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MicroRNAs are involved in the pathogenesis of various human malignant tumors. This study aims to explore the role of miR-513b-5p in the malignant proliferation of retinoblastoma (RB) cells and its potential molecular mechanisms. The function-gain and function-loss experiments were performed in Weri-RB1 cells using miR-513b-5 mimics and inhibitors. miR-513b-5p mimics inhibited the proliferation and clone formation and promoted apoptosis of Weri-RB1 cells. In contrast, the miR-513b-5p inhibitor promoted the proliferation and clone formation of Weri-RB1 cells and inhibited cell apoptosis. miR-513b-5p can directly bind to the 3′UTR region of TRIB1 mRNA, and inhibit its protein expression. Overexpression of TRIB1 promoted the proliferation and cloning of Weri-RB1 cells but inhibited their apoptosis. The knockdown of TRIB1 inhibited the proliferation and clone formation of Weri-RB1 cells and promoted cell apoptosis. In addition, miR-513b-5p mimics neutralized the effects of TRIB1 overexpression on the proliferation and apoptosis of Weri-RB1 cells. Finally, miR-513b-5p can inhibit the phosphorylation level of AKT, mTOR, and p70, while TRIB1 played the opposite role. miR-513b-5p inhibits the malignant proliferation of Weri-RB1 cells by repressing the expression of TRIB1. miR-513b-5p and TRIB1 may be the biomarkers and/or key targets for clinical diagnosis and treatment of RB.

Population pharmacokinetic (PopPK) models of posaconazole have been established to promote the precision dosing. However, the performance of these models extrapolated to other centers has not been evaluated. This study aimed to conduct an external evaluation of published posaconazole PopPK models to evaluate their predictive performance. Posaconazole PopPK models screened from the PubMed and MEDLINE databases were evaluated using an external dataset of 213 trough concentration samples collected from 97 patients. Their predictive performance was evaluated by prediction-based diagnosis (prediction error), simulation-based diagnosis (visual predictive check), and Bayesian forecasting. In addition, external cohorts with and without proton pump inhibitor were used to evaluate the models respectively. Ten models suitable for the external dataset were finally included into the study. In prediction-based diagnostics, none of the models met pre-determined criteria for predictive indexes. Only M4, M6, and M10 demonstrated favorable simulations in visual predictive check. The prediction performance of M5, M7, M8, and M9 evaluated using the cohort without proton pump inhibitor showed a significant improvement compared to that evaluated using the whole cohort. Consistent with our expectations, Bayesian forecasting significantly improved the predictive per-formance of the models with two or three prior observations. In general, the applicability of these published posaconazole PopPK models extrapolated to our center was unsatisfactory. Prospective studies combined with therapeutic drug monitoring are needed to establish a PopPK model for posaconazole in the Chinese population to promote individualized dosing.

Aims: To explore the population pharmacokinetics of colistin sulfate and to optimize the dosing strategy for critically ill patients.Methods: The study enrolled critically ill adult patients who received colistin sulfate intravenously for more than 72 h with at least one measurement of plasma concentration. Colistin concentrations in plasma or urine samples were measured by ultraperformance liquid chromatography tandem mass spectrometry (LC-MS/MS). The population pharmacokinetics (PPK) model for colistin sulfate was developed using the Phoenix NLME program. Monte Carlo simulation was conducted to evaluate the probability of target attainment (PTA) for optimizing dosing regimens.Results: A total of 98 plasma concentrations from 20 patients were recorded for PPK modeling. The data were adequately described by a two-compartment model with linear elimination. During modeling, creatinine clearance (CrCL) and alanine aminotransferase (ALT) were identified as covariates of the clearance (CL) and volume of peripheral compartment distribution (V2), respectively. In addition, colistin sulfate was predominantly cleared by the nonrenal pathway with a median urinary recovery of 10.05% with large inter-individual variability. Monte Carlo simulations revealed a greater creatinine clearance associated with a higher risk of sub-therapeutic exposure to colistin sulfate. The target PTA (≥90%) of dosage regimens recommended by the label sheet was achievable only in patients infected by pathogens with MIC ≤0.5 mg/L or with renal impairments.Conclusion: Our study showed that the dose of intravenous colistin sulfate was best adjusted by CrCL and ALT. Importantly, the recommended dosing regimen of 1.0–1.5 million units daily was insufficient for patients with normal renal functions (CrCL ≥80 ml/min) or those infected by pathogens with MIC ≥1.0 mg/L. The dosage of colistin sulfate should be adjusted according to renal function and drug exposure.

Background: Dexmedetomidine is a commonly used clinical sedative; however, the drug response varies among individuals. Thus, the purpose of this study was to explore the association between dexmedetomidine response and gene polymorphisms related to drug-metabolizing enzymes and drug response (CYP2A6, UGT2B10, UGT1A4, ADRA2A, ADRA2B, ADRA2C, GABRA1, GABRB2, and GLRA1).Methods: This study was a prospective cohort study. A total of 194 female patients aged 18–60 years, American Society of Anesthesiologists (ASA) score I-II, who underwent laparoscopy at the Third Xiangya Hospital of Central South University, were included. The sedative effect was assessed every 2 min using the Ramsay score, and the patient’s heart rate decrease within 20 min was recorded. Peripheral blood was collected from each participant to identify genetic variants in the candidate genes of metabolic and drug effects using the Sequenom MassARRAY® platform. Furthermore, additional peripheral blood samples were collected from the first 99 participants at multiple time points after dexmedetomidine infusion to perform dexmedetomidine pharmacokinetic analysis by Phoenix® WinNonlin 7.0 software.Results: Carriers of the minor allele (C) of CYP2A6 rs28399433 had lower metabolic enzyme efficiency and higher plasma concentrations of dexmedetomidine. In addition, the participants were divided into dexmedetomidine sensitive or dexmedetomidine tolerant groups based on whether they had a Ramsay score of at least four within 20 min, and CYP2A6 rs28399433 was identified to have a significant influence on the dexmedetomidine sedation sensitivity by logistic regression with Plink software [p = 0.003, OR (95% CI): 0.27 (0.11–0.65)]. C allele carriers were more sensitive to the sedative effects of dexmedetomidine than A allele carriers. GABRA2 rs279847 polymorphism was significantly associated with the degree of the heart rate decrease. In particular, individuals with the GG genotype had a 4-fold higher risk of heart rate abnormality than carriers of the T allele (OR = 4.32, 95% CI: 1.96–9.50, p = 0.00027).Conclusion:CYP2A6 rs28399433 polymorphism affects the metabolic rate of dexmedetomidine and is associated with susceptibility to the sedative effects of dexmedetomidine; GABRA2 rs279847 polymorphism is significantly associated with the degree of the heart rate decrease.

BackgroundWarfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index, and dosage can differ tremendously among individuals. The study aimed to develop an individualized international normalized ratio (INR) model based on time series anticoagulant data and simulate individualized warfarin dosing.MethodsWe used a long short-term memory (LSTM) network to develop an individualized INR model based on data from 4,578 follow-up visits, including clinical and genetic factors from 624 patients whom we enrolled in our previous randomized controlled trial. The data of 158 patients who underwent valvular surgery and were included in a prospective registry study were used for external validation in the real world.ResultsThe prediction accuracy of LSTM_INR was 70.0%, which was much higher than that of MAPB_INR (maximum posterior Bayesian, 53.9%). Temporal variables were significant for LSTM_INR performance (51.7 vs. 70.0%, P < 0.05). Genetic factors played an important role in predicting INR at the onset of therapy, while after 15 days of treatment, we found that it might unnecessary to detect genotypes for warfarin dosing. Using LSTM_INR, we successfully simulated individualized warfarin dosing and developed an application (AI-WAR) for individualized warfarin therapy.ConclusionThe results indicate that temporal variables are necessary to be considered in warfarin therapy, except for clinical factors and genetic factors. LSTM network may have great potential for long-term drug individualized therapy.Trial RegistrationNCT02211326; www.chictr.org.cn:ChiCTR2100052089.

Routine clinical meropenem therapeutic drug monitoring data can be applied to model-informed precision dosing. The current study aimed to evaluate the adequacy and predictive capabilities of the published models with routine meropenem data and identify the dosing adaptations using a priori and Bayesian estimation. For this, 14 meropenem models for the external evaluation carried out on an independent cohort of 134 patients with 205 meropenem concentrations were encoded in NONMEM 7.3. The performance was determined using: 1) prediction-based and simulation-based diagnostics; and 2) predicted meropenem concentrations by a priori prediction using patient covariates only; and Bayesian forecasting using previous observations. The clinical implications were assessed according to the required dose adaptations using the meropenem concentrations. All assessments were stratified based on the patients with or without continuous renal replacement therapy. Although none of the models passed all tests, the model by Muro et al. showed the least bias. Bayesian forecasting could improve the predictability over an a priori approach, with a relative bias of −11.63–68.89% and −302.96%–130.37%, and a relative root mean squared error of 34.99–110.11% and 14.78–241.81%, respectively. A dosing change was required in 40.00–68.97% of the meropenem observation results after Bayesian forecasting. In summary, the published models couldn’t adequately describe the meropenem pharmacokinetics of our center. Although the selection of an initial meropenem dose with a priori prediction is challenging, the further model-based analysis combining therapeutic drug monitoring could be utilized in the clinical practice of meropenem therapy.

Background: The present study evaluated the safety, pharmacokinetics/pharmacodynamics (PK/PD), and absolute bioavailability (Fabs) of Dex nasal spray in healthy adult subjects, which serves as a bridge for the subsequent study in children.Methods: Part 1: a double-blind, placebo-controlled, single ascending dose study was performed on 48 subjects. For 20-/40-μg groups, every 6/2 subjects received either Dex/placebo nasal spray or Dex/placebo injection in two periods. In total, 12/4 subjects each received 100 μg Dex/placebo nasal spray. Part 2: a randomized, double-blind, placebo-controlled study; 12/4 subjects received 150 μg Dex/placebo nasal spray. Part 3: a randomized, open, self-crossover study; 12 subjects received 20 μg and 100 μg Dex nasal spray in two periods alternately. The method of administration was optimized in Part 2 and Part 3.Results: In part 1, Dex nasal spray was well tolerated up to the maximum dose of 100 μg, whereas the Fabs was tolerated to only 28.9%–32.3%. In Part 2 and Part 3, the optimized nasal spray method was adopted to promote the Fabs of Dex nasal spray to 74.1%–89.0%. A severe adverse event was found in Part 2. In Part 3 (100 μg), the Ramsay score increased the most and lasted the longest, whereas the BIS score decreased most significantly.Conclusion: Using the optimized nasal spray method, a single dose of 20/100 μg of the test drug was safe and tolerable, and 100 μg may have approached or reached the plateau of sedation. In addition, it is found that the optimized method can greatly improve the bioavailability of the test drug, leading to its higher reference value.

Background: Ticagrelor belongs to a new class of P2Y12 receptor inhibitor that has been widely used for antiplatelet therapy. This study aimed to explore the effect of single nucleotide polymorphisms (SNPs) in metabolic enzymes, transporters, and other relevant variants on the pharmacokinetics (PK) of ticagrelor and its active metabolite, AR-C124910XX.Methods: The study population comprised 68 healthy Chinese volunteers who were enrolled in a ticagrelor bioequivalence clinical trial. The PK profile of ticagrelor was evaluated after orally administering a single 90-mg dose of ticagrelor in tablet form. The plasma concentrations of ticagrelor and AR-C124910XX were determined through liquid chromatography–tandem mass spectrometry. Plasma DNA samples were used to explore the effect of gene polymorphisms on the PK of ticagrelor and AR-C124910XX with whole-exome sequencing.Results: Female participants had a higher maximum plasma concentration/weight ratio (Cmax/W; p

Based on fracture mechanics theory, a finite element method was used to determine the stress intensity factors of the inclined crack on the inner surface of the pipe under axial compression load and external pressure. The effects of different influencing factors on the stress intensity factor along the crack front considering crack closure were systematically explored, which were different to those under internal pressure. The effects of high aspect ratio on KII, the crack inclination asymmetry caused by curvature and the effects of the friction coefficient on the stress intensity factors of the pipe with an inclined inner surface crack under axial compression load and external pressure were explored in this paper. To be fit for defect assessment, the solutions for stress intensity factors KII and KIII were derived, and new correction factors fθ and fμ were proposed in the empirical solutions to accommodate the crack inclination asymmetry and the friction coefficient, respectively.

Omeprazole is commonly prescribed to obese patients and patients after laparoscopic sleeve gastrectomy (LSG). The pharmacokinetics of oral omeprazole after LSG are still unknown. Therefore, the aim of this study was to investigate the pharmacokinetics of oral omeprazole in obese patients before and after LSG. A total of 331 blood samples were collected from 62 obese patients preoperatively (visit 1) followed by 41 patients 7 days post-LSG (visit 2) and 20 patients 1 month post-LSG (visit 3). Population pharmacokinetic analysis was performed using NONMEM to characterize the effect of LSG on omeprazole absorption and disposition. A one-compartment model with 12 transit absorption compartments and linear elimination successfully described the data. Compared with pre-surgery, the oral omeprazole time to maximum plasma concentration (Tmax) was reduced and maximum plasma concentration (Cmax) was higher, but the apparent clearance (CL/F) and area under the plasma concentration–time curve (AUC) were unchanged 7 days and 1 month after surgery. In addition, the CYP2C19 genotype and liver function exhibited a significant influence on omeprazole CL/F. LSG increased the rate of omeprazole absorption but did not affect omeprazole exposure. A dose of 20 mg omeprazole once daily may be adequate for relieving gastrointestinal tract discomfort at short-term follow-up post-LSG.

The introduction of basic groups in the polybenzimidazole (PBI) main chain or side chain with low phosphoric acid doping is an effective way to avoid the trade-off between proton conductivity and mechanical strength for high temperature proton exchange membrane (HT-PEM). In this study, the ethyl imidazole is grafted on the side chain of the PBI containing bipyridine in the main chain and blended with poly(2,2′-[p-oxydiphenylene]-5,5′-benzimidazole) (OPBI) to obtain a series of PBI composite membranes for HT-PEMs. The effects of the introduction of bipyridine in the main chain and the ethyl imidazole in the side chain on proton transport are investigated. The result suggests that the introduction of the imidazole and bipyridine group can effectively improve the comprehensive properties as HT-PEM. The highest of proton conductivity of the obtained membranes under saturated phosphoric acid (PA) doping can be up to 0.105 S cm−1 at 160 °C and the maximum output power density is 836 mW cm−2 at 160 °C, which is 2.3 times that of the OPBI membrane. Importantly, even at low acid doping content (~178%), the tensile strength of the membrane is 22.2 MPa, which is nearly 2 times that of the OPBI membrane, the proton conductivity of the membrane achieves 0.054 S cm−1 at 160 °C, which is 2.3 times that of the OPBI membrane, and the maximum output power density of a single cell is 540 mW cm−2 at 160 °C, which is 1.5 times that of the OPBI membrane. The results suggest that the introduction of a large number of nitrogen-containing sites in the main chain and side chain is an efficient way to improve the proton conductivity, even at a low PA doping level.

The three-dimensional (3D) printing of a SiO2-filled thermosetting polyimide (SiO2@TSPI) composite with outstanding performance is realized via the direct ink writing (DIW) of polyamide acid (PAA) composite ink and thermal treatment conducted thereafter. The composite ink consists of phenylethynyl-terminated PAA and silica nanoparticles, where the SiO2 nanoparticles serve as the rheology modifier that is necessary for the DIW technique to obtain self-supporting feedstock during 3D printing and the reinforcement filler that is used to enhance the performance of the final composite. As a result, printed parts with complex geometry and robust thermal stability are obtained. Due to the extrusion-based DIW technique, the printed structures exhibit anisotropic mechanical strength that highly depends on printing roads. This simple and convenient means of realizing 3D structures of thermosetting polyimides is a promising strategy in aerospace and other fields.

The inflammatory response and oxidative stress play key roles in the formation and development of atherosclerosis. Bazedoxifene is a new IL6/GP130 inhibitor recommended by the FDA for clinical use as a selective estrogen receptor modulator. However, its role in cardiovascular diseases has been poorly studied. In our study, we explored the mechanism of bazedoxifene’s protective effect against inflammatory injury of vascular endothelial cells (VECs) stimulated by TNF-α. Various methods were used to verify the effect of bazedoxifene on VECs, including a cell viability assay, a wound healing assay, immunofluorescence staining, and western blotting. Our results showed that TNF-α could induce inflammatory damage to VECs, which manifested as upregulated expression of CD40, increased production of ROS, enhanced adhesion of THP-1 cells to VECs, and impaired viability and migration of VECs, while bazedoxifene could significantly reduce the endothelial damage caused by TNF-α. In addition, we found that an siRNA targeting CD40 dramatically alleviated the VEC damage induced by TNF-α. Therefore, we explored the potential relationship between bazedoxifene and CD40. Our data suggest that bazedoxifene has a protective effect against VEC damage induced by TNF-α and that its underlying mechanism may be related to the regulation of CD40.

Background and Objective: Inhibition of thrombosis and platelet aggregation through a thromboxane synthetase inhibitor proved to be an effective and promising treatment for cardiovascular and/or cerebrovascular disease (CCVD) patients. This phase I study evaluated the safety, tolerability, and pharmacokinetics of sodium pyragrel, a novel thromboxane A2 synthetase inhibitor, in healthy volunteers.Methods: A total of 84 healthy Chinese volunteers were enrolled in the study and randomized into one of five dosing regimens of intravenous pyragrel, which were single ascending dose (30 to 300 mg), multiple doses (pyragrel 180 mg once daily on Day 1 and Day 6, twice daily from Day 2 to Day 5), 3×3 Latin square crossover (60, 120, 240 mg), and a continuous dose (360 mg in 24 h), respectively. Plasma concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis.Results: The maximum plasma concentrations of pyragrel were essentially reached at the end of the 3 h infusion. The pharmacokinetic process of pyragrel and two main metabolites (BBS and BJS) is linear over the 30–300 mg dose range, with no significant accumulation on multiple doses. The urinary excretion of pyragrel accounted for more than 70% of the total drug amount. Preliminary pharmacodynamic results demonstrated that the production of urinary 11-D-HTXB2 was time- and dose-dependently inhibited by single i.v. dose of pyragrel.Conclusions: Pyragrel was well tolerated after single ascending doses up to 300 mg, multiple doses of 180 mg, and continuous administration of 360 mg within 24 h. No drug-related, serious adverse drug reactions occurred during the five-part study. The most common pyragrel-related adverse events (AEs) were total bilirubin (TB)/direct bilirubin (DB) elevations with a relatively low incidence rate and seemed to be dose independent. Given the acceptable safety and appropriate pharmacokinetic properties of sodium pyragrel proven in this study, continued clinical development is warranted. The study was registered at http://www.chictr.org.cn (ChiCTR-IID-16010159).

OBJECTIVES: We aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy. METHODS: A single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples. RESULTS: The intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for Cmax and AUC0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%). CONCLUSIONS: Agomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies. TRIAL REGISTRATION: ChiCTR.org ChiCTR-TTRCC-13003835.

Background: Increasing evidence indicates a close relationship between alterations in human immune cells and plasma metabolites with Rheumatoid Arthritis (RA). However, limited studies have left the causal relationships behind these links unclear. Methods: A bidirectional Mendelian Randomization (MR) study was conducted, combined with mediation analysis, using data from genome-wide association study database covering 731 immune cell phenotypes and 1,400 plasma metabolite traits to explore their causal relationships with RA and potential mediating effects. The primary method used for MR analysis was inverse-variance weighted and False Discovery Rate (FDR) correction was applied to verify the robustness of our results. Results: HLA DR on CD33- HLA DR+ (myeloid cell group) (OR, 1.422; 95% CI, 1.194-1.694; P < 0.001; PFDR = 0.012) increased the risk of developing RA. CD19 on IgD+ CD38- naive (B cell group) (OR, 0.969; 95% CI, 0.954-0.985; P < 0.001; PFDR = 0.021) reduced the risk of developing RA. RA was a risk factor for HLA DR on CD14- CD16+ monocytes (monocyte group) (OR, 1.242; 95% CI, 1.102-1.401; P < 0.001; PFDR = 0.047). RA was a protective factor for memory B cell % lymphocyte (B cell group) (OR, 0.861; 95% CI, 0.795-0.933; P < 0.001; PFDR = 0.050), CD4+ CD8dim T cell %lymphocyte (TBNK group) (OR, 0.802; 95% CI, 0.711-0.904; P < 0.001; PFDR = 0.043), CD4+ CD8dim T cell %leukocyte (TBNK group) (OR, 0.814; 95% CI, 0.726-0.913; P < 0.001; PFDR = 0.046), CD24 on IgD+ CD24+ B cells (B cell group) (OR, 0.857; 95% CI, 0.793-0.927; P < 0.001; PFDR = 0.038), and CD24 on unswitched memory B cells (B cell group) (OR, 0.867; 95% CI, 0.797-0.942; P < 0.001; PFDR = 0.050). Increasing levels of docosatrienoate (22:3n3) (OR, 0.886; 95% CI, 0.838-0.936; P < 0.001; PFDR = 0.023) significantly reduced the risk of developing RA. The mediating effect of plasma metabolites in this context was not established. Conclusion: This study provides genetic evidence for the intricate relationships between immune cells, plasma metabolites, and RA, highlighting the potential mechanisms involved. This will contribute to future directions in precision medicine and research. [ABSTRACT FROM AUTHOR]

Simple Summary: In China, high-grain diets for ruminants due to forage scarcity cause metabolic disorders. Yeast culture promotes rumen health by stabilizing microbial composition and enhancing nutrition and immunity. Therefore, the objective of this experiment was mainly to investigate the effect of the addition of two different species of yeast culture on goat production performance, rumen fermentation profile, microbial balance, and immunity under high-grain conditions. The results indicated that the incorporation of yeast culture into a high-grain diet significantly enhanced the production performance of goats, augmented their immunity, and stabilized the rumen environment. However, different types of yeast cultures acted by different mechanisms. The results provide a reference for the rational application of yeast culture in production. It is a common practice among farmers to utilize high-grain diets with the intention of promoting ruminant growth. However, this approach bears the risk of inducing rumen disorders and nutrient metabolism diseases. Yeast culture (YC) showed advantages in ruminant applications. The objective of this study was to evaluate the effects of adding two different types of YC to high-grain conditions on production performance, rumen fermentation profile, microbial abundance, and immunity in goats. A total of 30 male goats with similar body condition were randomly distributed into 3 dietary treatments with 10 replicates per treatment as follows: basic diet group (CON); basic diet + 0.5% yeast culture 1 (YC1) group; basic diet + 0.5% yeast culture 2 (YC2) group. The trial lasted for 36 days. The results demonstrated that dietary YC supplementation led to an increase in the average daily gain and a reduction in feed intake and weight gain ratio in goats. It increased the apparent digestibility of crude protein, NDF, and ADF (p < 0.05). The serum concentrations of interleukin (IL)-1β, IL-6, and Tumor Necrosis Factor-α in the control group were significantly higher than those of the YC groups (p < 0.05). The serum concentrations of Immunoglobulin (Ig)A and IgG in the control group were significantly lower than those in the YC groups (p < 0.05). The rumen concentration of microbial protein (MCP) in the control group was significantly lower than that in the YC groups (p < 0.05). There was a negative correlation between the concentration of IL-10 and Bacteroidota, Spirochaetota, and Succinivibrio, while there was a positive correlation between concentrations of IL-10 and Firmicutes. Nevertheless, discrepancies were observed in the impact of the two different types of YC on the physiological and biochemical indicators of the animals. The concentration of triglyceride in the YC1 group was significantly higher than that of the CON and YC2 groups, while the concentration of urea in the YC2 group was significantly higher than that of the CON and YC1 groups (p < 0.05). At the phylum level, the addition of YC2 to the diet significantly increased the relative abundance of Bacteroidota and Fibrobacterota and significantly decreased Firmicutes compared to the control. At the genus level, the addition of YC1 to the HGD significantly reduced the relative abundance of Rikenellaceae_RC9_gut_group, while the addition of YC2 to the HGD significantly increased the relative abundance of Prevotellace-ae_UCG-001, Fibrobacter, and Prevotellaceae_UCG-003 (p < 0.05). The addition of YC significantly improved growth performance, increased nutrient digestibility, beneficially manipulated ruminal fermentation and microbial diversity, and improved immune function. The choice of yeast cultures can be customized according to specific production conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: Transportation is an inevitable part of the raising process of goats. During transportation, animals are subjected to 'transport stress' due to limited space, bumpy roads, lack of feed and drinking water, and other stimuli. In order to gain a comprehensive understanding of how transport stress affects goats, we conducted our experimental studies. Sixteen healthy goats were selected, and these goats were transported at a speed ranging from 35 to 45 km/h for 20 h. We measured changes in the physiological indexes, blood physiological indexes, biochemical indexes, rumen fermentation indexes, and rumen microbial structure composition of goats before and after transportation. Our experimental findings revealed that continuous transportation for a duration of 20 h can induce a severe stress response in goats, leading to compromised immune function, diminished antioxidant capacity, escalated inflammatory response, and altered rumen fermentation indices. However, they did not reveal any significant impact on the structure and composition of the rumen microbiota. The objective of this experiment was to delve into the impacts of transportation on goats. Sixteen healthy goats were selected as experimental animals; these goats were transported at a speed ranging from 35 to 45 km/h for 20 h. The changes in the physiological indexes, blood physiological indexes, biochemical indexes, rumen fermentation indexes, and rumen microbial structure composition of goats before and after transportation were measured. The results showed that after transportation, the contents of IgM, IgA, IgG, and Thyroxine decreased very significantly, while the contents of propionic acid, Hemoglobin and Epinephrine significantly increased, and the contents of VFA, acetic acid, butyric acid, isobutyric acid, isovaleric acid, LPS, IL-1β, IL-6, TNF-α, Major Acute Phase Protein, protein carbonyl, and cortisol increased very significantly. There was no significant difference in α-diversity and β-diversity, and the relative abundance of rumen microorganisms was not significantly different at either phylum or genus levels. The experimental findings revealed that continuous transportation for a duration of 20 h can induce a severe stress response in goats, leading to compromised immune function, diminished antioxidant capacity, escalated inflammatory response, and altered rumen fermentation indices. However, the experiment did not reveal any significant impact on the structure and composition of the rumen microbiota. [ABSTRACT FROM AUTHOR]