Search

Abstract Background Older patients with coronary artery disease (CAD) are particularly vulnerable to the efficacy and adverse drug reactions, and may therefore particularly benefit from personalized medication. Drug–gene interactions (DGIs) occur when an individual’s genotype affects the pharmacokinetics and/or pharmacodynamics of a victim drug. Objectives This study aimed to investigate the impact of cardiovascular-related DGIs on the clinical efficacy and safety outcomes in older patients with CAD. Methods Hospitalized older patients (≥ 65 years old) with CAD were consecutively recruited from August 2018 to May 2022. Eligible patients were genotyped for the actionable pharmacogenetic variants of CYP2C9, CYP2C19, CYP2D6, CYP3A5, and SLCO1B1, which had clinical annotations or implementation guidelines for cardiovascular drugs. Allele frequencies and DGIs were determined in the cohort for the 5 actionable PGx genes and the prescribed cardiovascular drugs. All patients were followed up for at least 1 year. The influence of DGIs on the cardiovascular drug-related efficacy outcomes (all-cause mortality and/or major cardiovascular events, MACEs) and drug response phenotypes of “drug-stop” and “dose-decrease” were evaluated. Results A total of 1,017 eligible older patients with CAD were included, among whom 63.2% were male, with an average age of 80.8 years old, and 87.6% were administrated with polypharmacy (≥ 5 medications). After genotyping, we found that 96.0% of the older patients with CAD patients had at least one allele of the 5 pharmacogenes associated with a therapeutic change, indicating a need for a therapeutic change in a mean of 1.32 drugs of the 19 cardiovascular-related drugs. We also identified that 79.5% of the patients had at least one DGI (range 0–6). The median follow-up interval was 39 months. Independent of age, negative association could be found between the number of DGIs and all-cause mortality (adjusted HR: 0.84, 95% CI: 0.73–0.96, P = 0.008), and MACEs (adjusted HR: 0.84, 95% CI: 0.72–0.98, P = 0.023), but positive association could be found between the number of DGIs and drug response phenotypes (adjusted OR: 1.24, 95% CI: 1.05–1.45, P = 0.011) in the elderly patients with CAD. Conclusions The association between cardiovascular DGIs and the clinical outcomes emphasized the necessity for the integration of genetic and clinical data to enhance the optimization of cardiovascular polypharmacy in older patients with CAD. The causal relationship between DGIs and the clinical outcomes should be established in the large scale prospectively designed cohort study.

Acute myeloid leukemia (AML) is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming. Here, we applied spatial metabolomics to achieve high-throughput, in situ identification of metabolites within the liver metastases of AML mice. Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics. This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle, coupled with an upregulation of the creatine metabolism. The upregulation of creatine synthetases Gatm and Gamt, as well as the creatine transporter Slc6a8, resulted in a marked accumulation of creatine within tumor foci. This process further enhances oxidative phosphorylation and glycolysis of leukemia cells, thereby boosting ATP production to foster proliferation and infiltration. Importantly, we discovered that inhibiting Slc6a8 can counter these detrimental effects, offering a new strategy for treating AML by targeting metabolic pathways.

Abstract The quest for reliable vehicle navigation in urban environments has led the integration of Light Detection and Ranging (LiDAR) Odometry (LO) with Global Navigation Satellite Systems (GNSS) and Inertial Measurement Units (IMU). However, the performance of the integrated system is limited by a lack of accurate LO error modeling. In this paper, we propose a weighted GNSS/IMU/LO integration-based navigation system with a novel LO error model. The Squared Exponential Gaussian Progress Regression (SE-GPR) based LO error model is developed by considering the vehicle velocity and number of point cloud features. Based on error prediction for GNSS positioning and LO, a weighting strategy is designed for integration in an Extended Kalman Filter (EKF). Furthermore, error accumulation of the navigation state, especially in GNSS-challenging scenarios, is restrained by the LiDAR-Aided Lateral Constraint (LALC) and Non-Holonomic Constraint (NHC). An experiment was conducted in a deep urban area to test the proposed algorithm. The results show that the proposed algorithm delivers horizontal and three-dimensional (3D) positioning Root Mean Square Errors (RMSEs) of 3.669 m and 5.216 m, respectively. The corresponding accuracy improvements are 35.9% and 50.0% compared to the basic EKF based GNSS/IMU/LO integration.

Alzheimer’s disease is a debilitating, progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins, including amyloid plaques and intracellular tau tangles, primarily within the brain. Lysosomes, crucial intracellular organelles responsible for protein degradation, play a key role in maintaining cellular homeostasis. Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases, including Alzheimer’s disease. Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease. Currently, the efficacy of drugs in treating Alzheimer’s disease is limited, with major challenges in drug delivery efficiency and targeting. Recently, nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties. This review aims to provide a comprehensive overview of recent advances in using nanomaterials (polymeric nanomaterials, nanoemulsions, and carbon-based nanomaterials) to enhance lysosomal function in treating Alzheimer’s disease. This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function. In conclusion, this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease. The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.

Abstract Background Matrix metalloproteinase-7 (MMP-7) is associated with biliary injury. This study aimed to evaluate the relationships of serum MMP-7 with clinical characteristics in choledochal cysts (CDC) children. Methods Between June 2020 and July 2022, we conducted a prospective study of CDCs who underwent one-stage definitive operation at our center. Serum MMP-7 was measured using an enzyme-linked immunosorbent assay. We evaluated the relationships between serum MMP-7 and age, laboratory tests, imaging examinations, liver fibrosis, MMP-7 expression, and perforation. Results A total of 328 CDCs were enrolled in the study, with a median serum MMP-7 of 7.67 ng/mL. Higher serum MMP-7 was correlated with younger age at diagnosis (p

Abstract Background Platelet is enriched with Circular RNAs (circRNAs), with circFAM13B rank among the 10 most abundant circRNAs in platelets. The aim of the present study was to evaluate the predictive value of platelet-derived circFAM13B for the antiplatelet responsiveness and efficacy of ticagrelor in patients with acute coronary syndrome (ACS). Methods Consecutive ACS patients treated with ticagrelor were enrolled, and the antiplatelet responsiveness of 3 days of ticagrelor maintenance treatment was assessed by measuring the adenosine diphosphate (ADP)-induced platelet inhibition rate (ADP%) using thromboelastography. The expression of circFAM13B in the patients’ platelets was analyzed by quantitative real-time polymerase chain reaction. The correlation between circFAM13B expression and ticagrelor antiplatelet responsiveness, as well as the independent contribution of circFAM13B to the composite of adverse ischemic events during a follow-up period of at least 12 months was evaluated. Results A total of 129 eligible ACS patients treated with ticagrelor were enrolled in the study. A negative correlation was found between the expression of circFAM13B and the ADP% value (r = -0.41, P 1.05 with clinical risk factors could effectively predict the risk of adverse ischemic events (AUC = 0.81, 95% CI: 0.69 to 0.92, P 1.05 had a significantly higher risk of adverse ischemic events compared to those with circFAM13B ≤ 1.05 (P = 0.003). Multivariate logistic hazard analysis identified circFAM13B > 1.05 as an independent risk factor for adverse ischemic events in in ticagrelor-treated ACS patients (adjusted OR: 5.60, 95% CI: 1.69–18.50; P = 0.005). Conclusions Platelet-derived circFAM13B could be utilized for predicting the antiplatelet responsiveness and efficacy of ticagrelor in patients with ACS.

BackgroundCytomegalovirus (CMV) reactivation is a significant concern following allogeneic stem cell transplantation. While previous research has highlighted the anti-CMV reactivation effect of γδ T cells in immunocompromised transplant patients, their characterization in recipients at high risk of CMV reactivation remains limited.MethodsThis study focused on D+/R+ recipients (where both donor and recipient are CMV seropositive) at high risk of CMV reactivation. We analyzed 28 patients who experienced CMV recurrence within 100 days post-allogeneic hematopoietic stem cell transplantation, along with 36 matched recipients who did not experience CMV recurrence. Clinical data from both groups were compared, and risk factors for CMV reactivation were identified. Additionally, CMV viral load was measured, and flow cytometric analysis was conducted to assess changes in peripheral blood γδ T cell proportions, subpopulation distribution, and differentiation status. We also analyzed the CDR3 repertoire of the TCR δ chain in different γδ T cell subsets. Functional analysis was performed by measuring the lysis of CMV-infected cells upon stimulation.ResultsCMV reactivation post-transplantation was associated with acute graft-versus-host disease (aGvHD) and reactivation of non-CMV herpesviruses. Notably, CMV reactivation led to sustained expansion of γδ T cells, primarily within the Vδ2neg γδ T cell subpopulation, with a trend toward differentiation from Naive to effector memory cells. Analysis of the δ chain CDR3 repertoire revealed a delay in the reconstitution of clonal diversity in Vδ2neg γδ T cells following CMV reactivation, while Vδ2pos T cells remained unaffected. Upon stimulation with CMV-infected MRC5 cells, the Vδ2neg γδ T cell subpopulation emerged as the primary effector cell group producing IFN-γ and capable of lysing CMV-infected cells. Moreover, our findings suggest that NKG2D is not necessary involved in Vδ2neg γδ T cell-mediated anti-CMV cytotoxicity.ConclusionThis study provides novel insights into the role of γδ T cells in the immune response to CMV reactivation in transplantation recipients at high risk of CMV infection. Specifically, the Vδ2neg γδ T cell subpopulation appears to be closely associated with CMV reactivation, underscoring their potential role in controlling infection and reflecting CMV reactivation in HSCT patients.

Backgroud: The co-administration of Chinese patent medicine with calcium channel blockers (CCBs) is a prevalent practice in China for treating essential hypertension (EH). However, robust evidence supporting the efficacy and safety of tailored combinations of different Chinese patent medicines with CCBs, according to individual patient conditions, is still limited. This study sought to elucidate the efficacy and safety of these combinations using a systematic review and network meta-analysis.Materials and methods: Relevant studies were sourced from established databases, incorporating randomized controlled trials published up to 1 February 2023. The ROB2 tool from the Cochrane Collaborative Network was employed to independently assess and cross-verify the quality of the included literature. A network meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 and PRISMA-Network Meta-Analyses (PRISMA-NMA) guidelines. A Bayesian network meta-analysis was utilized to gauge the efficacy and safety of distinct integrations of Chinese patent medicine and CCBs. Primary outcomes were interpreted using a paired fixed-effect meta-analysis. Publication bias was appraised through Egger’s test and represented with funnel plots. All statistical analyses were executed within the R statistical framework.Results: Following rigorous selection, data extraction, and bias evaluation, 36 articles were incorporated. Tianma Gouteng Granule, when combined with CCBs, displayed superior efficacy in reducing systolic blood pressure (SBP). In terms of diastolic blood pressure (DBP) reduction, Songling Xuemaikang Capsule combined with CCBs emerged as the most effective. Regarding enhancement of antihypertensive effective rates, Qinggan Jiangya Capsule paired with CCBs demonstrated optimal results. For diminishing Traditional Chinese Medicine syndrome scores, the Qiangli Dingxuan Tablet and CCBs combination proved most beneficial. When aiming to reduce total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels, Tianma Gouteng Granule and CCBs showcased superior results. In contrast, the combination of Songling Xuemaikang Capsule and CCBs was more effective in reducing LDL-C, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6).Conclusion: This study underscores variability in outcomes from combining Chinese patent medicine and CCBs for hypertension, emphasizing the importance of personalized medicinal combinations, especially Tianma Gouteng Granule and Songling Xuemaikang Capsule. The results offer robust evidence to inform clinical guidelines for essential hypertention and significantly aid clinician in seleting appropriate Chinese patent medicines for treatment.

Clinical annotations for the actionable pharmacogenetic variants affecting the efficacy of cardiovascular drugs have been collected, yet their impacts on elderly patients with coronary artery disease (CAD) undergoing polypharmacy remain uncertain. We consecutively enrolled 892 elderly patients (mean age 80.7 ± 5.2) with CAD and polypharmacy. All the included patients underwent genotyping for 13 variants in 10 pharmacogenes (CYP2C19, CYP2C9, CYP4F2, CYP2D6, VKORC1, SLCO1B1, APOE, ACE, ADRB1, and MTHFR), which have the clinical annotations for 12 drugs that are commonly prescribed for patients with CAD. We found that 80.3% of the elderly CAD patients had at least one drug–gene pair associated with a therapeutical drug change. After adjusting for covariates, the number of drug–gene pairs was independently associated with a decreased risk of both major cardiovascular events (MACEs) (adjusted hazard ratio [HR]: 0.803, 95% confidence interval [CI]: 0.683–0.945, p = 0.008) and all-cause mortality (adjusted HR: 0.848, 95% CI: 0.722–0.996, p = 0.045), but also with an increased risk of adverse drug reactions (ADRs) (adjusted HR: 1.170, 95% CI: 1.030–1.329, p = 0.016). The Kaplan–Meier survival curves showed that compared to patients without a drug–gene pair, a significantly lower risk of MACEs could be observed in patients with a drug–gene pair during a 4-year follow-up (HR: 0.556, 95% CI: 0.325–0.951, p = 0.013). In conclusion, the carrier status of the actionable drug–gene pair is predictive for the clinical outcomes in elderly patients with CAD and polypharmacy. Implementing early or preemptive pharmacogenetic panel-guided polypharmacy holds the potential to enhance clinical outcomes for these patients.

Abstract Pathogens or danger signals trigger the immune response. Moderate immune response activation removes pathogens and avoids excessive inflammation and tissue damage. Histone demethylases (KDMs) regulate gene expression and play essential roles in numerous physiological processes by removing methyl groups from lysine residues on target proteins. Abnormal expression of KDMs is closely associated with the pathogenesis of various inflammatory diseases such as liver fibrosis, lung injury, and autoimmune diseases. Despite becoming exciting targets for diagnosing and treating these diseases, the role of these enzymes in the regulation of immune and inflammatory response is still unclear. Here, we review the underlying mechanisms through which KDMs regulate immune-related pathways and inflammatory responses. In addition, we also discuss the future applications of KDMs inhibitors in immune and inflammatory diseases.

Background: With the increasing global prevalence of hypertension, a condition that can severely affect multiple organs, there is a growing need for effective treatment options. Uncaria rhynchophylla-Alisma plantago-aquatica L. (UR-AP) is a traditional drug pair used for treating hypertension based on the liver-kidney synergy concept. However, the detailed molecular mechanisms underlying its efficacy remain unclear.Methods: This study utilized an integrative approach combining network pharmacology, cluster analysis, and molecular docking to uncover the bioactive components and targets of UR-AP in the treatment of hypertension. Initially, we extracted data from public databases to identify these components and targets. A Protein-Protein Interaction (PPI) network was constructed, followed by enrichment analysis to pinpoint the bioactive components, core targets, and pivotal pathways. Cluster analysis helped in identifying key sub-networks and hypothesizing primary targets. Furthermore, molecular docking was conducted to validate the interaction between the core targets and major bioactive components, thus confirming their potential efficacy in hypertension treatment.Results: Network pharmacological analysis identified 58 bioactive compounds in UR-AP, notably quercetin, kaempferol, beta-sitosterol (from Uncaria rhynchophylla), and Alisol B, alisol B 23-acetate (from Alisma plantago-aquatica L.), as pivotal bioactives. We pinpointed 143 targets common to both UR-AP and hypertension, highlighting MAPK1, IL6, AKT1, VEGFA, EGFR, and TP53 as central targets involved in key pathways like diastolic and endothelial function, anti-atherosclerosis, AGE-RAGE signaling, and calcium signaling. Cluster analysis emphasized IL6, TNF, AKT1, and VEGFA’s roles in atherosclerosis and inflammation. Molecular docking confirmed strong interactions between these targets and UR-AP’s main bioactives, underscoring their therapeutic potential.Conclusion: This research delineates UR-AP’s pharmacological profile in hypertension treatment, linking traditional medicine with modern pharmacology. It highlights key bioactive components and their interactions with principal targets, suggesting UR-AP’s potential as a novel therapeutic option for hypertension. The evidence from molecular docking studies supports these interactions, indicating the relevance of these components in affecting hypertension pathways. However, the study acknowledges its limitations, including the reliance on in silico analyses and the need for in vivo validation. These findings pave the way for future clinical research, aiming to integrate traditional medicine insights with contemporary scientific approaches for developing innovative hypertension therapies.

Cardiovascular diseases represent a significant worldwide problem, jeopardizing individuals’ physical and mental wellbeing as well as their quality of life as a result of their widespread incidence and fatality. With the aging society, the occurrence of Cardiovascular diseases is progressively rising each year. However, although drugs developed for treating Cardiovascular diseases have clear targets and proven efficacy, they still carry certain toxic and side effect risks. Therefore, finding safe, effective, and practical treatment options is crucial. Scutellarin is the primary constituent of Erigeron breviscapus (Vant.) Hand-Mazz. This article aims to establish a theoretical foundation for the creation and use of secure, productive, and logical medications for Scutellarin in curing heart-related illnesses. Additionally, the examination and analysis of the signal pathway and its associated mechanisms with regard to the employment of SCU in treating heart diseases will impart innovative resolving concepts for the treatment and prevention of Cardiovascular diseases.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is not just confined to the older population. Although developments have been made in AD treatment, various limitations remain to be addressed. These are partly contributed by biological hurdles, such as the blood–brain barrier and peripheral side effects, as well as by lack of carriers that can efficiently deliver the therapeutics to the brain while preserving their therapeutic efficacy. The increasing AD prevalence and the unavailability of effective treatments have encouraged researchers to develop improved, convenient, and affordable therapies. Functional materials based on primitive cells and nanotechnology are emerging as attractive therapeutics in AD treatment. Cell primitives possess distinct biological functions, including long-term circulation, lesion site targeting, and immune suppression. This review summarizes the challenges in the delivery of AD drugs and recent advances in cell primitive–based materials for AD treatment. Various cell primitives, such as cells, extracellular vesicles, and cell membranes, are presented together with their distinctive biological functions and construction strategies. Moreover, future research directions are discussed on the basis of foreseeable challenges and perspectives.

ABSTRACT: The aim of the present study was an in-depth genomic analysis to understand the genomic mechanisms of the 3 claw disorders dermatitis digitalis (DD), interdigital hyperplasia (HYP), and sole ulcer (SU). In this regard, we estimated genetic parameters based on genomic relationship matrices, performed genome-wide association studies, annotated potential candidate genes, and inferred genetic associations with breeding goal traits considering the most important chromosomal segments. As a further novelty of this study, we inferred possible SNP × heat stress interactions for claw disorders. The study consisted of 17,264 first-lactation Holstein Friesian cows kept in 50 large-scale contract herds. The disease prevalence was 15.96, 2.36, and 8.20% for DD, HYP, and SU, respectively. The remaining breeding goal traits consisted of type traits of the feet and leg composite, female fertility, health traits, and 305-d production traits. The final genotype data set included 44,474 SNPs from the 17,264 genotyped cows. Heritabilities for DD, HYP, and SU were estimated in linear and threshold models considering the genomic relationship matrix (G matrix). Genetic correlations with breeding goal traits based on G were estimated in a series of bivariate linear models, which were verified via SNP effect correlations for specific chromosome segments (i.e., segments harboring potential candidate genes for DD, HYP, and SU). Genome-wide association studies were performed for all traits in a case-control design by applying a single SNP linear mixed model. Furthermore, for DD, HYP, and SU, we modeled SNP × heat stress interactions in genome-wide association studies. Single nucleotide polymorphism-based heritabilities were 0.04 and 0.08 for DD, 0.03 and 0.10 for SU, and 0.03 and 0.23 for HYP from linear and threshold models, respectively. The genetic correlations between DD, HYP, and SU with conformation traits from the feet and leg composite were positive throughout, indicating the value of indirect selection on conformation traits to improve claw health. Genetic correlations between DD, SU, and HYP with other breeding goal traits indicated impaired female fertility, impaired udder health status, and productivity decline of diseased cows. Genetic correlations among DD, SU, and HYP were moderate to large, indicating that different claw disorders have similar genetic mechanisms. Nevertheless, we identified disease-specific potential candidate genes, and genetic associations based on the surrounding SNPs partly differed from the genetic correlations. Especially for candidate genes contributing to 2 traits simultaneously, correlations based on SNP effects from the respective chromosome segment were close to 1 or to −1. In this regard, we annotated the candidate genes KRT33A and KRT33B for HYP and DD, KIF27 for HYP and calving to first insemination, and MAN1A1 for SU and the production traits. For SNP × heat stress interactions, we identified significant SNPs on BTA 2, 4, 5, 7, 8, 9, 13, 22, 25, and 28, and we annotated the potential candidate genes FSIP2, CLCN1, ADGRV1, DOP1A, THBD, and RHOBTB1. Results indicate gene-specific mechanisms of the claw disorders only in specific environments.

Abstract Background This study aimed to evaluate the efficacy and safety of oral anticoagulants (OACs) in real-world elderly patients with comorbidities of stable coronary artery disease (SCAD) and atrial fibrillation (AF). Methods Elderly patients (aged ≥ 65 years old) diagnosed with SCAD and AF were consecutively recruited and grouped into patients with or without oral anticoagulant (OAC) treatment. Follow-up was performed for 5 years. Major adverse cardiac events (MACEs) were defined as a composite of all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, and systemic embolism. Major bleeding outcomes were defined as events that were type ≥ 3 based on the Bleeding Academic Research Consortium (BARC) criteria. The net clinical outcomes were defined as the combination of MACEs and bleeding of BARC type ≥ 3. Results A cohort of 832 eligible patients (78 ± 6.70 years) was included. Compared to the patients without OAC treatment (n = 531, 63.82%), the patients treated with OAC (n = 301, 36.18%) were much younger, had higher body mass index (BMI), and had lower prevalence of heart failure, chronic obstructive pulmonary disease (COPD), renal insufficiency, and previous myocardial infarction. During the follow-up of 5 years, compared to the patients without OAC treatment, patients with OAC had a significantly lower risk of MACEs (20.60% vs. 58.95%, adjusted HR: 0.21, 95% CI: 0.15–0.30, p

Abstract Background Glycogen storage disease type 1a (GSD1a) is an inborn genetic disease caused by glucose-6-phosphatase-α (G6Pase-α) deficiency and is often observed to lead to endogenous glucose production disorders manifesting as hypoglycemia, hyperuricemia, hyperlipidemia, lactic acidemia, hepatomegaly, and nephromegaly. The development of GSD1a with diabetes is relatively rare, and the underlying pathogenesis remains unclear. Case presentation Here we describe a case of a 25-year-old Chinese female patient with GSD1a, who developed uncontrolled type 2 diabetes mellitus (T2DM) as a young adult. The patient was diagnosed with GSD1a disease at the age of 10 and was subsequently treated with an uncooked cornstarch diet. Recently, the patient was treated in our hospital for vomiting and electrolyte imbalance and was subsequently diagnosed with T2DM. Owing to the impaired secretory function of the patient’s pancreatic islets, liver dysfunction, hypothyroidism, severe hyperlipidemia, and huge hepatic adenoma, we adopted diet control, insulin therapy, and hepatic adenoma resection to alleviate this situation. The WES discovered compound heterozygous mutations at the exon 5 of G6PC gene at 17th chromosome in the patient, c.648G>T (p.L216 L, NM_000151.4, rs80356484) in her father and c.674T>C (p.L225 P, NM_000151.4, rs1555560128) in her mother. c.648G>T is a well-known splice-site mutation, which causes CTG changing to CTT at protein 216 and creates a new splicing site 91 bp downstream of the authentic splice site, though both codons encode leucine. c.674T>C is a known missense mutation that causes TGC to become CGC at protein 225, thereby changing from coding for leucine to coding for proline. Conclusion We report a rare case of GSD1a with T2DM. On the basis of the pathogenesis of GSD1a, we recommend attentiveness to possible development of fasting hypoglycemia caused by GSD and postprandial hyperglycemia from diabetes. As the disease is better identified and treated, and as patients with GSD live longer, this challenge may appear more frequently. Therefore, it is necessary to have a deeper and more comprehensive understanding of the pathophysiology of the disease and explore suitable treatment options.

A study was designed to identify the genomic regions associated with milk production traits in a dairy cattle population reared by smallholder farmers in the harsh and challenging tropical savanna climate of Bengaluru, India. This study is a first-of-its-kind attempt to identify the selection sweeps for the dairy cattle breeds reared in such an environment. Two hundred forty lactating dairy cows reared by 68 farmers across the rural–urban transiting regions of Bengaluru were selected for this study. A genome-wide association study (GWAS) was performed to identify candidate genes for test-day milk yield, solids-not-fat (SNF), milk lactose, milk density and clinical mastitis. Furthermore, the cross-population extended haplotype homozygosity (XP-EHH) methodology was adopted to scan the dairy cattle breeds (Holstein Friesian, Jersey and Crossbred) in Bengaluru. Two SNPs, rs109340659 and rs41571523, were observed to be significantly associated with test-day milk yield. No significant SNPs were observed for the remaining production traits. The GWAS for milk lactose revealed one SNP (rs41634101) that was very close to the threshold limit, though not significant. The potential candidate genes fibrosin-like 1 (FBRSL) and calcium voltage-gated channel auxiliary subunit gamma 3 (CACN) were identified to be in close proximity to the SNP identified for test-day milk yield. These genes were observed to be associated with milk production traits based on previous reports. Furthermore, the selection signature analysis revealed a number of regions under selection for the breed-group comparisons (Crossbred-HF, Crossbred-J and HF-J). Functional analysis of these annotated genes under selection indicated pathways and mechanisms involving ubiquitination, cell signaling and immune response. These findings point towards the probable selection of dairy cows in Bengaluru for thermotolerance.

Abstract Acute lung injury (ALI) is a potentially life-threatening, devastating disease with an extremely high rate of mortality. The underlying mechanism of ALI is currently unclear. In this study, we aimed to confirm the hub genes associated with ALI and explore their functions and molecular mechanisms using bioinformatics methods. Five microarray datasets available in GEO were used to perform Robust Rank Aggregation (RRA) to identify differentially expressed genes (DEGs) and the key genes were identified via the protein-protein interaction (PPI) network. Lipopolysaccharide intraperitoneal injection was administered to establish an ALI model. Overall, 40 robust DEGs, which are mainly involved in the inflammatory response, protein catabolic process, and NF-κB signaling pathway were identified. Among these DEGs, we identified two genes associated with ALI, of which the CAV-1/NF-κB axis was significantly upregulated in ALI, and was identified as one of the most effective targets for ALI prevention. Subsequently, the expression of CAV-1 was knocked down using AAV-shCAV-1 or CAV-1-siRNA to study its effect on the pathogenesis of ALI in vivo and in vitro. The results of this study indicated that CAV-1/NF-κB axis levels were elevated in vivo and in vitro, accompanied by an increase in lung inflammation and autophagy. The knockdown of CAV-1 may improve ALI. Mechanistically, inflammation was reduced mainly by decreasing the expression levels of CD3 and F4/80, and activating autophagy by inhibiting AKT/mTOR and promoting the AMPK signaling pathway. Taken together, this study provides crucial evidence that CAV-1 knockdown inhibits the occurrence of ALI, suggesting that the CAV-1/NF-κB axis may be a promising therapeutic target for ALI treatment.

Abstract Background Despite strong antiplatelet therapy with ticagrelor, serious ischemic events still occur in patients with acute coronary syndrome (ACS). The predictability of platelet reactivity to the residual risk of ischemic events during ticagrelor treatment remains uncertain. Objectives We aimed to investigate the predictability of the thromboelastography (TEG)-measured adenosine disphosphate (ADP)-induced platelet inhibition rate (ADP%) to the ischemic events in ticagrelor-treated patients with ACS. Methods A cohort of ticagrelor-treated patients with ACS were consecutively recruited. ADP% was measured by TEG after 3 days of ticagrelor maintenance treatment. The primary ischemic event was defined as rehospitalization for unstable angina (UA) within 1 year, and the secondary ischemic event was a composite of the primary ischemic event plus all-cause death, nonfatal myocardial infarction (MI), stent thrombosis, stroke, and unplanned revascularization within 1 year. Results A total of 751 eligible patients with ACS were included in the analysis, with 336 patients randomly assigned to the derivation group and 415 to the validation group. The overall rates of primary and secondary ischemic events were 14.51% (n = 109) and 16.91% (n = 127), respectively. Compared to the patients without ischemic events, those with ischemic events had a significantly lower ADP% both in the derivation group (for primary ischemic events: 66.05% vs. 92.80%, p

Glycation by transglutaminase (TGase)-type could effectively improve the structure and functional properties of proteins. However, the influence on intestinal inflammation or the underlying mechanisms has not been investigated. The goal of this research was to compare the bioactivities between glycated casein generated from the TGase-catalyzed reaction and oligochitosan as well as casein using a mouse model of dextran sulfate sodium (DSS)-induced intestinal inflammation to examine the protective effects and the underlying mechanism of glycated casein on intestinal inflammation. Eight groups of C57BL/6 mice were randomly assigned in this study: Control group: standard diet for 35 days; Model group: standard diet for 28 days and then colitis induction; Pretreated groups: different levels (200, 400, 800 mg/kg BW) of casein or glycated casein for 28 days before colitis induction. The mice were drinking water containing a 3% DSS solution for seven days of mice to cause colitis. The results indicated that glycated casein and casein at 200–800 mg/kg BW all relieved DSS-induced weight loss, reduced disease activity index (DAI) score, alleviated colon length shortening, weakened the destruction of colonic mucosal structure, decreased serum LPS, and MPO, IL-1β, IL-6 and TNF-α levels in serum and colon, as well as regulated the expression of proteins involved in the TLR4/NF-κB signaling pathway in a concentration-dependent manner. Glycated caseinate showed a better protective effect against DSS-induced colitis than casein, highlighting that the TGase-type glycation of proteins as a potential functional food ingredient might be a helpful method for gut health.

Objectives. Management of chronic coronary syndrome (CCS) encompasses a broad spectrum of practices, posing considerable complexity and variability. While guidelines have been established to augment the management quality of CCS, notable disparities persist across their recommendations. This study strives to scrutinize, compare, and reconcile these guideline recommendations pertaining to the diagnosis, treatment, and management of CCS patients. Our goal is to align these recommendations with contemporary clinical practices, thus laying a robust foundation for their pragmatic application in clinical settings. Methods. A comprehensive systematic search was conducted across multiple databases, including PubMed, EMBASE, China National Knowledge Infrastructure, Wanfang Database, China Science and Technology Journal Database, Chinese Biomedical Literature Service System, Chinese Science and Technology Periodical Database, and Chinese Biological Medicine Database. The timeframe for this search spanned from their inception up to May 30, 2022, aiming to collate all published guidelines relevant to CCS. Subsequently, two independent reviewers undertook the task of appraising the quality of these guidelines by utilizing the Appraisal of Guidelines for Research and Evaluation II instrument. Results. The search yielded a total of 10,699 citations. Following a thorough evaluation, fourteen clinical practice guidelines and four consensus statements, each offering specific recommendations for CCS, were selected. The quality of these guidelines showcased a broad spectrum of variation. The domain of “presentation clarity” received the highest accolades, while “applicability” languished at the lower end of the scoring spectrum. On average, the guidelines attained a quality score denoting sufficiency. Furthermore, recommendations across different guidelines for the diagnosis, treatment, and management of CCS displayed a striking level of divergence. Conclusion. The landscape of published CCS guidelines is marked by extensive variations in scope, quality, and recommendations. Hence, there is a compelling need for collaborative efforts amongst multidisciplinary professionals to forge comprehensive, higher-quality evidence-based guidelines; such a concerted approach is paramount to enhance treatment efficacy and health outcomes for patients grappling with CCS.

BackgroundThere are controversies on the pathophysiological alteration in patients with atrial fibrillation (AF) undergoing pulmonary vein isolation using different energy sources.ObjectivesWe evaluated the changes in plasma proteins in acute phase post-ablation in patients receiving cryoballoon ablation, radiofrequency balloon ablation, or radiofrequency ablation.MethodsBlood samples from eight healthy controls and 24 patients with AF were taken on the day of admission, day 1, and day 2 post-ablation and analyzed by the Olink proximity extension assay. Proteins were identified and performed with enrichment analysis. Protein–protein interaction network and module analysis were conducted using Cytoscape software.ResultsOf 181 proteins, 42 proteins in the cryoballoon group, 46 proteins in the radiofrequency balloon group, and 43 proteins in the radiofrequency group significantly changed after ablation. Most of the proteins altered significantly on the first day after ablation. Altered proteins were mainly involved in cytokine–cytokine receptor interaction. Both balloon-based ablations showed a similar shift toward enhancing cell communication and regulation of signaling while inhibiting neutrophil chemotaxis. However, radiofrequency ablation presented a different trend. Seed proteins, including osteopontin, interleukin-6, interleukin-10, C-C motif ligand 8, and matrix metalloproteinase-1, were identified. More significant proteins associated with hemorrhage and coagulation were selected in balloon-based ablations by machine learning.ConclusionPlasma protein response after three different ablations in patients with AF mainly occurred on the first day. Radiofrequency balloon ablation shared similar alteration in protein profile as cryoballoon ablation compared with radiofrequency ablation, suggesting that lesion size rather than energy source is the determinant in pathophysiological responses to the ablation.

BackgroundEven though presenting with similar clinical manifestations, necrotizing enterocolitis (NEC) and food protein-induced allergic protocolitis (FPIAP) have completely different treatments and prognosis. Our study aimed to quantify and evaluate differences in gut microbiota and short chain fatty acids (SCFAs) between infants with NEC and FPIAP to better identify these two diseases in clinical settings.MethodsA total of 43 infants with NEC or FPIAP in Children’s Hospital of Chongqing Medical University, China between December 2020 and December 2021 were enrolled. Stool samples were prospectively collected and froze. Infants defined as NEC were those who presented with clinical courses consistent with NEC and whose radiographs fulfilled criteria for Bell’s stage 2 or 3 NEC, while those who were healthy in appearance and had blood in the stool (visible or may be microscopic), had normal bowel sounds in physical examination, were resolved after eliminating the causative food, and/or had recurrence of symptoms after oral food challenge (OFC) were defined as FPIAP. Primers specific for bacterial 16S rRNA genes were used to amplify and pyrosequence fecal DNA from stool samples. Gas chromatography-mass spectrometry (GC-MS) technology was used to determine the concentrations of SCFAs.ResultsAmong the 43 infants, 22 were diagnosed with NEC and 21 were diagnosed with FPIAP. The microbial community structure in NEC infant stools differed significantly from those in FPIAP infant stools. NEC infants had significantly higher proportion of Actinobacteria and reduced proportion of Bacteroidetes compared with FPIAP infants, and the proportions of Halomonas, Acinetobacter, Bifidobacterium, and Stenotrophomonas in NEC infants were significantly higher than that of FPIAP infants. In addition, infants with NEC had significantly lower levels of acetic acid, propionic acid, butyric acid, isovaleric acid, and total SCFAs, and higher level of hexanoic acid as compared to the infants of the FPIAP group.ConclusionsThe differences of gut microbiota composition and concentrations of SCFAs might represent suitable biomarker targets for early identification of NEC and FPIAP.

Abstract The pathophysiology of coronavirus disease 19 (COVID-19) involves a multitude of host responses, yet how they unfold during the course of disease progression remains unclear. Here, through integrative analysis of clinical laboratory tests, targeted proteomes, and transcriptomes of 963 patients in Shanghai, we delineate the dynamics of multiple circulatory factors within the first 30 days post-illness onset and during convalescence. We show that hypercortisolemia represents one of the probable causes of acute lymphocytopenia at the onset of severe/critical conditions. Comparison of the transcriptomes of the bronchoalveolar microenvironment and peripheral blood indicates alveolar macrophages, alveolar epithelial cells, and monocytes in lungs as the potential main sources of elevated cytokines mediating systemic immune responses and organ damages. In addition, the transcriptomes of patient blood cells are characterized by distinct gene regulatory networks and alternative splicing events. Our study provides a panorama of the host responses in COVID-19, which may serve as the basis for developing further diagnostics and therapy.

BackgroundThe efficacy and safety of antithrombotic treatment with oral anticoagulants (OACs) in elderly patients with comorbidities of acute coronary syndrome (ACS) and atrial fibrillation (AF) are unclear.MethodsA cohort of hospitalized elderly patients (≥65 years of age) diagnosed with ACS and AF and treated with oral antithrombotic agents were consecutively recruited. Follow-up was performed for at least 1 year. Major adverse cardiac events (MACEs) were defined as a composite of all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, and systemic embolism. The safety outcomes of bleeding were defined according to the Bleeding Academic Research Consortium (BARC) criteria.ResultsA cohort of 548 eligible patients (76 ± 6.6 years) was analyzed. Compared to the patients with OAC treatment (n = 184, 33.6%), patients treated without OAC (n = 364, 66.4%) were older, had a lower prevalence of persistent AF and unstable angina (UA), and more often presented with paroxysmal AF, acute myocardial infarction (AMI), stent implantation and dual antiplatelet therapy (DAPT). Compared to the patients without OAC treatment (n = 364, 66.4%), patients treated with OAC (n = 184, 33.6%) had a lower risk of MACEs at both the 1-year (4.3 vs. 15.1%, adjusted HR: 0.34, 95% CI: 0.15–0.80, p = 0.014) and 5-year (17.5 vs. 48.4%, adjusted HR: 0.36, 95% CI: 0.19–0.67, p = 0.001) follow-up. No significant difference was observed for bleeding events of BARC ≥2 between the groups (8.0 vs. 9.0%, adjusted HR: 1.17, 95% CI: 0.58–2.34, p = 0.667). Compared with warfarin-treated patients, the non-vitamin K antagonist oral anticoagulant-treated patients had lower risks of all-cause mortality (2.1 vs. 9.5%, HR: 0.18, 95% CI: 0.03–0.98, p = 0.047) and bleeding events of BARC ≥ 3 (2.1 vs. 4.8%, HR: 0.14, 95% CI: 0.02–1.10, p = 0.062).ConclusionsAntithrombotic therapy with OACs in elderly patients with ACS and AF was associated with a lower risk of ischemic events without an increase in bleeding events. In real-world practice, the clinical awareness of anticoagulation treatments in elderly patients with ACS and AF needs to be strengthened.

Background Dysimmunity plays a key role in diabetes, especially type 1 diabetes mellitus. Islet-specific autoantibodies (ISAs) have been used as diagnostic markers for different phenotypic classifications of diabetes. This study was aimed to explore the relationships between ISA titers and the clinical characteristics of diabetic patients. Methods A total of 509 diabetic patients admitted to Department of Endocrinology and Metabolism at the Affiliated Hospital of Nantong University were recruited. Anthropometric parameters, serum biochemical index, glycosylated hemoglobin, urinary microalbumin/creatinine ratio, ISAs, fat mass, and islet β-cell function were measured. Multiple linear regression analysis was performed to identify relationships between ISA titers and clinical characteristics. Results Compared with autoantibody negative group, blood pressure, weight, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), visceral fat mass, fasting C-peptide (FCP), 120 minutes C-peptide (120minCP) and area under C-peptide curve (AUCCP) of patients in either autoantibody positive or glutamate decarboxylase antibody (GADA) positive group were lower. Body mass index (BMI), waist circumference, triglycerides (TGs), body fat mass of patients in either autoantibody positive group were lower than autoantibody negative group. GADA titer negatively correlated with TC, LDL-C, FCP, 120minCP, and AUCCP. The islet cell antibody and insulin autoantibody titers both negatively correlated with body weight, BMI, TC, TG, and LDL-C. After adjusting confounders, multiple linear regression analysis showed that LDL-C and FCP negatively correlated with GADA titer. Conclusion Diabetic patients with a high ISA titer, especially GADA titer, have worse islet β-cell function, but less abdominal obesity and fewer features of the metabolic syndrome.

Abstract Background Specific adaptive features including disease resistance and growth abilities in harsh environments are attributed to indigenous cattle breeds of Benin, but these breeds are endangered due to crossbreeding. So far, there is a lack of systematic trait recording, being the basis for breed characterizations, and for structured breeding program designs aiming on conservation. Bridging this gap, own phenotyping for morphological traits considered measurements for height at withers (HAW), sacrum height (SH), heart girth (HG), hip width (HW), body length (BL) and ear length (EL), including 449 cattle from the four indigenous Benin breeds Lagune, Somba, Borgou and Pabli. In order to utilize recent genomic tools for breed characterizations and genetic evaluations, phenotypes for novel traits were merged with high-density SNP marker data. Multi-breed genetic parameter estimations and genome-wide association studies (GWAS) for the six morphometric traits were carried out. Continuatively, we aimed on inferring genomic regions and functional loci potentially associated with conformation, carcass and adaptive traits. Results SNP-based heritability estimates for the morphometric traits ranged between 0.46 ± 0.14 (HG) and 0.74 ± 0.13 (HW). Phenotypic and genetic correlations ranged from 0.25 ± 0.05 (HW-BL) to 0.89 ± 0.01 (HAW-SH), and from 0.14 ± 0.10 (HW-BL) to 0.85 ± 0.02 (HAW-SH), respectively. Three genome-wide and 25 chromosome-wide significant SNP positioned on different chromosomes were detected, located in very close chromosomal distance (±25 kb) to 15 genes (or located within the genes). The genes PIK3R6 and PIK3R1 showed direct functional associations with height and body size. We inferred the potential candidate genes VEPH1, CNTNAP5, GYPC for conformation, growth and carcass traits including body weight and body fat deposition. According to their functional annotations, detected potential candidate genes were associated with stress or immune response (genes PTAFR, PBRM1, ADAMTS12) and with feed efficiency (genes MEGF11 SLC16A4, CCDC117). Conclusions Accurate measurements contributed to large SNP heritabilities for some morphological traits, even for a small mixed-breed sample size. Multi-breed GWAS detected different loci associated with conformation or carcass traits. The identified potential candidate genes for immune response or feed efficiency indicators reflect the evolutionary development and adaptability features of the breeds.

The Dwarf Lagune and the Savannah Somba cattle in Benin are typical representatives of the endangered West African indigenous Shorthorn taurine. The Lagune was previously exported to African and European countries and bred as Dahomey cattle, whereas the Somba contributed to the formation of two indigenous hybrids known as Borgou and Pabli cattle. These breeds are affected by demographic, economic, and environmental pressures in local production systems. Considering current and historical genomic data, we applied a formal test of admixture, estimated admixture proportions, and computed genomic inbreeding coefficients to characterize the five breeds. Subsequently, we unraveled the most recent selection signatures using the cross-population extended haplotype homozygosity approach, based on the current and historical genotypes. Results from principal component analyses and high proportion of Lagune ancestry confirm the Lagune origin of the European Dahomey cattle. Moreover, the Dahomey cattle displayed neither indicine nor European taurine (EUT) background, but they shared on average 40% of autozygosity from common ancestors, dated approximately eight generations ago. The Lagune cattle presented inbreeding coefficients larger than 0.13; however, the Somba and the hybrids (Borgou and Pabli) were less inbred (≤0.08). We detected evidence of admixture in the Somba and Lagune cattle, but they exhibited a similar African taurine (AFT) ancestral proportion (≥96%) to historical populations, respectively. A moderate and stable AFT ancestral proportion (62%) was also inferred for less admixed hybrid cattle including the Pabli. In contrast, the current Borgou samples displayed a lower AFT ancestral proportion (47%) than historical samples (63%). Irrespective of the admixture proportions, the hybrid populations displayed more selection signatures related to economic traits (reproduction, growth, and milk) than the taurine. In contrast, the taurine, especially the Somba, presented several regions known to be associated with adaptive traits (immunity and feed efficiency). The identified subregion of bovine leukocyte antigen (BoLA) class IIb (including DSB and BOLA-DYA) in Somba cattle is interestingly uncommon in other African breeds, suggesting further investigations to understand its association with specific adaptation to endemic diseases in Benin. Overall, our study provides deeper insights into recent evolutionary processes in the Beninese indigenous cattle and their aptitude for conservation and genetic improvement.

Purpose: Coronary artery disease (CAD) and atrial fibrillation (AF) often coexist and lead to a much higher risk of mortality in the elderly population. The aim of this study was to investigate whether the CHA2DS2-VASc score could predict the risk of death in elderly patients with CAD and AF.Methods: Hospitalized patients aged ≥65 years with a diagnosis of CAD and AF were recruited consecutively. Patients were divided into 5 groups according to the CHA2DS2-VASc score (≤2, =3, =4, =5, and ≥6). At least a 1-year follow-up was carried out for the assessment of all-cause death.Results: A total of 1,579 eligible patients were recruited, with 582 all-cause deaths (6.86 per 100 patient-years) occurring during a follow-up of at least 1 year. With the increase in the CHA2DS2-VASc score, the 1-year and 5-year survival rate decreased (96.4% vs. 95.7% vs. 94.0% vs. 86.5% vs. 85.7%, respectively, P < 0.001; 78.4% vs. 68.9% vs. 64.6% vs. 55.5% vs. 50.0%, respectively, P < 0.001). Compared with the patients with CHA2DS2-VASc score

A comprehensive study was conducted to assess the effects of seasonal transition and temperature humidity index (THI) on the adaptive responses in crossbred dairy cows reared in a tropical savanna region. A total of 40 lactating dairy cattle reared by small-scale dairy farmers in Bengaluru, India, were selected for this study. The research period comprised the transitioning season of summer to monsoon, wherein all traits were recorded at two points, one representing late summer (June) and the other early monsoon (July). A set of extensive variables representing physiological responses (pulse rate, respiration rate, rectal temperature, skin surface temperature), hematological responses (hematological profile), production (test day milk yield, milk composition) and molecular patterns (PBMC mRNA relative expression of selective stress response genes) were assessed. A significant effect of seasonal transition was identified on respiration rate (RR), skin surface temperature, mean platelet volume (MPV), platelet distribution width (PDWc), test day milk yield and on milk composition variables (milk density, lactose, solids-not-fat (SNF) and salts). The THI had a significant effect on RR, skin surface temperature, platelet count (PLT), plateletcrit (PCT) and PDWc. Lastly, THI and/or seasonal transition significantly affected the relative PBMC mRNA expression of heat shock protein 70 (HSP70), interferon beta (IFNβ), IFNγ, tumor necrosis factor alpha (TNFα), growth hormone (GH) and insulin-like growth factor-1 (IGF-1) genes. The results from this study reveal environmental sensitivity of novel physiological traits and gene expressions to climatic stressors, highlighting their potential as THI-independent heat stress biomarkers.

Abstract Background The mitochondrial genotype 5178 cytosine/adenine (5178 C > A) within the NADH dehydrogenase subunit-2 gene (ND2) was proved to associate with longevity and predispose resistance to adult-onset diseases. This study aimed to confirm the interactive effects between ND 25178 C > A and clinical risk factors on the susceptibility of essential hypertension in Chinese general population. Materials and Methods The relationship between the ND2 5178 C > A variation and the risk of hypertension was investigated in 817 hypertensives and 821 matched normotensives. The interactive effects between ND2 5178 C > A and clinical risk factors were evaluated. Results The ND2 5178 A allele was more frequent in normotensives than in hypertensives (32.64% vs. 24.24%; adjusted OR: 0.62, 95% CI: 0.49–0.79, P = 1.3 × 10− 4). After stratification, the significant association between ND2 5178 C > A and hypertension was found only in current smokers (OR: 0.44, 95% CI: 0.31–0.62), but not in non-current smokers (p

Abstract Background Gastrointestinal nematodes (GIN), liver flukes (Fasciola hepatica) and bovine lungworms (Dictyocaulus viviparus) are the most important parasitic agents in pastured dairy cattle. Endoparasite infections are associated with reduced milk production and detrimental impacts on female fertility, contributing to economic losses in affected farms. In quantitative-genetic studies, the heritabilities for GIN and F. hepatica were moderate, encouraging studies on genomic scales. Genome-wide association studies (GWAS) based on dense single nucleotide polymorphism (SNP) marker panels allow exploration of the underlying genomic architecture of complex disease traits. The current GWAS combined the identification of potential candidate genes with pathway analyses to obtain deeper insights into bovine immune response and the mechanisms of resistance against endoparasite infections. Results A 2-step approach was applied to infer genome-wide associations in an endangered dual-purpose cattle subpopulation [Deutsches Schwarzbuntes Niederungsrind (DSN)] with a limited number of phenotypic records. First, endoparasite traits from a population of 1166 Black and White dairy cows [including Holstein Friesian (HF) and DSN] naturally infected with GIN, F. hepatica and D. viviparus were precorrected for fixed effects using linear mixed models. Afterwards, the precorrected phenotypes were the dependent traits (rFEC-GIN, rFEC-FH, and rFLC-DV) in GWAS based on 423,654 SNPs from 148 DSN cows. We identified 44 SNPs above the genome-wide significance threshold (p Bonf = 4.47 × 10− 7), and 145 associations surpassed the chromosome-wide significance threshold (range: 7.47 × 10− 6 on BTA 1 to 2.18 × 10− 5 on BTA 28). The associated SNPs identified were annotated to 23 candidate genes. The DAVID analysis inferred four pathways as being related to immune response mechanisms or involved in host-parasite interactions. SNP effect correlations considering specific chromosome segments indicate that breeding for resistance to GIN or F. hepatica as measured by fecal egg counts is genetically associated with a higher risk for udder infections. Conclusions We detected a large number of loci with small to moderate effects for endoparasite resistance. The potential candidate genes regulating resistance identified were pathogen-specific. Genetic antagonistic associations between disease resistance and productivity were specific for specific chromosome segments. The 2-step approach was a valid methodological approach to infer genetic mechanisms in an endangered breed with a limited number of phenotypic records.

Abstract Background Body weight (BW) at different ages are of increasing importance in dairy cattle breeding schemes, because of their strong correlation with energy efficiency traits, and their impact on cow health, longevity and farm economy. In total, 15,921 dairy cattle from 56 large-scale test-herds with BW records were genotyped for 45,613 single nucleotide polymorphisms (SNPs). This dataset was used for genome-wide association studies (GWAS), in order to localize potential candidate genes for direct and maternal genetic effects on BW recorded at birth (BW0), at 2 to 3 months of age (BW23), and at 13 to 14 months of age (BW1314). Results The first 20 principal components (PC) of the genomic relationship matrix ($${\mathbf{G}}$$ G ) grouped the genotyped cattle into three clusters. In the statistical models used for GWAS, correction for population structure was done by including polygenic effects with various genetic similarity matrices, such as the pedigree-based relationship matrix ($${\mathbf{A}}$$ A ), the $${\mathbf{G}}$$ G -matrix, the reduced $${\mathbf{G}}$$ G -matrix LOCO (i.e. exclusion of the chromosome on which the candidate SNP is located), and LOCO plus chromosome-wide PC. Inflation factors for direct genetic effects using $${\mathbf{A}}$$ A and LOCO were larger than 1.17. For $${\mathbf{G}}$$ G and LOCO plus chromosome-wide PC, inflation factors were very close to 1.0. According to Bonferroni correction, ten, two and seven significant SNPs were detected for the direct genetic effect on BW0, BW23, and BW1314, respectively. Seventy-six candidate genes contributed to direct genetic effects on BW with four involved in growth and developmental processes: FGF6, FGF23, TNNT3, and OMD. For maternal genetic effects on BW0, only three significant SNPs (according to Bonferroni correction), and four potential candidate genes, were identified. The most significant SNP on chromosome 19 explained only 0.14% of the maternal de-regressed proof variance for BW0. Conclusions For correction of population structure in GWAS, we suggest a statistical model that considers LOCO plus chromosome-wide PC. Regarding direct genetic effects, several SNPs had a significant effect on BW at different ages, and only two SNPs on chromosome 5 had a significant effect on all three BW traits. Thus, different potential candidate genes regulate BW at different ages. Maternal genetic effects followed an infinitesimal model.

Abstract Background Treatment of hemophiliacs with inhibitors remains challenging, and new treatments are in urgent need. Coagulation factor X plays a critical role in the downstream of blood coagulation cascade, which could serve as a bypassing agent for hemophilia therapy. Base on platelet‐targeted gene therapy for hemophilia by our and other groups, we hypothesized that activated factor X (FXa) targeted stored in platelets might be effective in treating hemophilia A (HA) and B (HB) with or without inhibitors. Methods To achieve the storage of FXa in platelets, we constructed a FXa precursor and used the integrin αIIb promoter to control the targeted expression of FXa precursor in platelets. The expression cassette (2bFXa) was carried by lentivirus and introduced into mouse hematopoietic stem and progenitor cells (HSPCs), which were then transplanted into HA and HB mice. FXa expression and storage in platelets was examined in vitro and in vivo. We evaluated the therapeutic efficacy of platelet‐stored FXa by tail bleeding assays and the thrombelastography. In addition, thrombotic risk was assessed in the recipient mice and the lipopolysaccharide induced inflammation mice. Results By transplanting 2bFXa lentivirus‐transduced HSPCs into HA and HB mice, FXa was observed stably stored in platelet α‐granules, the stored FXa is releasable and functional upon platelet activation. The platelet‐stored FXa can significantly ameliorate bleeding phenotype in HA and HB mice as well as the mice with inhibitors. Meanwhile, no FXa leakage in plasma and no signs of increased risk of hypercoagulability were found in transplantation recipients and lipopolysaccharide induced septicemia recipients. Conclusions Our proof‐of‐principle data indicated that target expression of the FXa precursor to platelets can generate a storage pool of FXa in platelet α‐granules, the platelet‐stored FXa is effective in treating HA and HB with inhibitors, suggesting that this could be a novel choice for hemophilia patients with inhibitors.

Background. This study aimed to analyse the role of the HAS-BLED score with the addition of genotype bins for bleeding risk prediction in warfarin-treated patients with atrial fibrillation (AF). Methods and Results. Consecutive patients with AF on initial warfarin treatment were recruited. For each patient, CYP2C9∗3 and VKORC1-1639 A/G genotyping was performed to create 3 genotype functional bins. The predictive values of the HAS-BLED score with or without the addition of genotype bins were compared. According to the carrier status of the genotype bins, the numbers of normal, sensitive, and highly sensitive responders among 526 patients were 64 (12.17%), 422 (80.23%), and 40 (7.60%), respectively. A highly sensitive response was independently associated with clinically relevant bleeding (HR: 3.85, 95% CI: 1.88–7.91, P=0.001) and major bleeding (HR:3.75, 95% CI: 1.17–11.97, P=0.03). With the addition of genotype bins, the performance of the HAS-BLED score for bleeding risk prediction was significantly improved (c-statistic from 0.60 to 0.64 for clinically relevant bleeding and from 0.64 to 0.70 for major bleeding, P

The aim of this study was to estimate genotype by time-lagged heat stress (HS) variance components as well as main and interaction SNP-marker effects for maternal HS during the last eight weeks of cow pregnancy, considering milk production traits recorded in the offspring generation. The HS indicator was the temperature humidity index (THI) for each week. A dummy variable with the code = 1 for the respective week for THI ≥ 60 indicated HS, otherwise, for no HS, the code = 0 was assigned. The dataset included test-day and lactation production traits from 14,188 genotyped first parity Holstein cows. After genotype quality control, 41,139 SNP markers remained for the genomic analyses. Genomic animal models without (model VC_nHS) and with in-utero HS effects (model VC_wHS) were applied to estimate variance components. Accordingly, for genome-wide associations, models GWA_nHS and GWA_wHS, respectively, were applied to estimate main and interaction SNP effects. Common genomic and residual variances for the same traits were very similar from models VC_nHS and VC_wHS. Genotype by HS interaction variances varied, depending on the week with in-utero HS. Among all traits, lactation milk yield with HS from week 5 displayed the largest proportion for interaction variances (0.07). For main effects from model GWA_wHS, 380 SNPs were suggestively associated with all production traits. For the SNP interaction effects from model GWA_wHS, we identified 31 suggestive SNPs, which were located in close distance to 62 potential candidate genes. The inferred candidate genes have various biological functions, including mechanisms of immune response, growth processes and disease resistance. Two biological processes excessively represented in the overrepresentation tests addressed lymphocyte and monocyte chemotaxis, ultimately affecting immune response. The modelling approach considering time-lagged genotype by HS interactions for production traits inferred physiological mechanisms being associated with health and immunity, enabling improvements in selection of robust animals.

In China, most normal BMI (body mass index of ≥18.5 to

Compost-bedded pack barns (CBP) are of increasing interest in dairy farming due to their positive effect on animal welfare. The temperature and the moisture content of the bedding material characterising the composting process can promote the growth of thermophilic aerobic sporeformers (TAS). Therefore, the aim of this study was to determine CBP bedding material characteristics, such as moisture content and temperature, and to determine TAS species. The dilution, the heat inactivation of all non-TAS species and the incubation of 13 bedding samples from four CBP groups resulted in a mean TAS amount over all samples of 4.11 log10 cfu/g bedding material. Based on the subsequent sequencing of parts of the 16S rRNA-gene of 99 TAS colonies, the TAS species Aneurinibacillus thermoaerophilus, Bacillus licheniformis, Geobacillus thermodenitrificans, Laceyella sacchari, Thermoactinomyces vulgaris and Ureibacillus thermosphaericus were identified. The moisture content of the bedding material, the relative humidity above the bedding material and the sampling season significantly affected the amount of TAS. The moisture content or relative humidity above the bedding material significantly influenced the concentration of Ureibacillus thermophaericus or Laceyella sacchari. Consequently, an optimal CBP management including a dry lying surface and an optimal composting process will contribute to a moderate microbial, especially TAS amount, and TAS species distribution.

Despite the protracted battle against coronavirus acute respiratory infection (COVID-19) and the rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), no specific and effective drugs have to date been reported. Angiotensin-converting enzyme 2 (ACE2) is a zinc metalloproteinase and a critical modulator of the renin-angiotensin system (RAS). In addition, ACE2 has anti-inflammatory and antifibrosis functions. ACE has become widely known in the past decade as it has been identified as the primary receptor for SARS-CoV and SARS-CoV-2, being closely associated with their infection. SARS-CoV-2 primarily targets the lung, which induces a cytokine storm by infecting alveolar cells, resulting in tissue damage and eventually severe acute respiratory syndrome. In the lung, innate immunity acts as a critical line of defense against pathogens, including SARS-CoV-2. This review aims to summarize the regulation of ACE2, and lung host cells resist SARS-CoV-2 invasion by activating innate immunity response. Finally, we discuss ACE2 as a therapeutic target, providing reference and enlightenment for the clinical treatment of COVID-19.

Tuberculosis, caused by the pathogen Mycobacterium tuberculosis, is a serious infectious disease worldwide. Multidrug-resistant TB (MDR-TB) remains a global problem, and the understanding of this resistance is incomplete. Studies suggested that DNA methylation promotes bacterial adaptability to antibiotic treatment, but the role of mycobacterial HsdM in drug susceptibility has not been explored. Here, we constructed an inactivated Mycobacterium bovis (BCG) strain, ΔhsdM. ΔhsdM shows growth advantages over wild-type BCG under isoniazid treatment and hypoxia-induced stress. Using high-precision PacBio single-molecule real-time sequencing to compare the ΔhsdM and BCG methylomes, we identified 219 methylated HsdM substrates. Bioinformatics analysis showed that most HsdM-modified genes were enriched in respiration- and energy-related pathways. qPCR showed that HsdM-modified genes directly affected their own transcription, indicating an altered redox regulation. The use of the latent Wayne model revealed that ΔhsdM had growth advantages over wild-type BCG and that HsdM regulated trcR mRNA levels, which may be crucial in regulating transition from latency to reactivation. We found that HsdM regulated corresponding transcription levels via gene methylation; thus, altering the mycobacterial redox status and decreasing the bacterial susceptibility to isoniazid, which is closely correlated with the redox status. Our results provide valuable insight into DNA methylation on drug susceptibility.

The aim of the present study was to detect significant SNP (single-nucleotide polymorphism) effects and to annotate potential candidate genes for novel udder health traits in two different farming systems. We focused on specific mastitis pathogens and differential somatic cell fractions from 2198 udder quarters of 537 genotyped Holstein Friesian cows. The farming systems comprised compost-bedded pack and conventional cubicle barns. We developed a computer algorithm for genome-wide association studies allowing the estimation of main SNP effects plus consideration of SNPs by farming system interactions. With regard to the main effect, 35 significant SNPs were detected on 14 different chromosomes for the cell fractions and the pathogens. Six SNPs were significant for the interaction effect with the farming system for most of the udder health traits. We inferred two possible candidate genes based on significant SNP interactions. HEMK1 plays a role in the development of the immune system, depending on environmental stressors. CHL1 is regulated in relation to stress level and influences immune system mechanisms. The significant interactions indicate that gene activity can fluctuate depending on environmental stressors. Phenotypically, the prevalence of mastitis indicators differed between systems, with a notably lower prevalence of minor bacterial indicators in compost systems.

AD converter is one of the core components in the signal acquisition system. The quality of the signal acquisition system is mainly determined by its internal analogue-to-digital converter (ADC) characteristics. However, because of the non-linearity of the ADC itself, the dynamic acquisition range of the ADC is greatly affected. Here, the broadband dither technique in the signal acquisition process is studied. Dither signals are added to the input signal to increase the dynamic acquisition range of ADC. Here, the dithering process was first simulated through Simulink and subsequently an FPGA-based broadband dithering module experiment platform was built. The process of signal dithering was implemented. The data were analysed with Simulink and the Spurious Free Dynamic Range (SFDR) of the ADC is obtained. The broadband dither signal can randomise the harmonic distortion phenomenon, verifying that the dithering technique can improve the SFDR of ADC.

Basic bovine behavior is a crucial parameter influencing cattle domestication. In addition, behavior has an impact on cattle productivity, welfare and adaptation. The aim of the present study was to infer quantitative genetic and genomic mechanisms contributing to natural dual-purpose cow behavior in grazing systems. In this regard, we genotyped five dual-purpose breeds for a dense SNP marker panel from four different European countries. All cows from the across-country study were equipped with the same electronic recording devices. In this regard, we analyzed 97,049 longitudinal sensor behavior observations from 319 local dual-purpose cows for rumination, feeding, basic activity, high active, not active and ear temperature. According to the specific sensor behaviors and following a welfare protocol, we computed two different welfare indices. For genomic breed characterizations and multi-breed genome-wide association studies, sensor traits and test-day production records were merged with 35,826 SNP markers per cow. For the estimation of variance components, we used the pedigree relationship matrix and a combined similarity matrix that simultaneously included both pedigree and genotypes. Heritabilities for feeding, high active and not active were in a moderate range from 0.16 to 0.20. Estimates were very similar from both relationship matrix-modeling approaches and had quite small standard errors. Heritabilities for the remaining sensor traits (feeding, basic activity, ear temperature) and welfare indices were lower than 0.09. Five significant SNPs on chromosomes 11, 17, 27 and 29 were associated with rumination, and two different SNPs significantly influenced the sensor traits "not active" (chromosome 13) and "feeding" (chromosome 23). Gene annotation analyses inferred 22 potential candidate genes with a false discovery rate lower than 20%, mostly associated with rumination (13 genes) and feeding (8 genes). Mendelian randomization based on genomic variants (i.e., the instrumental variables) was used to infer causal inference between an exposure and an outcome. Significant regression coefficients among behavior traits indicate that all specific behavioral mechanisms contribute to similar physiological processes. The regression coefficients of rumination and feeding on milk yield were 0.10 kg/% and 0.12 kg/%, respectively, indicating their positive influence on dual-purpose cow productivity. Genomically, an improved welfare behavior of grazing cattle, i.e., a higher score for welfare indices, was significantly associated with increased fat and protein percentages.

Research has shown that digestion of A1 β-casein (β-CN) affects gastrointestinal motility and opioid activity through the release of the peptide β-casomorphin-7 (β-CM7). In the case of the A2 variant, the cleavage of β-CM7 does not occur or occurs at a very low rate. Therefore, the aim of the study was to compare the effects of milk containing either homozygote A1 or A2 β-CN on health and growth parameters of dairy calves. Forty-seven neonatal calves (24 females, 23 males) of the breeds German Holstein (GH, n = 9), German Simmental (GS, n = 33) and their crossing (GH × GS, n = 5) were used in a 21-day feeding study. Fecal score (FS), respiratory frequency (RF), and rectal body temperature (BT) were recorded daily, whereas body weight was measured at birth and at day 21 to estimate the average daily weight gain (ADG). Additionally, blood was collected from calves three times during the experimental period and, for the first time, the respective plasma samples were analyzed for intact β-CM7. Consumption of A2-milk led to a lower daily milk intake (dMI) (p < 0.05). Furthermore, fecal consistency was softer for calves fed A2-milk (p < 0.05). Although 44% of A2-calves had diarrhea or revealed a tendency towards it (FS ≥ 3), A1-calves had a prevalence of 21%. Calves with a FS of 4 were offered an electrolyte solution and received a dietary food supplement for the stabilization of the fluid and electrolyte balance. Nevertheless, similar ADG and end weights (EW) of calves fed A1- or A2-milk (p > 0.05) indicate that A2-milk may compensate higher diarrhea rates and lower dMI due to the associated higher protein content. This is the first report of intact β-CM7 in plasma of calves fed milk of either A1 or A2 β-CN. Evidence from this study suggests that due to the change in the amino-acid sequence, A2-milk might be able to prevent or, at least, to minimize the cleavage of β-CM7 in calves.

Greenhouse gas emissions from livestock farming and in particular enteric methane (CH4) from ruminants are criticized for being one of the main contributors to climate change. Different breeding, feeding and management strategies are tested to decrease these emissions, but a status quo analysis is also relevant to implement such measures. The present study aimed to analyze the concentration of CH4 in air exhaled by dairy cows along a rural-urban gradient of Bangalore, India. Urban, mixed and rural areas were defined based on a survey stratification index (SSI) comprising build-up density and distance to the city center. Using a laser methane detector (LMD), CH4 concentration was determined in 2-min spot measurements of exhaled air of 448 cows at three equally spaced visits between June 2017 and April 2018. Mean, maximum and CH4 concentration per duration of the overall measurement, eructation and respiration bouts were calculated. For the overall mean and respiration bouts, CH4 concentration was higher in cows from urban areas, which had also higher milk yield than cows from mixed and rural areas. Although no differences were found in terms of the intake level of fibrous diet components, the type of measurement location (indoor, half-outdoor or outdoor) and pasture access had an impact on CH4 concentration. To our knowledge, this is the first study using the LMD on-farm and in an urbanizing environment. The LMD measurements show variations in enteric CH4 emissions along the rural-urban gradient of Bangalore that reflect differences in dairy husbandry systems governed by the social-ecological context.

Constructing deeply-buried stormwater sewage and storage tunnels is an effective method to mitigate the waterlogging and sewer overflow problems in modern cities. Prior to construction of such tunnels, a structural loading test is essential for acquiring the mechanical responses under complex loading conditions, such as cyclic inner hydraulic head, during which capturing the full-ring deformation of the tunnel lining is significant for a comprehensive understanding of the tunnel’s mechanical behaviors. This paper introduces the application of terrestrial laser scanning (TLS) technology in the full-scale structural loading tests of a large stormwater sewage and storage tunnel, which gives the full-ring deformation throughout the tests. A data processing methodology was developed to extract the key data points of the lining segments from the original data cloud by removing noise points and mitigating data jump, based on which the deformation of testing the lining segments at arbitrary locations can be calculated. Furthermore, a post-processing software was developed to visualize the full-ring deformation. The full-ring deformation at different loading conditions and its evolution under cyclic loading were captured. It is shown that the lining’s convergence deformation is more sensitive to the inner hydraulic head than to the external soil-water pressure, and the deformation cannot fully recover in a water-inflow-and-drainage cycle due to the presence of joints.

Tunneling in highly permeable ground using a slurry shield machine can be challenging because it is difficult to form the so-called filter cake on the tunnel face to transport the support pressure. Consequently, destructive accidents might happen, such as face instability and water inrush. How to form an efficient filter cake in time is crucial during engineering practice, especially in ground with high permeability. Various theoretical and experimental analyses regarding the formation of filter cakes have been conducted. However, due to the complexity of this problem, which has to incorporate the mechanical and hydraulic behaviors of the fluid–solid mixture system, few numerical simulations are found in the literature. In this paper, with the aid of a newly developed numerical tool, a coupled CFD (computational fluid dynamics)–DEM (discrete element method) simulation is established to study the slurry infiltration and filter cake formation during slurry shield tunneling. The slurry infiltration process is simulated by modelling the scheme of the infiltration column test, in which sedimentation behaviors of slurry particles are captured and compared with experimental results. The results show that the sedimentation behaviors of the slurry particles and filter cake formation phenomenon are well captured by simulations and in accordance with the experiments, which indicates the robustness of the coupled CFD–DEM simulation used in present work.