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The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis‐induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single‐cell RNA sequencing (scRNA‐seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis‐associated ARDS and is positively correlated with disease severity. Mechanically, scRNA‐seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta‐1 (KPNB1), promoting abluminal‐to‐luminal neutrophil rTEM. Additionally, EC‐derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC‐derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis‐associated lung injury. [ABSTRACT FROM AUTHOR]

Simple Summary: Heat stress during pregnancy can negatively affect the intrauterine environment, compromising fetal development and resulting in long-term physiological and structural changes that impact the postnatal outcomes of the offspring. The aim of this retrospective longitudinal study was to identify how exposure to summer season at different trimesters of intrauterine development and dam parity affect postpartum disease incidence, milk production, and herd lifespan of the offspring (F1 generation) of Holstein cows. Our preliminary findings confirmed less milk production capacity and greater culling risk in offspring experiencing the summer season during the first trimester of their intrauterine development than those during later stages. Daughters born to nulliparous dams had a lower risk of dystocia and metritis, a higher risk of retained placenta, and were more likely to remain in the herd than those born to parous dams. Minimizing summer heat exposure during the early intrauterine development of offspring through implementing heat-abatement strategies may help alleviate the risk of future production losses. A suboptimal intrauterine environment during gestation may result in the programming of long-lasting structural and physiological alterations in the developing fetus, leading to health and production complications in adulthood. This observational study aimed to identify the impact of exposure to the summer season at different trimesters of gestation, dam parity, and their interaction on the postpartum disease incidence, first-lactation milk production, and herd lifespan of the offspring (F1 generation). Using a dataset collected from two commercial herds, the female offspring were categorized into three groups based on the trimester their dams experienced summer season during pregnancy: (1) first trimester (n = 2345), (2) second trimester (n = 3513), and (3) final trimester (n = 4988). The estimated 305-day milk production was lower in daughters (as a first-lactation cow) born to dams exposed to summer season during the first vs. third trimester. Summer season exposure during the first vs. third trimester resulted in the offspring that were less likely to remain in the herd (hazard ratio = 0.90; 95% CI = 0.84–0.95). Daughters of parous vs. nulliparous dams were more likely to experience dystocia and metritis but less likely to experience retained placenta. The risk of culling was higher in daughters of parous vs. nulliparous dams. Our preliminary findings suggest that the first trimester is a critical determinant of the female progeny's future productive performance and survivability. Dam parity was also identified as an influential factor affecting offspring health, as dystocia and metritis were more prevalent, and the culling risk was greater in daughters born to parous dams. [ABSTRACT FROM AUTHOR]

The economic significance of ruminants in agriculture underscores the need for advanced research methodologies to enhance their traits. This review aims to elucidate the transformative role of pan-omics technologies in ruminant research, focusing on their application in uncovering the genetic mechanisms underlying complex traits such as growth, reproduction, production performance, and rumen function. Pan-omics analysis not only helps in identifying key genes and their regulatory networks associated with important economic traits but also reveals the impact of environmental factors on trait expression. By integrating genomics, epigenomics, transcriptomics, metabolomics, and microbiomics, pan-omics enables a comprehensive analysis of the interplay between genetics and environmental factors, offering a holistic understanding of trait expression. We explore specific examples of economic traits where these technologies have been pivotal, highlighting key genes and regulatory networks identified through pan-omics approaches. Additionally, we trace the historical evolution of each omics field, detailing their progression from foundational discoveries to high-throughput platforms. This review provides a critical synthesis of recent advancements, offering new insights and practical recommendations for the application of pan-omics in the ruminant industry. The broader implications for modern animal husbandry are discussed, emphasizing the potential for these technologies to drive sustainable improvements in ruminant production systems. [ABSTRACT FROM AUTHOR]

Introduction: Low body weight in patients with COPD is associated with a poor prognosis and more comorbidities. However, the impact of increased body weight in patients with COPD remains controversial. The aim of this study was to explore the clinical features of overweight patients with AECOPD. Methods: In this multicenter cross‐sectional study, a total of 647 AECOPD patients were recruited. Finally, 269 normal weight and 162 overweight patients were included. Baseline characteristics and clinical and laboratory data were collected. The least absolute shrinkage and selection operator (LASSO) regression was performed to determine potential features, which were substituted into binary logistic regression to reveal overweight‐associated clinical features. The nomogram and its associated curves were established to visualize and verify the logistic regression model. Results: Six potential overweight‐associated variables were selected by LASSO regression. Subsequently, a binary logistic regression model identified that the rates of type 2 diabetes (T2DM) and hypertension and levels of lymphocytes (LYM)%, and alanine aminotransferase (ALT) were independent variables of overweight in AECOPD patients. The C‐index and AUC of the ROC curve of the nomogram were 0.671 and 0.666, respectively. The DCA curve revealed that the nomogram had more clinical benefits if the threshold was at a range of 0.22~0.78. Conclusions: Collectively, we revealed that T2DM and hypertension were more common, and LYM% and ALT were higher in AECOPD patients with overweight than those with normal weight. The result suggests that AECOPD patients with overweight are at risk for additional comorbidities, potentially leading to worse outcomes. [ABSTRACT FROM AUTHOR]

Growing evidence shows that maternal nutrition from preconception until lactation has an important effect on the development of non-communicable diseases in the offspring. Biological responses to environmental stress during pregnancy, including undernutrition or overnutrition of various nutrients, are transmitted in part by DNA methylation. The aim of the present narrative review is to summarize literature data on altered DNA methylation patterns caused by maternal macronutrient or vitamin intake and its association with offspring's phenotype (obesity and related metabolic changes). With our literature search, we found evidence for the association between alterations in DNA methylation pattern of different genes caused by maternal under- or overnutrition of several nutrients (protein, fructose, fat, vitamin D, methyl-group donor nutrients) during 3 critical periods of programming (preconception, pregnancy, lactation) and the development of obesity or related metabolic changes (glucose, insulin, lipid, leptin, adiponectin levels, blood pressure, non-alcoholic fatty liver disease) in offspring. The review highlights that maternal consumption of several nutrients could individually affect the development of offspring's obesity and related metabolic changes via alterations in DNA methylation. [ABSTRACT FROM AUTHOR]

Simple Summary: The study examines how different prenatal nutrition plans affect muscle development and epigenetic mechanisms in Nellore cows' offspring. It looks at 63 male calves from cows given no supplementation (NP), partial supplementation (PP), or full supplementation (CP) during pregnancy. RNA sequencing showed no difference in epigenetic mechanisms, but did reveal 1823 transcripts at 15 months and 1533 at 22 months. Among these, a few showed differences between groups. Interestingly, while maternal nutrition didn't affect epigenetic mechanisms directly, it seemed to influence how certain RNA molecules regulated them. Maternal nutrition has the ability of influence critical processes in fetal life, including muscle development. Also, in this period, epigenetic sensitivity to external stimuli is higher and produces long-lasting effects. Thus, the aim of this study was to investigate epigenetic mechanisms, including the identification and characterization of long non-coding RNA (lncRNA) from animals that had undergone different strategies of prenatal supplementation. A group of Nellore cows (n = 126) were separated into three nutritional plans: NP (control)—Not Programmed, without protein–energy supplementation; PP—Partially Programmed, protein–energy supplementation in the final third of pregnancy; and CP—Complete Programming, protein–energy supplementation during the full period of gestation. A total of 63 male offspring were used in this study, of which 15 (5 per treatment) had Longissimus thoracis muscle at 15 (biopsy) and 22 months (slaughter). Biopsy samples were subjected to RNA extraction and sequencing. Differential expression (DE) of remodeling factors and chromatin-modifying enzyme genes were performed. For the identification and characterization of lncRNA, a series of size filters and protein coding potential tests were performed. The lncRNAs identified had their differential expression and regulatory potential tested. Regarding DE of epigenetic mechanisms, no differentially expressed gene was found (p > 0.1). Identification of potential lncRNA was successful, identifying 1823 transcripts at 15 months and 1533 at 22 months. Among these, four were considered differentially expressed between treatments at 15 months and 6 were differentially expressed at 22 months. Yet, when testing regulatory potential, 13 lncRNAs were considered key regulators in the PP group, and 17 in the CP group. PP group lncRNAs possibly regulate fat-cell differentiation, in utero embryonic development, and transforming growth factor beta receptor, whereas lncRNA in the CP group regulates in utero embryonic development, fat-cell differentiation and vasculogenesis. Maternal nutrition had no effect on differential expression of epigenetic mechanisms; however, it seems to impair lncRNA regulation of epigenetics. [ABSTRACT FROM AUTHOR]

Early embryonic mortality is a major cause of infertility in cattle, yet the underlying molecular causes remain a mystery. Over the past half century, assisted reproductive technologies such as in vitro fertilisation and somatic cell nuclear transfer have been used to improve cattle reproductive efficiency; however, reduced embryo developmental potential is seen compared to their in vivo counterparts. Recent years have seen exciting progress across bovine embryo research, including genomic profiling of embryogenesis, new methods for improving embryo competence, and experimenting on building bovine embryos from stem cell cultures. These advances are beginning to define bovine embryo molecular and cellular programs and could potentially lead to improved embryo health. Here, I highlight the current status of molecular determinants and cellular programs of bovine embryo development and new opportunities to improve the bovine embryo health. This mini-review highlights the current status of genomic characterisations of bovine pre-implantation embryo development, programming bovine embryo health with early life interventions, as well as building bovine embryos from stem cell cultures. [ABSTRACT FROM AUTHOR]

Background: Early introduction of palliative care can improve patient-centered outcomes for older adults with complex medical conditions. However, identifying the need for and introducing palliative care with patients and caregivers is often difficult. We aim to identify how and why a multi-setting approach to palliative care discussions may improve the identification of palliative care needs and how to facilitate these conversations. Methods: Descriptive qualitative study to inform the development and future pilot testing of a model to improve recognition of, and support for, unmet palliative care needs in home health care (HHC). Thematic analysis of semi-structured interviews with providers across inpatient (n = 11), primary care (n = 17), and HHC settings (n = 10). Results: Four key themes emerged: 1) providers across settings can identify palliative care needs using their unique perspectives of the patient's care, 2) identifying palliative care needs is challenging due to infrequent communication and lack of shared information between providers, 3) importance of identifying a clinical lead of patient care who will direct palliative care discussions (primary care provider), and 4) importance of identifying a care coordination lead (HHC) to bridge communication among multi-setting providers. These themes highlight a multi-setting approach that would improve the frequency and quality of palliative care discussions. Conclusions: A lack of structured communication across settings is a major barrier to introducing and providing palliative care. A novel model that improves communication and coordination of palliative care across HHC, inpatient and primary care providers may facilitate identifying and addressing palliative care needs in medically complex older adults. [ABSTRACT FROM AUTHOR]

A digital platform that can rapidly and accurately diagnose pathogenic viral variants, including SARS-CoV-2, will minimize pandemics, public anxiety, and economic losses. We recently reported an artificial intelligence (AI)-nanopore platform that enables testing for Wuhan SARS-CoV-2 with high sensitivity and specificity within five minutes. However, which parts of the virus are recognized by the platform are unknown. Similarly, whether the platform can detect SARS-CoV-2 variants or the presence of the virus in clinical samples needs further study. Here, we demonstrated the platform can distinguish SARS-CoV-2 variants. Further, it identified mutated Wuhan SARS-CoV-2 expressing spike proteins of the delta and omicron variants, indicating it discriminates spike proteins. Finally, we used the platform to identify omicron variants with a sensitivity and specificity of 100% and 94%, respectively, in saliva specimens from COVID-19 patients. Thus, our results demonstrate the AI-nanopore platform is an effective diagnostic tool for SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]

Stroke is one of the most common causes of disability, and there are few treatments that can improve recovery after stroke. Therapeutic development has been hindered because of a lack of understanding of precisely how neural circuits are affected by stroke, and how these circuits change to mediate recovery. Indeed, some of the hypotheses for how the CNS changes to mediate recovery, including remapping, redundancy, and diaschisis, date to more than a century ago. Recent technological advances have enabled the interrogation of neural circuits with ever greater temporal and spatial resolution. These techniques are increasingly being applied across animal models of stroke and to human stroke survivors, and are shedding light on the molecular, structural, and functional changes that neural circuits undergo after stroke. Here we review these studies and highlight important mechanisms that underlie impairment and recovery after stroke. We begin by summarizing knowledge about changes in neural activity that occur in the peri-infarct cortex, specifically considering evidence for the functional remapping hypothesis of recovery. Next, we describe the importance of neural population dynamics, disruptions in these dynamics after stroke, and how allocation of neurons into spared circuits can restore functionality. On a more global scale, we then discuss how effects on long-range pathways, including interhemispheric interactions and corticospinal tract transmission, contribute to post-stroke impairments. Finally, we look forward and consider how a deeper understanding of neural circuit mechanisms of recovery may lead to novel treatments to reduce disability and improve recovery after stroke. [ABSTRACT FROM AUTHOR]

Background: COVID-19 pandemic has caused more than 6 million deaths worldwide. Co-morbid conditions such as Type 2 Diabetes (T2D) have increased mortality in COVID-19. With limited translatability of in vitro and small animal models to human disease, human organ-on-a-chip models are an attractive platform to model in vivo disease conditions and test potential therapeutics. Methods: T2D or non-diabetic patient-derived macrophages and human liver sinusoidal endothelial cells were seeded, along with normal hepatocytes and stellate cells in the liver-on-a-chip (LAMPS – liver acinus micro physiological system), perfused with media mimicking non-diabetic fasting or T2D (high levels of glucose, fatty acids, insulin, glucagon) states. The macrophages and endothelial cells were transduced to overexpress the SARS-CoV2-S (spike) protein with appropriate controls before their incorporation into LAMPS. Cytokine concentrations in the efflux served as a read-out of the effects of S-protein expression in the different experimental conditions (non-diabetic-LAMPS, T2D-LAMPS), including incubation with tocilizumab, an FDA-approved drug for severe COVID-19. Findings: S-protein expression in the non-diabetic LAMPS led to increased cytokines, but in the T2D-LAMPS, this was significantly amplified both in the number and magnitude of key pro-inflammatory cytokines (IL6, CCL3, IL1β, IL2, TNFα, etc.) involved in cytokine storm syndrome (CSS), mimicking severe COVID-19 infection in T2D patients. Compared to vehicle control, tocilizumab (IL6-receptor antagonist) decreased the pro-inflammatory cytokine secretion in T2D-COVID-19-LAMPS but not in non-diabetic-COVID-19-LAMPS. Interpretation: macrophages and endothelial cells play a synergistic role in the pathophysiology of the hyper-inflammatory response seen with COVID-19 and T2D. The effect of Tocilizumab was consistent with large clinical trials that demonstrated Tocilizumab's efficacy only in critically ill patients with severe disease, providing confirmatory evidence that the T2D-COVID-19-LAMPS is a robust platform to model human in vivo pathophysiology of COVID-19 in T2D and for screening potential therapeutics. [ABSTRACT FROM AUTHOR]

Background: The management and care of older patients with multiple health problems is demanding and complex. Interprofessional and intraprofessional collaboration has the potential to improve both the efficiency and the quality of care for these patients. However, it has proven difficult to demonstrate the efficacy of this approach in terms of objective patient-related outcomes. Recently, a care model with interprofessional and intraprofessional care was started, the Intensive Collaboration Ward (ICW). This ward combines interprofessional care and intraprofessional care for older patients with multiple health problems. The aim of this study was to evaluate the effects of ICW care in older patients with multiple health problems. Methods: This retrospective cohort study evaluated the effects on patients outcomes. This was done by comparing patients of the new model, the ICW (ICW group), to a historical cohort of comparable patients who would have been eligible for the ICW (control group). Outcomes were medical consultations, allied health professional consultations, radiological procedures, waiting time for radiological procedures, change in primary treating specialty, length of hospital stay, readmission rate, and mortality rate. Linear and logistic regression analyses were performed, adjusted for baseline differences. Results: The ICW group required significantly fewer medical consultations than the control group. Calls to specialists from the emergency room decreased significantly, but there was no change in in-person consultations on the ER. 51% of control patients had ≥ 1 in-hospital consultation compared to 21% of ICW patients (p < 0.05). Patients in the ICW group received significantly more consultations with allied health professionals and more often had a change in primary treating specialty. Conclusions: Interprofessional and intraprofessional clinical collaboration on the ICW reduced in-hospital consultations and increased allied health professionals' consultations. This approach may decrease fragmentation of care and provide more integrated, efficient and patient centered care. This may improve the overall care of older patients with multiple health problems. [ABSTRACT FROM AUTHOR]

Background: Non-pharmacological interventions such as Cognitive Stimulation Therapy (CST) have been shown to help persons living with dementia in improving cognitive function and recall. While previous CST interventions have been conducted largely with community populations, none have explored the outcomes of CST in larger healthcare settings. Our study explored differences of cognitive function, mood, and quality-of-life from CST groups both community and residential-based groups. Method: Participants (N = 258) from academic and rural, hospital-based settings in Missouri engaged in 14-session psychosocial groups to aid reminiscence for enhanced cognitive function and recall. Results: Post-intervention cognitive function improvements occurred for community (t = −7.48, p <.001) and residential samples (t = −2.46, p <.05). Community groups showed significant improvement in overall mood related to their dementia (t = 6.37, p <.001). Conclusion: Healthcare providers should consider CST as a supplemental intervention for older patients receiving usual care for dementia-related symptoms. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) neutralizing antibodies are shown to be effective therapeutics for providing coronavirus disease 2019 (COVID‐19) protection. However, recurrent variants arise and facilitate significant escape from current antibody therapeutics. Bispecific antibodies (bsAbs) represent a unique platform to increase antibody breadth and to reduce neutralization escape. Herein, a novel immunoglobulin G–variable domains of heavy‐chain‐only antibody (IgG–VHH) format bsAb derived from a potent human antibody R15‐F7 and a humanized nanobody P14‐F8‐35 are rationally engineered. The resulting bsAb SYZJ001 efficiently neutralizes wild‐type SARS‐CoV‐2 as well as the alpha, beta, gamma, and delta variants, with superior efficacy to its parental antibodies. Cryo‐electron microscopy structural analysis reveals that R15‐F7 and P14‐F8‐35 bind to nonoverlapping epitopes within the RBD and sterically hindered ACE2 receptor binding. Most importantly, SYZJ001 shows potent prophylactic and therapeutic efficacy against SARS‐CoV‐2 in three established mouse models. Collectively, the current results demonstrate that the novel bsAb format is feasible and effective, suggesting great potential as an inspiring antiviral strategy. [ABSTRACT FROM AUTHOR]

The spike glycoprotein on the surface of the SARS-CoV-2 envelope plays an important role in its invasion into host cells. The binding of the spike glycoprotein RBD to the angiotensin-converting enzyme 2 (ACE2) receptor as a critical step in the spread of the virus has been explored intensively since the outbreak of COVID-19, but the high transmissibility of the virus such as the Delta variant is still not fully understood. Here, molecular simulations on the binding interactions of the wild-type spike protein and its four variants (Beta, Kappa, Delta, and Mu) with ACE2 and the antibody were performed, and the present results reveal that the residue mutations will not strengthen the binding affinity of the variant for ACE2, but remarkably influences the spatial orientation of the spike protein. Only the up-right conformational receptor binding domain (RBD) can bind ACE2, which is stabilized by the nearby RBDs in the down state, revealing that the RBD bears dual functional characteristics. The present results provide new insights into plausible mechanisms for high infectivity of the virus variants and their immune escape. [ABSTRACT FROM AUTHOR]

Simple Summary: Methionine is an essential amino acid that contributes to protein formation, fetal development, and milk synthesis. Thus, we hypothesized that a supplementation with Optimethione® during the last third of gestation in female goats will increase the maternal body live weight, the milk yield and milk composition and the offspring weight and body mass index at birth and postnatal performance. We fed (n = 30) or not (n = 30) herbal methionine Optimethione® to pregnant multiparous Alpine goats from gestational day 100 until delivery. We evaluated the productive variables from the dams and offspring. Maternal intake of herbal methionine Optimethione® during pregnancy did not increase the live weight or increase the milk yield and composition. However, the tested offspring variables were influenced by the maternal intake of herbal methionine Optimethione® during gestation by improving the birth weight, body mass index, and postnatal growth pattern. An increase in birth weight would be expected to increase neonatal survival up to weaning. Moreover, a relative fatness is required for reproductive success; thus, offspring that are born heavier and bigger can display a faster postnatal growth and accelerate the onset of puberty and increase reproductive success. The last third of gestation is a period of high energy and protein demand for the dam to support fetal growth and the following onset of lactation. Methionine is an essential amino acid that contributes to protein formation, fetal development, and milk synthesis; thus, is likely to have positive effects on the weight and size of the newborn and, afterward, milk yield and milk composition, which may improve growth patterns of the progeny. To test these hypotheses, we used 60 pregnant multiparous Alpine goats with similar live weights and gestational ages (~Day 100 of pregnancy; Mean ± SD; 1410 ± 14 days old and 50.4 ± 6.6 kg) and were separated into two groups: control and supplemented with the delivery. Treatments were T-MET (n = 30; received 1% herbal methionine Optimethione® dry matter based on from Day 100 of the pregnancy to delivery) or T-CTL (n = 30; served as the control and did not receive methionine). The methionine powder provided individual supplementation and was adjusted every week as the live weight and dry matter intake changed. At birth, the weight, body mass index (BMI), birth type, and sex of the kids were determined. Subsequently, the progeny was weighed weekly up to weaning. Two weeks after parturition, the milk composition was recorded weekly, and the milk yield was recorded monthly. The maternal live weight at the start (Mean ± SEM; T-CTL: 50.5 ± 1.1 vs. T-MET: 50.3 ± 1.3 kg) and end (T-CTL: 54.2 ± 1.3 vs. T-MET: 52.8 ± 1.4 kg) of the experiment did not differ statistically among treatments (p > 0.05); however, daily live weight changes tended to differ between groups (T-CTL: 73 ± 10 vs. T-MET: 51 ± 7 g day−1; p = 0.06). The birth weight (T-CTL: 3.1 ± 0.1 vs. T-MET: 3.5 ± 0.1 kg; p < 0.001), daily live weight change (T-CTL: 121 ± 6 vs. T-MET: 141 ± 6 g day−1; p < 0.01), and weaning weight (T-CTL: 8.3 ± 0.2 vs. T-MET: 9.3 ± 0.3 kg; p < 0.01) differed between treatments. The BMI at birth (T-CTL: 0.28 ± 0.01 vs. T-MET: 0.3 ± 0.01 units kg m−2; p < 0.01) and at weaning (T-CTL: 0.85 ± 0.1 kg vs. T-MET: 1.00 ± 0.06 units kg m−2; p < 0.05) differed between treatments. Milk components (protein, fat, lactose, and solids non-fat) and milk yield were similar between treatments (p > 0.05). It is concluded that the inclusion of methionine in the maternal goat diet during the last third of gestation increases the birth and growth variables of the progeny but without significant influence on the milk yield and composition. [ABSTRACT FROM AUTHOR]

The recent incidence of terrible acute respiratory syndrome coronavirus 2 (SARS CoV‐2) has presently experienced some noteworthy mutations since its discovery in 2019 in Wuhan, China. The present research work focuses on the synthesis of three triazole derivatives (BMTPP, BMTTP, and BMTIP) and their inhibition activities against SARS‐Cov‐2 spike and ACE2 receptor proteins. The crystal structure for BMTTP was determined by the SCXRD method and optimized geometrical parameters for the three triazole derivatives were obtained by DFT calculations. HOMO‐LUMO, Global reactive descriptors [GRD], and Molecular electrostatic potential (MEP) investigations exposed that all three compounds have biological properties. The drug‐likeness ability of the synthesized compounds was examined using Molinspiration and a pre‐ADMET online Server. Further, to explore the binding nature of three synthesized compounds with SARS‐Cov‐2 spike proteins/ACE2 receptor molecular docking studies were executed. The outcomes we obtained from molecular docking simulation studies suggest that the synthesized triazole derivatives may be well utilized as curing medicines against COVID‐19. Ultimately, animal tests and precise clinical tests are required to prove the potent nature of these compounds against COVID‐19. Finally, the present outcomes must be proved to utilize in‐vitro and in‐vivo antiviral methods. [ABSTRACT FROM AUTHOR]

Mass mapping using high resolution mass spectrometry has been applied to identify and rapidly distinguish the omicron variant of the SARS-CoV2 coronavirus strains from other major variants of concern. Insertions, deletions and mutations within the surface spike protein result in associated mass differences in the mass maps that distinguish the variant from the originating strain and the preceding alpha, beta, gamma and delta variants of concern. The same mass map profiles can also be used to construct phylogenetic trees, without the need for protein (or gene) sequences or their alignment, in order to chart and study the origins of the variants, or any other strains. The speed and sensitivity of mass spectrometric analysis is demonstrated for a preliminary set of clinical specimens with comparable sample handling to that required in PCR based approaches. [ABSTRACT FROM AUTHOR]

Background: Milk samples from 10,641 dairy cattle were screened by a mass spectrometry method for extreme concentrations of the A or B isoforms of the whey protein, β-lactoglobulin (BLG), to identify causative genetic variation driving changes in BLG concentration. Results: A cohort of cows, from a single sire family, was identified that produced milk containing a low concentration of the BLG B protein isoform. A genome-wide association study (GWAS) of BLG B protein isoform concentration in milk from AB heterozygous cows, detected a group of highly significant single nucleotide polymorphisms (SNPs) within or close to the BLG gene. Among these was a synonymous G/A variation at position + 78 bp in exon 1 of the BLG gene (chr11:103256256G > A). The effect of the A allele of this SNP (which we named B') on BLG expression was evaluated in a luciferase reporter assay in transfected CHO-K1 and MCF-7 cells. In both cell types, the presence of the B' allele in a plasmid containing the bovine BLG gene from -922 to + 898 bp (relative to the transcription initiation site) resulted in a 60% relative reduction in mRNA expression, compared to the plasmid containing the wild-type B sequence allele. Examination of a mammary RNAseq dataset (n = 391) identified 14 heterozygous carriers of the B' allele which were homozygous for the BLG B protein isoform (BB'). The level of expression of the BLG B' allele was 41.9 ± 1.0% of that of the wild-type BLG B allele. Milk samples from three cows, homozygous for the A allele at chr11:103,256,256 (B'B'), were analysed (HPLC) and showed BLG concentrations of 1.04, 1.26 and 1.83 g/L relative to a mean of 4.84 g/L in milk from 16 herd contemporaries of mixed (A and B) BLG genotypes. The mechanism by which B' downregulates milk BLG concentration remains to be determined. Conclusions: High-throughput screening and identification of outliers, enabled the discovery of a synonymous G > A mutation in exon 1 of the B allele of the BLG gene (B'), which reduced the milk concentration of β-lactoglobulin B protein isoform, by more than 50%. Milk from cows carrying the B' allele is expected to have improved processing characteristics, particularly for cheese-making. [ABSTRACT FROM AUTHOR]

Approximately 70% of the cost of beef production is impacted by dietary intake. Maximizing production efficiency of beef cattle requires not only genetic selection to maximize feed efficiency (i.e., residual feed intake (RFI)), but also adequate nutrition throughout all stages of growth and development to maximize efficiency of growth and reproductive capacity, even during gestation. RFI as a measure of feed efficiency in cattle has been recently accepted and used in the beef industry, but the effect of selection for RFI upon the dynamics of gestation has not been extensively studied, especially in the context of fluctuating energy supply to the dam and fetus. Nutrient restriction during gestation has been shown to negatively affect postnatal growth and development as well as fertility of beef cattle offspring. This, when combined with the genetic potential for RFI, may significantly affect energy partitioning in the offspring and subsequently important performance traits. In this review, we discuss: 1) the importance of RFI as a measure of feed efficiency and how it can affect other economic traits in beef cattle; 2) the influence of prenatal nutrition on physiological phenotypes in calves; 3) the benefits of investigating the interaction of genetic selection for RFI and prenatal nutrition; 4) how metabolomics, transcriptomics, and epigenomics have been employed to investigate the underlying biology associated with prenatal nutrition, RFI, or their interactions in beef cattle; and 5) how the integration of omics information is adding a level of deeper understanding of the genetic architecture of phenotypic traits in cattle. [ABSTRACT FROM AUTHOR]

The way in which living organisms mobilize a combination of long-term adaptive mechanisms and short-term phenotypic plasticity to face environmental variations is still largely unknown. In the context of climate change, understanding the genetic and epigenetic bases for adaptation and plasticity is a major stake for preserving genomic resources and the resilience capacity of livestock populations. We characterized both epigenetic and genetic variations by contrasting 22 sheep and 21 goats from both sides of a climate gradient, focusing on free-ranging populations from Morocco. We produced for each individual Whole-Genome Sequence at 12X coverage and MeDIP-Seq data, to identify regions under selection and those differentially methylated. For both species, the analysis of genetic differences (FST) along the genome between animals from localities with high vs. low temperature annual variations detected candidate genes under selection in relation to environmental perception (5 genes), immunity (4 genes), reproduction (8 genes) and production (11 genes). Moreover, we found for each species one differentially methylated gene, namely AGPTA4 in goat and SLIT3 in sheep, which were both related, among other functions, to milk production and muscle development. In both sheep and goats, the comparison between genomic regions impacted by genetic and epigenetic variations suggests that climatic variations impacted similar biological pathways but different genes. [ABSTRACT FROM AUTHOR]

Maternal nutrition during gestation can cause epigenetic effects that translate to alterations in gene expression in offspring. This 2-year study employed RNA-sequencing technology to evaluate the pre- and post-vaccination muscle transcriptome of early-weaned Bos indicus-influenced beef calves born from dams offered different supplementation strategies from 57 ± 5 d prepartum until 17 ± 5 d postpartum. Seventy-two Brangus heifers (36 heifers/yr) were stratified by body weight and body condition score and assigned to bahiagrass pastures (3 heifers/pasture/yr). Treatments were randomly assigned to pastures and consisted of (i) no pre- or postpartum supplementation (NOSUP), (ii) pre- and postpartum supplementation of protein and energy using 7.2 kg of dry matter/heifer/wk of molasses + urea (MOL), or (iii) MOL fortified with 105 g/heifer/wk of methionine hydroxy analog (MOLMET). Calves were weaned on d 147 of the study. On d 154, 24 calves/yr (8 calves/treatment) were randomly selected and individually limit-fed a high-concentrate diet until d 201. Calves were vaccinated on d 160. Muscle biopsies were collected from the same calves (4 calves/treatment/day/yr) on d 154 (pre-vaccination) and 201 (post-vaccination) for gene expression analysis using RNA sequencing. Molasses maternal supplementation led to a downregulation of genes associated with muscle cell differentiation and development along with intracellular signaling pathways (e.g., Wnt and TGF-β signaling pathway) compared to no maternal supplementation. Maternal fortification with methionine altered functional gene-sets involved in amino acid transport and metabolism and the one-carbon cycle. In addition, muscle transcriptome was impacted by vaccination with a total of 2,396 differentially expressed genes (FDR ≤ 0.05) on d 201 vs. d 154. Genes involved in cell cycle progression, extracellular matrix, and collagen formation were upregulated after vaccination. This study demonstrated that maternal supplementation of energy and protein, with or without, methionine has long-term implications on the muscle transcriptome of offspring and potentially influence postnatal muscle development. [ABSTRACT FROM AUTHOR]

The epigenome is dynamic and forged by epigenetic mechanisms, such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA species. Increasing lines of evidence support the concept that certain acquired traits are derived from environmental exposure during early embryonic and fetal development, i.e., fetal programming, and can even be "memorized" in the germline as epigenetic information and transmitted to future generations. Advances in technology are now driving the global profiling and precise editing of germline and embryonic epigenomes, thereby improving our understanding of epigenetic regulation and inheritance. These achievements open new avenues for the development of technologies or potential management interventions to counteract adverse conditions or improve performance in livestock species. In this article, we review the epigenetic analyses (DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs) of germ cells and embryos in mammalian livestock species (cattle, sheep, goats, and pigs) and the epigenetic determinants of gamete and embryo viability. We also discuss the effects of parental environmental exposures on the epigenetics of gametes and the early embryo, and evidence for transgenerational inheritance in livestock. [ABSTRACT FROM AUTHOR]

Adipogenesis is closely related to human health, livestock growth, and meat quality. A previous study identified that bovine lncFAM200B promoter has high activity in 3T3‐L1 mice preadipocytes. Thus, lncFAM200B was a candidate gene for regulating adipogenesis. This study aimed to uncover the role of lncFAM200B in bovine adipogenesis and identify novel genetic variations within the bovine lncFAM200B gene. An expression analysis found that lncFAM200B was expressed higher in fat than that in muscle, but the difference was not related to the total methylation level of the promoter active region. Moreover, the expression of lncFAM200B exhibited a significant positive correlation with the expression of C/EBPa during bovine adipocyte differentiation. To uncover the function of lncFAM200B, the full‐length lncFAM200B was cloned, and four kinds of transcript variants were found. Protein‐coding potential prediction and prokaryotic expression system analysis showed that these four transcript variants were noncoding RNAs. The quantitative reverse‐transcription polymerase chain reaction and 5‐ethynyl‐2′‐deoxyuridine assay showed that the transcript variants decreased the messenger RNA expression of Cyclin D1 and inhibited the proliferation of bovine preadipocytes. Considering the important role of lncFAM200B in adipogenesis, we identified genetic variations in lncFAM200B. Three single‐nucleotide polymorphisms (SNPs) were revealed, and two of them (SNP1 and SNP3) were associated with Nanyang cattle body measurement traits. In conclusion, this study found that bovine lncFAM200B inhibited preadipocyte proliferation, and two genetic variations of lncFAM200B could be used in cattle breeding. [ABSTRACT FROM AUTHOR]

Objective. To develop and validate a risk assessment model for the prediction of the acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) in patients with idiopathic pulmonary fibrosis (IPF). Methods. We enrolled a total of 110 patients with IPF, hospitalized or treated as outpatients at Xuzhou Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine from July 2012 to July 2020. Of these, 78 and 32 patients were randomly assigned to training and test groups, respectively. The risk factors for AE-IPF were analyzed using logistic regression analysis, and a nomographic model was constructed. The accuracy, degree of calibration, and clinical usefulness of the model were assessed with the consistency index (C-index), calibration diagram, and decision curve analysis (DCA). Finally, the stability of the model was tested using internal validation. Results. The results of logistic regression analysis showed that a history of occupational exposure, diabetes mellitus (DM), essential hypertension (EH), and diffusion capacity for carbon monoxide (DLCO)% predicted were independent risk factors for AE-IPF prediction. The nomographic model was constructed based on these independent risk factors, and the C-index was 0.80. The C-index for the internal validation was 0.75, suggesting that the model had good accuracy. The decision curve indicated that for a threshold value of 0.04–0.66, greater clinical benefit was obtained with the AE-IPF risk prediction model. Conclusion. A customized AE-IPF prediction model based on a history of occupational exposure, DM, EH, and DLCO% predicted provided a reference for the clinical prediction of AE-IPF. [ABSTRACT FROM AUTHOR]

Knowledge of non-genomic inheritance of traits is currently limited. Although it is well established that maternal diet influences offspring inheritance of traits through DNA methylation, studies on the impact of prepubertal paternal diet on DNA methylation are rare. This study aimed to evaluate the impact of prepubertal diet in Polypay rams on complex traits, DNA methylation, and transmission of traits to offspring. A total of 10 littermate pairs of F0 rams were divided so that one ram was fed a control diet, and the other was fed the control diet with supplemental methionine. Diet was associated with earlier age at puberty in treatment vs. control F0 rams. F0 treatment rams tended to show decreased pubertal weight compared to control rams; however, no differences were detected in overall growth. A total of ten F0 rams were bred, and the entire F1 generation was fed a control diet. Diet of F0 rams had a significant association with scrotal circumference (SC) and weight at puberty of F1 offspring. The paternal diet was not significantly associated with F1 ram growth or age at puberty. The DNA methylation of F0 ram sperm was assessed, and genes related to both sexual development (e.g., DAZAP1 , CHD7 , TAB1 , MTMR2 , CELSR1 , MGAT1) and body weight (e.g., DUOX2 , DUOXA2) were prevalent in the data. These results provide novel information about the mechanisms through which the prepubertal paternal diet may alter body weight at puberty and sexual development. [ABSTRACT FROM AUTHOR]

Objective: Geriatricians are skilled in the recognition of asymptomatic and atypical presentations that occur in the elderly and provide comprehensive medication management including recognizing adverse drug events, reducing polypharmacy, and de-prescribing. However, despite the increasing average age of the U.S. population, with the number of individuals above 65 years old predicted to increase 55% by 2030, the geriatric workforce capacity in the United States has actually decreased from 10,270 in 2000 to 8,502 in 2010. Method: We describe physiologic changes in older adults, historical trends in geriatric training, and propose solutions for this looming crisis. Results: Many factors are responsible for the shortage of skilled geriatric providers. Discussion: We discuss the historical context of the lack of geriatricians including changes to the training system, describe the impact of expert geriatric care on patient care and health system outcomes, and propose methods to improve recruitment and retention for geriatric medicine. [ABSTRACT FROM AUTHOR]

The aim of this study was to perform a Bayesian genomewide association study (GWAS) to identify genomic regions associated with growth traits in Hereford and Braford cattle, and to select Tag‐SNPs to represent these regions in low‐density panels useful for genomic predictions. In addition, we propose candidate genes through functional enrichment analysis associated with growth traits using Medical Subject Headings (MeSH). Phenotypic data from 126,290 animals and genotypes for 131 sires and 3,545 animals were used. The Tag‐SNPs were selected with BayesB (π = 0.995) method to compose low‐density panels. The number of Tag‐single nucleotide polymorphism (SNP) ranged between 79 and 103 SNP for the growth traits at weaning and between 78 and 100 SNP for the yearling growth traits. The average proportion of variance explained by Tag‐SNP with BayesA was 0.29, 0.23, 0.32 and 0.19 for birthweight (BW), weaning weight (WW205), yearling weight (YW550) and postweaning gain (PWG345), respectively. For Tag‐SNP with BayesA method accuracy values ranged from 0.13 to 0.30 for k‐means and from 0.30 to 0.65 for random clustering of animals to compose reference and validation groups. Although genomic prediction accuracies were higher with the full marker panel, predictions with low‐density panels retained on average 76% of the accuracy obtained with BayesB with full markers for growth traits. The MeSH analysis was able to translate genomic information providing biological meanings of more specific gene products related to the growth traits. The proposed Tag‐SNP panels may be useful for future fine mapping studies and for lower‐cost commercial genomic prediction applications. [ABSTRACT FROM AUTHOR]

Paired-like homeodomain transcription factor 1 (PITX1) is a pivotal gene in the hypothalamic–pituitary–adrenal axis, which is a well-known pathway affecting lactation performance. The aim of this study was to analyze the DNA methylation profile of the PITX1 gene and its relevance to milk performance in Xinong Saanen dairy goats; thus, potential epigenetic markers of lactation performance were identified. A total of 267 goat blood samples were divided into "low" and "high" groups according to two milk traits: the average milk yield (AMY) and the average milk density (AMD). One CpG island in the 3 ′ -flanking region of the PITX1 gene was identified as being related to milk performance. Fisher's exact test demonstrated that the methylation rates of the overall CpG island and the 3rd and 12th CpG-dinucleotide loci in the blood were significantly associated with the AMY, and the overall methylation rate of the high AMY group was relative hypomethylation compared with the low AMY group. The overall methylation rates of this CpG island in mammary gland tissue from dry and lactation periods again exhibited a significant difference: the lactation period showed relative hypomethylation compared with the dry period. Bioinformatic transcription factor binding site prediction identified some lactation performance related transcription factors in this CpG island, such as CTCF, STAT, SMAD, CDEF, SP1, and KLFS. Briefly, overall methylation changes of the CpG island in the PITX1 gene are relevant to lactation performance, which will be valuable for future studies and epigenetic marker-assisted selection (eMAS) in the breeding of goats with respect to lactation performance. [ABSTRACT FROM AUTHOR]

Epidemiological studies in humans and animal models (including ruminants and horses) have highlighted the critical role of nutrition on developmental programming. Indeed, it has been demonstrated that the nutritional environment during the periconceptional period and foetal development can altered the postnatal performance of the resultant offspring. This nutritional programming can be exerted by maternal and paternal lineages and can affect offspring beyond the F1 generation. Alterations in epigenetic mechanisms have been proposed as the causative link behind the programming trajectories observed in the offspring. Although a clear cause–effect relationship between epigenetic modifications during early development and later offspring phenotype has not been demonstrated in livestock species, strong associations have been reported for some epigenetic marks (e.g. messenger RNA) that are worth exploring as possible predictors of future offspring phenotype. In this review, we shortly describe the main epigenetic mechanisms studied so far in mammals (i.e. mainly in the mouse) thought to be associated with developmental programming, and discuss the few studies available in mammalian herbivores (e.g. cattle) showing the effect of nutrition on epigenetic marks and the associated phenotype. Clearly, there is a need to develop research on nutritional strategies capable of modulating the epigenetic machinery with positive influence on the phenotype of livestock herbivores. This type of research is needed to alleviate the challenges currently faced by the livestock industry (e.g. impaired fertility of high-yielding dairy cows). This in turn will have a positive influence on animal welfare and productivity of livestock enterprises. [ABSTRACT FROM AUTHOR]

Milk fever is an important metabolic disorder that affects dairy cows around parturition. It is associated with a breakdown in the mechanisms of calcium homeostasis, resulting in very low blood calcium levels (hypocalcemia). The main objective of this study was to dissect the genetic basis underlying milk fever incidence in Holstein cattle. Data consisted of 31.6 k producer-recorded lactation incidence records from 15.3 k cows. The analysis included a whole-genome scan and a subsequent gene-set analysis in order to reveal individual genes, genetic mechanisms and biological pathways implicated in the incidence of periparturient hypocalcemia. The association analysis identified at least eight different genomic regions that explain considerable amounts of additive genetic variance for milk fever incidence. Notably, some of these regions harbor genes, such as CYP27A1, CYP2J2, GC, SNAI2 , and PIM1 , that are directly involved in vitamin D metabolic pathway. Moreover, the gene-set analysis revealed several functional terms, such as calcium ion binding, calcium ion transportation, T cell differentiation, B cell activation, protein phosphorylation, apoptosis, and protein kinase activity, among others, that could be implicated in the development of periparturient hypocalcemia. Overall, this comprehensive study contributes to a better understanding of the genetic control of this complex disease. In addition, these findings may contribute to the development of novel breeding strategies for reducing the incidence of milk fever in dairy cattle. [ABSTRACT FROM AUTHOR]

Summary: The service sire has been recognized as an important factor affecting herd fertility in dairy cattle. Recent studies suggest that genetic factors explain part of the difference in fertility among Holstein sires. The main objective of this study was to dissect the genetic architecture of sire fertility in US Jersey cattle. The dataset included 1.5 K Jersey bulls with sire conception rate (SCR) records and 96 K single nucleotide polymorphism (SNP) markers spanning the whole genome. The analysis included whole‐genome scans for both additive and non‐additive effects and subsequent functional enrichment analyses using KEGG Pathway, Gene Ontology (GO) and Medical Subject Headings (MeSH) databases. Ten genomic regions located on eight different chromosomes explained more than 0.5% of the additive genetic variance for SCR. These regions harbor genes, such as PKDREJ, EPB41L2, PDGFD, STX2, SLC25A20 and IP6K1, that are directly implicated in testis development and spermatogenesis, sperm motility and the acrosome reaction. In addition, the genomic scan for non‐additive effects identified two regions on BTA11 and BTA25 with marked recessive effects. These regions harbor three genes—FER1L5, CNNM4 and DNAH3—with known roles in sperm biology. Moreover, the gene‐set analysis revealed terms associated with calcium regulation and signaling, membrane fusion, sperm cell energy metabolism, GTPase activity and MAPK signaling. These gene sets are directly implicated in sperm physiology and male fertility. Overall, this integrative genomic study unravels genetic variants and pathways affecting Jersey bull fertility. These findings may contribute to the development of novel genomic strategies for improving sire fertility in Jersey cattle. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study was to identify genomic regions associated with fat‐related traits using a Japanese Black cattle population in Hyogo. From 1836 animals, those with high or low values were selected on the basis of corrected phenotype and then pooled into high and low groups (n = 100 each), respectively. DNA pool‐based genome‐wide association study (GWAS) was performed using Illumina BovineSNP50 BeadChip v2 with three replicate assays for each pooled sample. GWAS detected that two single nucleotide polymorphisms (SNPs) on BTA7 (ARS‐BFGL‐NGS‐35463 and Hapmap23838‐BTA‐163815) and one SNP on BTA12 (ARS‐BFGL‐NGS‐2915) significantly affected fat percentage (FAR). The significance of ARS‐BFGL‐NGS‐35463 on BTA7 was confirmed by individual genotyping in all pooled samples. Moreover, association analysis between SNP and FAR in 803 Japanese Black cattle revealed a significant effect of SNP on FAR. Thus, further investigation of these regions is required to identify FAR‐associated genes and mutations, which can lead to the development of DNA markers for marker‐assisted selection for the genetic improvement of beef quality. [ABSTRACT FROM AUTHOR]

Background: In food animal agriculture, there is a need to identify the mechanisms that can improve the efficiency of muscle growth and protein accretion. Callipyge sheep provide excellent machinery since the up-regulation of DLK1 and RTL1 results in extreme postnatal muscle hypertrophy in distinct muscles. The aim of this study is to distinguish the genes that directly respond to DLK1 and RTL1 signaling from the genes that change as the result of muscle specific effects. Results: The quantitative PCR results indicated that DLK1 expression was significantly increased in hypertrophied muscles but not in non-hypertrophied muscles. However, RTL1 was up-regulated in both hypertrophied and non-hypertrophied muscles. Five genes, including PARK7, DNTTIP1, SLC22A3, METTL21E and PDE4D, were consistently co-expressed with DLK1, and therefore were possible transcriptional target genes responding to DLK1 signaling. Treatment of myoblast and myotubes with DLK1 protein induced an average of 1.6-fold and 1.4-fold increase in Dnttip1 and Pde4d expression respectively. Myh4 expression was significantly elevated in DLK1-treated myotubes, whereas the expression of Mettl21e was significantly increased in the DLK1-treated myoblasts but reduced in DLK1-treated myotubes. DLK1 treatment had no impact on Park7 expression. In addition, Park7 and Dnttip1 increased Myh4 and decreased Myh7 promoter activity, resemble to the effects of Dlk1. In contrast, expression of Mettl21e increased Myh7 and decreased Myh4 luciferase activity. Conclusion: The study provided additional supports that RTL1 alone was insufficient to induce muscle hypertrophy and concluded that DLK1 was likely the primary effector of the hypertrophy phenotype. The results also suggested that DNTTIP1 and PDE4D were secondary effector genes responding to DLK1 signaling resulting in muscle fiber switch and muscular hypertrophy in callipyge lamb. [ABSTRACT FROM AUTHOR]

Maternal consumption of a high fat diet during early development has been shown to impact the formation of hypothalamic neurocircuitry, thereby contributing to imbalances in appetite and energy homeostasis and increasing the risk of obesity in subsequent generations. Early in postnatal life, the neuronal projections responsible for energy homeostasis develop in response to appetite-related peptides such as leptin. To date, no study characterises the genome-wide transcriptional changes that occur in response to exposure to high fat diet during this critical window. We explored the effects of maternal high fat diet consumption on hypothalamic gene expression in Sprague Dawley rat offspring at postnatal day 10. RNA-sequencing enabled discovery of differentially expressed genes between offspring of dams fed a high fat diet and offspring of control diet fed dams. Female high fat diet offspring displayed altered expression of 86 genes (adjusted P-value<0.05), including genes coding for proteins of the extra cellular matrix, particularly Collagen 1a1 (Col1a1), Col1a2, Col3a1, and the imprinted Insulin-like growth factor 2 (Igf2) gene. Male high fat diet offspring showed significant changes in collagen genes (Col1a1 and Col3a1) and significant upregulation of two genes involved in regulation of dopamine availability in the brain, tyrosine hydroxylase (Th) and dopamine reuptake transporter Slc6a3 (also known as Dat1). Transcriptional changes were accompanied by increased body weight, body fat and body length in the high fat diet offspring, as well as altered blood glucose and plasma leptin. Transcriptional changes identified in the hypothalamus of offspring of high fat diet mothers could alter neuronal projection formation during early development leading to abnormalities in the neuronal circuitry controlling appetite in later life, hence priming offspring to the development of obesity. [ABSTRACT FROM AUTHOR]

Background: Maternal nutrition during pregnancy and infant nutrition in the early postnatal period (lactation) are critically involved in the development and health of the newborn infant. The Maternal Nutrition and Offspring's Epigenome (MANOE) study was set up to assess the effect of maternal methyl-group donor intake (choline, betaine, folate, methionine) on infant DNA methylation. Maternal intake of dietary methyl-group donors was assessed using a food-frequency questionnaire (FFQ). Before and during pregnancy, we evaluated maternal methyl-group donor intake through diet and supplementation (folic acid) in relation to gene-specific (IGF2 DMR, DNMT1, LEP, RXRA) buccal epithelial cell DNA methylation in 6 months old infants (n = 114) via pyrosequencing. In the early postnatal period, we determined the effect of maternal choline intake during lactation (in mothers who breast-fed for at least 3 months) on gene-specific buccal DNA methylation (n = 65). Results: Maternal dietary and supplemental intake of methyl-group donors (folate, betaine, folic acid), only in the periconception period, was associated with buccal cell DNA methylation in genes related to growth (IGF2 DMR), metabolism (RXRA), and appetite control (LEP). A negative association was found between maternal folate and folic acid intake before pregnancy and infant LEP (slope = -1.233, 95% CI -2.342; -0.125, p = 0.0298) and IGF2 DMR methylation (slope = -0.706, 95% CI -1.242; -0.107, p = 0.0101), respectively. Positive associations were observed for maternal betaine (slope = 0.875, 95% CI 0.118; 1.633, p = 0.0241) and folate (slope = 0.685, 95% CI 0.245; 1.125, p = 0. 0027) intake before pregnancy and RXRA methylation. Buccal DNMT1 methylation in the infant was negatively associated with maternal methyl-group donor intake in the first and second trimester of pregnancy and negatively in the third trimester. We found no clear association between maternal choline intake during lactation and buccal infant DNA methylation. Conclusions: This study suggests that maternal dietary and supplemental intake of methyl-group donors, especially in the periconception period, can influence infant's buccal DNA methylation in genes related to metabolism, growth, appetite regulation, and maintenance of DNA methylation reactions. [ABSTRACT FROM AUTHOR]

Background: Fertility is considered an important economic trait in dairy cattle. Most studies have investigated cow fertility while bull fertility has received much less consideration. The main objective of this study was to perform a comprehensive genomic analysis in order to unravel the genomic architecture underlying sire fertility in Holstein dairy cattle. The analysis included the application of alternative genome-wide association mapping approaches and the subsequent use of diverse gene set enrichment tools. Results: The association analyses identified at least eight genomic regions strongly associated with bull fertility. Most of these regions harbor genes, such as KAT8, CKB, TDRD9 and IGF1R, with functions related to sperm biology, including sperm development, motility and sperm-egg interaction. Moreover, the gene set analyses revealed many significant functional terms, including fertilization, sperm motility, calcium channel regulation, and SNARE proteins. Most of these terms are directly implicated in sperm physiology and male fertility. Conclusions: This study contributes to the identification of genetic variants and biological processes underlying sire fertility. These findings can provide opportunities for improving bull fertility via marker-assisted selection. [ABSTRACT FROM AUTHOR]

Bovine leukosis virus is an oncogenic virus that infects B cells, causing bovine leukosis disease. This disease is known to have a negative impact on dairy cattle production and, because no treatment or vaccine is available, finding a possible genetic solution is important. Our objective was to perform a comprehensive genetic analysis of leukosis incidence in dairy cattle. Data on leukosis occurrence, pedigree and molecular information were combined into multitrait GBLUP models with milk yield (MY) and somatic cell score (SCS) to estimate genetic parameters and to perform whole-genome scans and pathway analysis. Leukosis data were available for 11 554 Holsteins daughters of 3002 sires from 112 herds in 16 US states. Genotypes from a 60K SNP panel were available for 961 of those bulls as well as for 2039 additional bulls. Heritability for leukosis incidence was estimated at about 8%, and the genetic correlations of leukosis disease incidence with MY and SCS were moderate at 0.18 and 0.20 respectively. The genome-wide scan indicated that leukosis is a complex trait, possibly modulated by many genes. The gene set analysis identified many functional terms that showed significant enrichment of genes associated with leukosis. Many of these terms, such as G-Protein Coupled Receptor Signaling Pathway, Regulation of Nucleotide Metabolic Process and different calcium-related processes, are known to be related to retrovirus infection. Overall, our findings contribute to a better understanding of the genetic architecture of this complex disease. The functional categories associated with leukosis may be useful in future studies on fine mapping of genes and development of dairy cattle breeding strategies. [ABSTRACT FROM AUTHOR]

Background Maternal nutrition during different stages of pregnancy can induce significant changes in the structure, physiology, and metabolism of the offspring. These changes could have important implications on food animal production especially if these perturbations impact muscle and adipose tissue development. Here, we evaluated the impact of different maternal isoenergetic diets, alfalfa haylage (HY; fiber), corn (CN; starch), and dried corn distillers grains (DG; fiber plus protein plus fat), on the transcriptome of fetal muscle and adipose tissues in sheep. Results Prepartum diets were associated with notable gene expression changes in fetal tissues. In longissimus dorsi muscle, a total of 224 and 823 genes showed differential expression (FDR ⩽0.05) in fetuses derived from DG vs. CN and HY vs. CN maternal diets, respectively. Several of these significant genes affected myogenesis and muscle differentiation. In subcutaneous and perirenal adipose tissues, 745 and 208 genes were differentially expressed (FDR ⩽0.05), respectively, between CN and DG diets. Many of these genes are involved in adipogenesis, lipogenesis, and adipose tissue development. Pathway analysis revealed that several GO terms and KEGG pathways were enriched (FDR ⩽0.05) with differentially expressed genes associated with tissue and organ development, chromatin biology, and different metabolic processes. Conclusions These findings provide evidence that maternal nutrition during pregnancy can alter the programming of fetal muscle and fat tissues in sheep. The ramifications of the observed gene expression changes, in terms of postnatal growth, body composition, and meat quality of the offspring, warrant future investigation. [ABSTRACT FROM AUTHOR]

Interaction of DNA methylation and sequence variants that are methylation quantitative trait loci (mQTLs) may influence susceptibility to diseases such as alcohol dependence (AD). We used genome-wide genotype data from 268 African Americans (AAs: 129 AD cases and 139 controls) and 143 European Americans (EAs: 129 AD cases and 14 controls) to identify mQTLs that were associated with promoter CpGs in 82 AD risk genes. 282 significant mQTL-CpG pairs (9.9 × 10 ≤ P ≤ 7.7 × 10) in AAs and 313 significant mQTL-CpG pairs (2.7 × 10 ≤ P ≤ 9.9 × 10) in EAs were identified [i.e., mQTL-CpG associations survived multiple-testing correction, q values (false discovery rate) ≤ 0.05]. The most significant mQTL was rs1800759, which was strongly associated with CpG cg12011299 in both AAs ( P = 9.9 × 10; q = 6.7 × 10) and EAs ( P = 2.7 × 10; q = 1.4 × 10). Rs1800759 (previously known to be associated to AD) and CpG cg12011299 (distance: 37 bp) are both located in alcohol dehydrogenase (ADH) 4 gene ( ADH4) promoter region. In general, the strength of association between mQTLs and CpGs was inversely correlated with the distance between them. Association was also influenced by race and AD. Additionally, 48.3 % of the mQTLs identified in AAs and 65.6 % of the mQTLs identified in EAs were predicted to be expression QTLs. Three mQTLs (rs2173201, rs4147542, and rs4147541 in ADH1B- AHD1C gene cluster region) found in AAs were previously identified by our genome-wide association studies as being significantly associated with AD in AAs. Thus, DNA methylation, which can be influenced by sequence variants and is implicated in gene expression regulation, appears to at least partially underlie the association of genetic variation with AD. [ABSTRACT FROM AUTHOR]

Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1–31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1–31 days gestation) or 50% nutritional requirements (104–127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development induces changes in mechanisms of lipid and glucose metabolism which differ between tissues and sexes dependent on the period of nutritional restriction. Such changes may increase later life obesity and dyslipidaemia risk. [ABSTRACT FROM AUTHOR]

Maternal nutrition exclusively during the periconceptional period can induce remarkable effects on both oocyte maturation and early embryo development, which in turn can have lifelong consequences. The objective of this study was to evaluate the effect of maternal methionine supplementation on the transcriptome of bovine preimplantation embryos. Holstein cows were randomly assigned to one of two treatments differing in level of dietary methionine (1.89 Met vs. 2.43 Met % of metabolizable protein) from calving until embryo flushing. High quality preimplantation embryos from individual cows were pooled and then analyzed by RNA sequencing. Remarkably, a subtle difference in methionine supplementation in maternal diet was sufficient to cause significant changes in the transcriptome of the embryos. A total of 276 genes out of 10,662 showed differential expression between treatments (FDR <0.10). Interestingly, several of the most significant genes are related to embryonic development (e.g., VIM, IFI6, BCL2A1, and TBX15) and immune response (e.g., NKG7, TYROBP, SLAMF7, LCP1, and BLA-DQB). Likewise, gene set enrichment analysis revealed that several Gene Ontology terms, InterPro entries, and KEGG pathways were enriched (FDR <0.05) with differentially expressed genes involved in embryo development and immune system. The expression of most genes was decreased by maternal methionine supplementation, consistent with reduced transcription of genes with increased methylation of specific genes by increased methionine. Overall, our findings provide evidence that supplementing methionine to dams prior to conception and during the preimplantation period can modulate gene expression in bovine blastocysts. The ramifications of the observed gene expression changes for subsequent development of the pregnancy and physiology of the offspring warrant further investigation in future studies. [ABSTRACT FROM AUTHOR]