factor for heart disease, stroke, chronic obstructive pulmonary disease, and chronic kidney disease. Prognostic models such as the CH risk score and MN-prediction models can provide a framework for risk stratification and clinical management of CHIP/CCUS and identify high-risk individuals who may benefit from close surveillance. For CH or related disorders, therapeutic strategies targeting specific CH-associated mutations and specific selection pressure may have a potential role in the future. Full article

The reactivity of primiparous goats during milking can significantly affect animal welfare and performance. The aim of this study was to investigate the progression of milking reactivity during lactation and its effects at early lactation on milk yield, milk quality, and plasma cortisol concentration in primiparous Saanen goats. The milking reactivity of 31 primiparous Saanen goats was evaluated on days 10, 30, and 60 of the lactation period by scoring step-kick behavior (SK) and head, ear, and tail movements (MOV). Milk yield, milk protein and fat percentages, somatic cell count (SCC), and plasma cortisol concentration were measured on day 10 of lactation. Goats’ milking reactivity was classified as low or high (according to the SK and MOV scores measured on day 10 of lactation). SK and MOV scores decreased over the lactation period, indicating that the goats habituated to the milking procedures. Milking reactivity only affected milk fat percentage, with the less reactive goats having more milk fat than the highly reactive ones. There was no evidence of stress when goats were subjected to milking procedures during early lactation. Further studies are needed to clarify the relationships of milking reactivity with stress response and their effects on milk yield and quality. Full article

This study investigated the prevalence and severity of lameness in dairy cow herds, focusing on its relationship with milk traits, metabolic profile, and dry period management. Lameness was evaluated in 4221 multiparous Holstein dairy cows during early lactation (up to 60 days postpartum) using a 1-to-5 scale. The average lameness score was 1.67, with a prevalence of 10.66% (scores 3 to 5) and 4.55% classified as severe (scores 4 to 5). Severe lameness was associated with energy-corrected milk losses of −11.00 kg/day (p < 0.001) and a decrease in milk lactose concentration by −0.16 percentage points (p < 0.001), alongside a rise in somatic cell scores by +0.11. The incidence of cows with a milk fat-to-protein ratio below 1.2 increased by 21.7 percentage points, while those with a ratio above 1.4 rose by 19.1 percentage points as lameness worsened. Additionally, non-esterified fatty acid concentrations increased by 1.46 times as lameness severity intensified (p < 0.001). Cows without lameness had blood cortisol levels 1.86 times lower than affected cows, with cortisol tripling in those with the highest scores. A dry period of 30 to 60 days was correlated with more healthy cows, whereas periods over 90 days resulted in 1.586 times higher odds of lameness (p < 0.05). This research underscores the need for improved management strategies to enhance dairy cow welfare and productivity. Full article

Fatty acid is an important factor affecting the nutritional quality of milk. In this study, we collected and assessed 78,086 milk samples from 12,065 Chinese Holstein cows from 11 farms in Northern China from November 2019 to September 2022. The contents of eight fatty acid groups were predicted using FT-MIRS-based models. The contents of TFAs, SFAs, UFAs, MUFAs, PUFAs, and LCFAs in milk reached the highest at 96–125 DIM, and SCFA and MCFA contents reached the highest at 276–305 DIM. With the increase in somatic cell score, the contents of various fatty acid groups in milk gradually decreased, and the nutritional value of milk and flavor of dairy products gradually deteriorated. The contents of high-quality fatty acids in milk, particularly UFAs and MUFAs, were significantly higher in the non-pregnant state than in the pregnant state. However, SCFA and MCFA contents exhibited the opposite pattern. Our findings provided valuable information on the content and distribution range of fatty acid groups in milk from Chinese Holstein cows. Further analysis is warranted to explore the breeding of Chinese Holstein cows providing milk with abundant beneficial fatty acids. Full article