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ABSTRACT The impact of a concentrate-rich (CR) diet on the gut microbiome and epithelium homeostasis is well documented. However, it has not been systematically studied whether and how host-microbial interaction contributes to the immune homeostasis in the rumen and colon of lambs fed alfalfa hay and wheat straw, alone or combined, in a CR diet. In all, 63 lambs (initial body weight, 16.69 ± 1.50 kg) were randomly allotted to three dietary groups, each consisting of three pens with seven lambs per pen. Over 14 weeks, the lambs were fed diets as follows: 60% concentrate supplemented with either 40% wheat straw (WG), 20% alfalfa hay combined with 20% wheat straw (MG), or 40% alfalfa hay (AG). The present findings showed that lambs in the AG group had greater (P < 0.05) IgG and lower (P = 0.067) tumor necrosis factor-alpha concentrations relative to those in the MG and WG groups. The 16S rRNA analysis highlighted that various bacterial phyla and genera in the rumen and colon preferentially degrade fiber and starch derived from alfalfa hay and wheat straw. The weighted gene co-expression network analysis revealed that the bacterial genera from the Firmicutes are broadly associated with genes involved in various signaling pathways, underscoring the potential role of Firmicutes as key drivers of host-microbial interactions under the present feeding conditions. These findings shed light on the fact that the rumen and colon immune homeostasis is distinctively influenced by diets of alfalfa hay, wheat straw, or their combination in a CR diet. Further studies should examine the prolonged effects of replacing wheat straw with alfalfa hay in a concentrate-rich diet formulated to provide equivalent neutral detergent fiber levels. This could reveal how various forage fibers influence host-microbial interactions and gut health.IMPORTANCEIn contemporary feedlots, a growing trend is to feed animals a concentrate-rich (CR) diet that could disrupt the synchronized interplay between microbes and host metabolism, leading to altered metabolic functions. Wheat straw and alfalfa hay have different levels of protein and neutral detergent fiber, each with varying rates of digestion. It is unclear how including alfalfa hay and wheat straw, alone or combined in a CR diet, influences the host-microbial consortia and immune homeostasis. Herein, we showed that rumen and colon showed differential immune responses to the alfalfa hay, wheat straw, or both. Bacterial genera preferentially degrade fiber and starch derived from alfalfa hay, wheat straw, or both. Bacterial genera from Firmicutes phylum play a pivotal role in driving the host-microbial interactions, as indicated by their extensive association with genes across various signaling pathways.

Background Cell division cycle protein 45 (CDC45) has been demonstrated to play vital roles in the progression of various malignancies. However, the clinical significance of CDC45 in gastric cancer (GC) remains unreported. Method In this study, we employed the TCGA database and the TCGA & GTEx dataset to compare the mRNA expression levels of CDC45 between gastric cancer tissues and adjacent or normal tissues (p < 0.05 was considered statistically significant), which was further validated in multiple datasets including GSE13911, GSE29272, GSE118916, GSE66229, as well as RT-qPCR. Furthermore, we harnessed the Human Protein Atlas (HPA) to evaluate the protein expression of CDC45, which was subsequently verified through immunohistochemistry (IHC). To ascertain the diagnostic utility of CDC45, receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were calculated in TCGA database, and further validated it in TCGA & GTEx and GSE66229 datasets. The Kaplan–Meier method was used to reveal the prognostic importance of CDC45 in The Cancer Genome Atlas (TCGA) database and authenticated through the GSE66229, GSE84433, and GSE84437 datasets. Through cBioPortal, we identified co-expressed genes of CDC45, and pursued enrichment analysis. Additionally, we availed gene set enrichment analysis (GSEA) to annotate the biological functions of CDC45. Results Differential expression analysis revealed that CDC45 was significantly upregulated at both the mRNA and protein levels in GC (all p < 0.05). Remarkably, CDC45 emerged as a promising prognostic indicator and a novel diagnostic biomarker for GC. In a comprehensive the drug susceptibility analysis, we found that patients with high expression of CDC45 had high sensitivity to various chemotherapeutic agents, among which 5-fluorouracil, docetaxel, cisplatin, and elesclomol were most evident. Furthermore, our findings suggested a plausible association between CDC45 and immune cell infiltration. Enrichment analysis revealed that CDC45 and its associated genes may play crucial roles in muscle biofunction, whereas GSEA demonstrated significant enrichment of gene sets pertaining to G protein-coupled receptor ligand binding and G alpha (i) signaling events. Conclusion Our study elucidates that upregulation of CDC45 is intricately associated with immune cell infiltration and holds promising potential as a favorable prognostic marker and a novel diagnostic biomarker for GC.

Abstract Background The liver is a principal metabolic organ and has a major role in regulating lipid metabolism. With the development of rapidly fattening livestock in the modern breeding industry, the incidence of hepatic steatosis and accumulation in animals was significantly increased. However, the molecular mechanisms responsible for hepatic lipid metabolic disturbances in a high concentrate diet remain unclear. The objective of this study was to evaluate the effects of increasing concentrate level in a fattening lamb diet on biochemical indices, hepatic triglycerides (TG) concentration, and hepatic transcriptomic profiles. In the present study, 42 weaned lambs (about 3 ± 0.3 months old) were randomly assigned to the GN60 group (60% concentrate of dry matter, GN60, n = 21) or GN70 group (70% concentrate of dry matter, n = 21) for a 3-months feeding trial. Results No difference was observed in the growth performance or plasma biochemical parameters between the GN60 group and the GN70 group. The hepatic TG concentration was higher in the GN70 group than GN60 group (P

Abstract Background Methionine or lysine has been reported to influence DNA methylation and fat metabolism, but their combined effects in N6-methyl-adenosine (m6A) RNA methylation remain unclarified. The combined effects of rumen-protected methionine and lysine (RML) in a low-protein (LP) diet on lipid metabolism, m6A RNA methylation, and fatty acid (FA) profiles in the liver and muscle of lambs were investigated. Sixty-three male lambs were divided into three treatment groups, three pens per group and seven lambs per pen. The lambs were fed a 14.5% crude protein (CP) diet (adequate protein [NP]), 12.5% CP diet (LP), and a LP diet plus RML (LP + RML) for 60 d. Results The results showed that the addition of RML in a LP diet tended to lower the concentrations of plasma leptin (P = 0.07), triglyceride (P = 0.05), and non-esterified FA (P = 0.08). Feeding a LP diet increased the enzyme activity or mRNA expression of lipogenic enzymes and decreased lipolytic enzymes compared with the NP diet. This effect was reversed by supplementation of RML with a LP diet. The inclusion of RML in a LP diet affected the polyunsaturated fatty acids (PUFA), n-3 PUFA, and n-6 PUFA in the liver but not in the muscle, which might be linked with altered expression of FA desaturase-1 (FADS1) and acetyl-CoA carboxylase (ACC). A LP diet supplemented with RML increased (P

Abstract Scarce high-quality protein feed resources has limited the development of animal husbandry. In this study, we used a dual-flow continuous culture system to evaluate effects of difference dietary protein sources including soybean meal (SBM), cottonseed meal (CSM), and rapeseed meal (RSM), on nutrient disappearance, rumen fermentation, and microbiota of XiongDong black goats. Dietary proteins of either CSM, RSM or SBM had no effect on nutrient disappearance (P > 0.05). CSM or RSM significantly reduced (P 0.10). Although the bacterial community changed with different dietary protein sources, the disappearances of nutrients were not affected, suggesting that CSM and RSM could be used by rumen bacteria, as in case with SBM, and are suitable protein sources for ruminant diets.

This study aimed to assess the impact of the dietary supplementation of N-carbamoylglutamate (NCG) on nutrient digestibility, rumen fermentation, milk quality, oxidative stress, and metabolites in the plasma and feces of Jersey cattle under high altitude with the hypoxic condition. A total of 14 healthy lactating Jersey dairy cows with similar body conditions were selected and randomly divided into 2 groups. The control group (CON group, N = 6 replicates) was fed with a conventional complete diet, whereas the experimental group (NCG group, N = 8 replicates) received 20 g/d per head NCG supplementation. The experiment lasted for 60 days, the adaptation period was 12 days, and the formal experiment period was 48 days. Except that the NCG group showed an upward trend in dry matter intake (DMI) (p = 0.09) and the fermentation parameters, the molar proportion of butyric acid tended to decrease (p = 0.08); the two groups had no significant differences (p > 0.05) in nutrients digestibility, plasma immunity, and antioxidant ability. However, compared with the CON group, the milk fat rate and blood oxygen saturation of the NCG group showed an upward trend (p = 0.09). For indexes associated with altitude stress, the contents of thyroxine, transferrin, and endothelin both decreased significantly (p < 0.05) in the NCG group. Meanwhile, heat shock protein (p = 0.07) and aldosterone (p = 0.06) also showed a downward trend. A total of 114 different metabolites were identified from feces and plasma, 42 metabolites were derived from plasma that mainly included 5 kinds of Super Class, and 72 metabolites were derived from feces that mainly included 9 kinds of Super Class. The significantly increased plasma differential metabolites were 2,5-dihydroxybenzoate and salicyluric acid, and the significantly increased fecal differential metabolites were Butenafine (fold change > 2). Pathway analysis showed that after applying NCG as a feed additive, the changes of the Jersey dairy cows mainly focused on amino acid metabolism and lipid metabolism. These results indicated that adding NCG to the diet can prevent the hypoxic stress state of lactating Jersey cows in high-altitude areas and has a tendency to improve milk quality.

The objective of this study was to investigate the effects of low-protein diets on blood calcium (Ca) level, bone metabolism, and the correlation between bone metabolism and blood calcium in goats. Twenty-four female Xiangdong black goats with similar body weight (19.55 ± 3.55 kg) and age (8.0 ± 0.3 months) were selected and allocated into two groups: control group (CON, 10.77% protein content) and low-protein group (LP, 5.52% protein content). Blood samples were collected on days 1, 4, 7, 16 and 36 before morning feeding to determine the concentration of calcium (Ca), parathyroid hormone (PTH), bone gla protein (BGP), C-terminal telopeptide of type 1 collagen (CTX-1), bone alkaline phosphatase (BALP), and 1, 25-dihydroxyvitamin D3 [1,25(OH)2D3]. Liver samples were collected to determine the expression of bone metabolism-related genes. There was no difference observed between LP and CON in concentration of plasma Ca or any of bone metabolism markers (P > 0.05). In the liver, the mRNA expression of bone gamma carboxyglutamate protein (BGLAP), alkaline phosphatase (ALPL), and mothers against decapentaplegic homolog-1 (SMAD1) were increased (P < 0.05) in LP as compared with CON. The correlation analysis of Ca and bone metabolism markers showed no significant correlation between Ca and bone metabolism. These results suggest that the blood Ca concentration in mature goats may keep at a stable level through nitrogen cycling when the providing protein is not enough.

Background/Aims: Intestinal mucositis (IM) is a commonly encountered side effect in cancer patients receiving chemotherapy. This study aimed to investigate the effect of Bifidobacterium infantis (B. infantis) in attenuating the severity of chemotherapy-induced intestinal mucositis by regulating the T cell subsets in rats with colorectal cancer (CRC). Methods: Thirty male Sprague-Dawley (SD) rats were injected dimethyl hydrazine (DMH) subcutaneously for 10 weeks, and then injected SW480 cells in rectal mucosa to create a CRC model, and the rats were randomly divided into three groups: Control group (saline + saline), Chemotherapy group (saline + 5-FU+Oxaliplatin), B. infantis group (B. infantis + 5-FU+Oxaliplatin). IM was evaluated based on diarrhea severity, intestinal villus height, crypt depth, pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), T cell subsets (CD4+ IL17A+ cells and CD4+ CD25+ Foxp3+ Tregs) and related cytokine profiles. Results: The results showed that the B. infantis group demonstrated a higher body weight (BW) and intestinal villus height and a deeper crypt depth compared to the Chemotherapy group. The level of IL-6, IL-1β and TNF-α which increased by chemotherapy, was lowered by B. infantis administration. Real time reverse transcription- polymerase chain reaction (RT-PCR) showed B. infantis reduced relative expression of Th17 and Th1 cells related cytokines, and increased relative expression of CD4+ CD25+ Foxp3+ Tregs related cytokines. Furthermore, Flow cytometry analysis showed B. infantis reduced CD4+ IL17A+ cells and increased CD4+ CD25+ Foxp3+ Tregs in mesenteric lymph nodes (MLNs) compared to the Chemotherapy group. Conclusion: B. infantis effectively attenuates chemotherapy-induced intestinal mucositis by decreasing Th1 and Th17 response and increasing CD4+ CD25+ Foxp3+ Tregs response.

Abstract Background Elevated mammographic density (MD) for a woman’s age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD). Methods ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35–85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest. Results Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (β: − 0.05, 95% confidence interval (CI): − 0.07, − 0.03) and √DA (β: − 0.08, 95% CI: − 0.12, − 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (β:0.06, 95% CI:0.03, 0.10) and √DA (β:0.06, 95% CI:0.02, 0.10), and lower √NDA (β: − 0.06, 95% CI: − 0.11, − 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD. Conclusions Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk.

Abstract In this pilot study, we investigated the utility of handheld ultrasound-guided photoacoustic (US-PA) imaging probe for analyzing ex-vivo breast specimens obtained from female patients who underwent breast-conserving surgery (BCS). We aimed to assess the potential of US-PA in detecting biochemical markers such as collagen, lipids, and hemoglobin, and compare these findings with routine imaging modalities (mammography, ultrasound) and histopathology results, particularly across various breast densities. Twelve ex-vivo breast specimens were obtained from female patients with a mean age of 59.7 ± 9.5 years who underwent BCS. The tissues were illuminated using handheld US-PA probe between 700 and 1100 nm across all margins and analyzed for collagen, lipids, and hemoglobin distribution. The obtained results were compared with routine imaging and histopathological assessments. Our findings revealed that lipid intensity and distribution decreased with increasing breast density, while collagen exhibited an opposite trend. These observations were consistent with routine imaging and histopathological analyses. Moreover, collagen intensity significantly differed (P

Abstract Occupational crystalline silica (CS) particle exposure leads to silicosis. The burden of CS-associated disease remains high, and treatment options are limited due to vague mechanisms. Here we show that pulmonary CD4+ tissue-resident memory T cells (TRM) accumulate in response to CS particles, mediating the pathogenesis of silicosis. The TRM cells are derived from peripheral lymphocyte recruitment and in situ expansion. Specifically, CD69+CD103+ TRM-Tregs depend more on circulating T cell replenishment. CD69 and CD103 can divide the TRM cells into functionally distinct subsets, mirroring the immuno-balance within CD4+ TRM cells. However, targeting CD103+ TRM-Tregs do not mitigate disease phenotype since the TRM subsets exert immunosuppressive but not pro-fibrotic roles. After identifying pathogenic CD69+CD103- subsets, we highlight IL-7 for their maintenance and function, that present a promising avenue for mitigating silicosis. Together, our findings highlight the distinct role of CD4+ TRM cells in mediating CS-induced fibrosis and provide potential therapeutic strategies.

Abstract Objectives Pulmonary neuroendocrine neoplasms (NENs) are the most frequent cause of ectopic adrenocorticotropic hormone syndrome (EAS); lung infection is common in EAS. An imaging finding of infection in EAS patients can mimic NENs. This retrospective study investigated EAS-associated pulmonary imaging indicators. Methods Forty-five pulmonary NENs and 27 tumor-like infections from 59 EAS patients (45 NEN and 14 infection patients) were included. Clinical manifestations, CT features, 18F-FDG, or 68Ga-DOTATATE-PET/CT images and pathological results were collected. Results High-sensitivity C-reactive protein (p

Abstract Mucus stasis is a pathologic hallmark of muco-obstructive diseases, including cystic fibrosis (CF). Mucins, the principal component of mucus, are extensively modified with hydroxyl (O)-linked glycans, which are largely terminated by sialic acid. Sialic acid is a negatively charged monosaccharide and contributes to the biochemical/biophysical properties of mucins. Reports suggest that mucin sialylation may be altered in CF; however, the consequences of reduced sialylation on mucus clearance have not been fully determined. Here, we investigated the consequences of reduced sialylation on the charge state and conformation of the most prominent airway mucin, MUC5B, and defined the functional consequences of reduced sialylation on mucociliary transport (MCT). Reduced sialylation contributed to a lower charged MUC5B form and decreased polymer expansion. The inhibition of total mucin sialylation de novo impaired MCT in primary human bronchial epithelial cells and rat airways, and specific α-2,3 sialylation blockade was sufficient to recapitulate these findings. Finally, we show that ST3 beta-galactoside alpha-2,3-sialyltransferase (ST3Gal1) expression is downregulated in CF and partially restored by correcting CFTR via Elexacaftor/Tezacaftor/Ivacaftor treatment. Overall, this study demonstrates the importance of mucin sialylation in mucus clearance and identifies decreased sialylation by ST3Gal1 as a possible therapeutic target in CF and potentially other muco-obstructive diseases.

IntroductionDespite using beta oscillations within the subthalamic nucleus as a biomarker of akinesia or rigidity in Parkinson’s disease, a specific biomarker for freezing of gait (FOG) remains unclear. Recently, scalp phase-amplitude coupling (PAC) measured through scalp electroencephalography (EEG) has emerged as a promising tool for analyzing brain function. In this study, we examined whether PAC could be a biomarker for FOG.MethodsWe enrolled 11 patients with Parkinson’s disease and recorded scalp EEG in preparation for and during gait while simultaneously assessing motor function, including FOG. We investigated changes in cortical PAC during walking with and without FOG and examined its correlation with the postural instability and gait difficulty (PIGD) score.ResultsPatient characteristics were as follows: mean age 59.1 ± 6.9 years, disease duration 13.9 ± 4.1 years, and seven men. Four trials were excluded from the analysis owing to artifacts. In the trials without FOG (n = 18), beta-gamma PAC in the sensorimotor area decreased during gait preparation (p = 0.011; linear mixed-effects model), which was not the case in trials with FOG (n = 6) (p = 0.64; linear mixed-effects model). Using a support vector machine, machine learning of PAC during preparation for walking predicted the presence of FOG with an accuracy of 71.2%. Conversely, PAC increased during walking in trials with FOG (p = 0.0042; linear mixed-effects model), and PAC 20 s after the start of walking was positively correlated with the PIGD score (correlation coefficient = 0.406, p = 0.032; Pearson’s rank correlation).ConclusionBeta-gamma PAC in the sensorimotor area during preparation for walking differs depending on the emergence of FOG. As gait symptoms worsened, beta-gamma PAC in the sensorimotor area during walking gradually increased. Cortical PAC may be a biomarker for FOG in Parkinson’s disease and may lead to the development of strategies to prevent falls in the future.

Circulating triglyceride (TG) and leukocytes, the main components of the vascular system, may impact each other and co-fuel atherosclerosis. While the causal relationship between plasma TG levels and leukocyte counts remains unclear. Bidirectional Mendelian randomization (MR) analysis was conducted to investigate the potential causal relationship between TG levels and the counts of leukocytes and their subtypes. A cross-lagged panel model (CLPM) using longitudinal healthy screening data (13,389 adults with a follow-up of 4 years) was fitted to examine the temporal relationship between them. Genetically predicted plasma TG levels were positively associated with total leukocyte counts (TLC) [β(se) = 0.195(0.01)], lymphocyte counts (LC) [β(se) = 0.196(0.019)], and neutrophil counts (NC) [β(se) = 0.086(0.01)], which remained significant after adjusting for several confounders. Inversely, the genetically predicted TLC [β(se) = 0.033(0.008)], LC [β(se) = 0.053(0.008)], and NC [β(se) = 0.034(0.008)] were positively associated with plasma TG levels. However, when all three of them were put into the MR model adjusted for each other, only LC was significantly associated with TG levels. There was no association between genetically predicted TG levels and monocyte counts (MC), basophil counts, and eosinophil counts. The results of CLPM showed that the temporal effect of elevated TLC, MC, LC, and NC on plasma TG levels was stronger than the inverse effect. Our findings suggest causal associations of plasma TG levels with TLC, LC, and NC. In turn, LC was positively associated with plasma TG levels. Additionally, elevated circulating LC may precede high plasma TG levels.