GWAS and post-GWAS functional study reveal regulatory mechanism of piglet diarrhea.

Objective: Piglet diarrhea poses a serious threat to piglet health and the livestock economy, and is one of the most pressing problems in animal husbandry. This study aims to investigate the genetic factors involved in piglet diarrhea and to identify key genes that regulate this condition. Methods: We screened 600 diarrheal piglets based on unique diarrhea scores for resequencing and conducted a genome-wide association study (GWAS). Through this process, we identified 308 single nucleotide polymorphisms (SNPs) and annotated 151 candidate genes. Extensive functional validation and systematic analysis were performed on key candidate genes KSR1, SKAP1, SLC35F6, and OR12. Results: The study found that the four key genes were involved in the regulation of piglet diarrhea through various mechanisms. OR12 affects the levels of ZO-1 and claudin-1. Changes in the expression levels of KSR1 could alter the expression of IL1-ß, IL6, and TNF-α, as well as cell migration and proliferation. SKAP1 could affect the expression of CD3 and CD4, and influence the migration and proliferation ability of cells. SLC35F6 is involved in cell apoptosis through the Bcl2/BAX/caspase3 pathway and can also affect mitochondrial membrane potential. Conclusion: The results of this study provide strong support for breeding programs aimed at disease resistance and offer potential solutions to the problem of piglet diarrhea.

Transcriptome analysis of liver and ileum reveals potential regulation of long non-coding RNA in pigs with divergent feed efficiency.

Objective: LncRNA plays a significant role in regulating feed efficiency. This study aims to explore the key long non-coding RNAs, associated genes, and pathways in pigs with extreme feed efficiencies. Methods: We screened pigs with extremely high and low RFI through a 12-week animal growth trial and then conducted transcriptome analysis on their liver and ileum tissues. We analyzed the differential expressed lncRNAs, miRNAs, and mRNAs through target gene prediction and functional analysis. And we identified key lncRNAs and their potential regulatory genes associated with feed efficiency through the construction of competitive endogenous RNA network. Results: Differentially expressed lncRNAs were pinpointed in the liver, revealing 23 crucial target genes primarily associated with GTP metabolism and glycolipid biosynthesis. In the ileum, a screening identified 92 pivotal target genes, mainly linked to lipid and small molecule metabolism. Moreover, LOC106504303 and LOC102160805 emerged as potentially significant lncRNAs respectively, playing roles in mitochondrial oxidative phosphorylation in the liver, and lipid and cholesterol metabolism in the ileum. Conclusion: The lncRNAs regulate energy metabolism and biosynthesis in the liver, and the digestive absorption capacity in the small intestine, affecting the feed efficiency of pigs.

USP26 Combats Age-Related Declines in Self-Renewal and Multipotent Differentiation of BMSC by Maintaining Mitochondrial Homeostasis.

Age-related declines in self-renewal and multipotency of bone marrow mesenchymal stem cells (BMSCs) limit their applications in tissue engineering and clinical therapy. Thus, understanding the mechanisms behind BMSC senescence is crucial for maintaining the rejuvenation and multipotent differentiation capabilities of BMSCs. This study reveals that impaired USP26 expression in BMSCs leads to mitochondrial dysfunction, ultimately resulting in aging and age-related declines in the self-renewal and multipotency of BMSCs. Specifically, decreased USP26 expression results in decreased protein levels of Sirtuin 2 due to its ubiquitination degradation, which leads to mitochondrial dysfunction in BMSCs and ultimately resulting in aging and age-related declines in self-renewal and multilineage differentiation potentials. Additionally, decreased USP26 expression in aging BMSCs is a result of dampened hypoxia-inducible factor 1α (HIF-1α) expression. HIF-1α facilitates USP26 transcriptional expression by increasing USP26 promoter activity through binding to the -191 - -198 bp and -262 - -269 bp regions on the USP26 promoter. Therefore, the identification of USP26 as being correlated with aging and age-related declines in self-renewal and multipotency of BMSCs, along with understanding its expression and action mechanisms, suggests that USP26 represents a novel therapeutic target for combating aging and age-related declines in the self-renewal and multipotent differentiation of BMSCs.

Multi-omics unveils tryptophan metabolic pathway as a key pathway influencing residual feed intake in Duroc swine.

The genetic trait of residual feed intake (RFI) holds considerable importance in the swine industry. Recent research indicates that the gut microbiota of pigs plays a pivotal role in the manifestation of the RFI trait. Nevertheless, the metabolic pathways involved in the functioning of these microorganisms remain elusive. Thus, based on the ranking of the RFI trait in Duroc pigs, the present study selected the top 10 and bottom 10 pigs as the experimental subjects. The distribution and metabolite differences of cecal microbiota were analyzed using 16S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. The low RFI cecal group was named LRC, and the high RFI cecal group was named HRC. The results indicate that the LRC group had lower RFI, feed conversion ratio (FCR), average daily feed intake (ADFI) (p < 0.001), and thinner backfat (p < 0.05) compared with the HRC group. We simultaneously recorded the foraging behavior as well, the LRC group had a significant increase in total time spent at the feeder per day (TPD) (p < 0.05) and a significant increase in average feed intake per mins (AFI) and the number of visits to the feeder per day (NVD) compared to the HRC group (p < 0.001). Clostridium_XVIII, Bulleidia, and Intestinimonas were significantly enriched in the LRC group (p < 0.01), while Sutterella, Fusobacterium, and Bacteroides were significantly increased in the HRC group (p < 0.01). In the metabolome, we detected 390 (248 metabolites up and 142 down in the LRC compared with HRC), and 200 (97 metabolites up and 103 down in the LRC compared with HRC) differential metabolites in positive and negative ionization modes. The comprehensive analysis found that in the LRC group, Escherichia and Eubacterium in the gut may increase serotonin content, respectively. Bacteroides may deplete serotonin. We suggest that the RFI may be partly achieved through tryptophan metabolism in gut microbes. In individuals with low RFI, gut microbes may enhance feed efficiency by enhancing host synthesis and metabolism of tryptophan-related metabolites.

Activation of the osteoblastic HIF-1α pathway partially alleviates the symptoms of STZ-induced type 1 diabetes mellitus via RegIIIγ.

The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose uptake by osteoblasts, which reduces blood glucose levels. However, it is unclear whether activating the HIF-1α pathway in osteoblasts can help normalize glucose metabolism under diabetic conditions through its endocrine function. In addition to increasing bone mass and reducing blood glucose levels, activating the HIF-1α pathway by specifically knocking out Von Hippel‒Lindau (Vhl) in osteoblasts partially alleviated the symptoms of streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM), including increased glucose clearance in the diabetic state, protection of pancreatic ß cell from STZ-induced apoptosis, promotion of pancreatic ß cell proliferation, and stimulation of insulin secretion. Further screening of bone-derived factors revealed that islet regeneration-derived protein III gamma (RegIIIγ) is an osteoblast-derived hypoxia-sensing factor critical for protection against STZ-induced T1DM. In addition, we found that iminodiacetic acid deferoxamine (SF-DFO), a compound that mimics hypoxia and targets bone tissue, can alleviate symptoms of STZ-induced T1DM by activating the HIF-1α-RegIIIγ pathway in the skeleton. These data suggest that the osteoblastic HIF-1α-RegIIIγ pathway is a potential target for treating T1DM.

Geranylgeranylacetone mitigates sepsis-associated intestinal injury through CHIP-dependent anti-inflammation and anti-oxidative effect.

Geranylgeranylacetone (GGA), an isoprenoid compound widely utilized as an antiulcer agent in Asia, confers protection against ischemia, anoxia, and oxidative stress by rapidly enhancing the expression of HSP70. Nevertheless, the impact of GGA on sepsis-associated intestinal injury remains unexplored. Thus, this study is crafted to elucidate the protective efficacy and underlying mechanisms of GGA against septic intestinal damage. Our findings revealed that GGA significantly extended the survival duration of septic mice, and mitigated lipopolysaccharide (LPS)-induced alterations in intestinal permeability and tissue damage. Furthermore, GGA effectively suppressed LPS-induced cytokine release, attenuated levels of reactive oxygen species (ROS) and malondialdehyde, and bolstered antioxidant-related parameters within the intestinal tissue of LPS-stimulated mice. Mechanistically, GGA significantly increased HSP70 expression and promoted E3 ubiquitin ligase CHIP to play the role in ubiquitination and degradation of karyopherin-α2 (KPNA2), resulting in inhibition of nuclear translocation of NF-κB and reduced NOX1, NOX2 and NOX4 expression. The inhibitory action of GGA on cytokine release and ROS generation was abolished by CHIP knockdown in IEC-6 cells treated with LPS. Simultaneously, the downregulation of CHIP reversed the suppressive role of GGA in the LPS-induced NF-κB activation and the expression of NOX1, NOX2 and NOX4 in IEC-6 cells. The effects of GGA on mitigating intestinal damage, inflammation and oxidative stress caused by LPS were eliminated in CHIP knockout mice. Our results demonstrate that the protective effect of GGA against LPS-caused intestinal injury of mice is dependent on CHIP activation, which promotes KPNA2 degradation and restrains translocation of NF-κB into nucleus, leading to suppressing LPS-induced inflammatory response and oxidative stress.

A chromosome-level genome of Chenghua pig provides new insights into the domestication and local adaptation of pigs.

As a country with abundant genetic resources of pigs, the domestication history of pigs in China and the adaptive evolution of Chinese pig breeds at different latitudes have rarely been elucidated at the genome-wide level. To fill this gap, we first assembled a high-quality chromosome-level genome of the Chenghua pig and used it as a benchmark to analyse the genomes of 272 samples from three genera of three continents. The divergence of the three species belonging to three genera, Phacochoerus africanus, Potamochoerus porcus, and Sus scrofa, was assessed. The introgression of pig breeds redefined that the migration routes were basically from southern China to central and southwestern China, then spread to eastern China, arrived in northern China, and finally reached Europe. The domestication of pigs in China occurred ∼12,000 years ago, earlier than the available Chinese archaeological domestication evidence. In addition, FBN1 and NR6A1 were identified in our study as candidate genes related to extreme skin thickness differences in Eurasian pig breeds and adaptive evolution at different latitudes in Chinese pig breeds, respectively. Our study provides a new resource for the pig genomic pool and refines our understanding of pig genetic diversity, domestication, migration, and adaptive evolution at different latitudes.

Haplotype-resolved 3D chromatin architecture of the hybrid pig.

In diploid mammals, allele-specific three-dimensional (3D) genome architecture may lead to imbalanced gene expression. Through ultradeep in situ Hi-C sequencing of three representative somatic tissues (liver, skeletal muscle, and brain) from hybrid pigs generated by reciprocal crosses of phenotypically and physiologically divergent Berkshire and Tibetan pigs, we uncover extensive chromatin reorganization between homologous chromosomes across multiple scales. Haplotype-based interrogation of multi-omic data revealed the tissue dependence of 3D chromatin conformation, suggesting that parent-of-origin-specific conformation may drive gene imprinting. We quantify the effects of genetic variations and histone modifications on allelic differences of long-range promoter-enhancer contacts, which likely contribute to the phenotypic differences between the parental pig breeds. We also observe the fine structure of somatically paired homologous chromosomes in the pig genome, which has a functional implication genome-wide. This work illustrates how allele-specific chromatin architecture facilitates concomitant shifts in allele-biased gene expression, as well as the possible consequential phenotypic changes in mammals.

Black Phosphorus Accelerates Bone Regeneration Based on Immunoregulation.

A fundamental understanding of inflammation and tissue healing suggests that the precise regulation of the inflammatory phase, both in terms of location and timing, is crucial for bone regeneration. However, achieving the activation of early inflammation without causing chronic inflammation while facilitating quick inflammation regression to promote bone regeneration continues to pose challenges. This study reveals that black phosphorus (BP) accelerates bone regeneration by building an osteogenic immunological microenvironment. BP amplifies the acute pro-inflammatory response and promotes the secretion of anti-inflammatory factors to accelerate inflammation regression and tissue regeneration. Mechanistically, BP creates an osteoimmune-friendly microenvironment by stimulating macrophages to express interleukin 33 (IL-33), amplifying the inflammatory response at an early stage, and promoting the regression of inflammation. In addition, BP-mediated IL-33 expression directly promotes osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), which further facilitates bone repair. To the knowledge, this is the first study to reveal the immunomodulatory potential of BP in bone regeneration through the regulation of both early-stage inflammatory responses and later-stage inflammation resolution, along with the associated molecular mechanisms. This discovery serves as a foundation for the clinical use of BP and is an efficient approach for managing the immune microenvironment during bone regeneration.

Corrigendum: Zilucoplan, a macrocyclic peptide inhibitor of human complement component 5, uses a dual mode of action to prevent terminal complement pathway activation.

[This corrects the article DOI: 10.3389/fimmu.2023.1213920.].

Genomic prediction of pig growth traits based on machine learning.

This study aimed to assess and compare the performance of different machine learning models in predicting selected pig growth traits and genomic estimated breeding values (GEBV) using automated machine learning, with the goal of optimizing whole-genome evaluation methods in pig breeding. The research employed genomic information, pedigree matrices, fixed effects, and phenotype data from 9968 pigs across multiple companies to derive four optimal machine learning models: deep learning (DL), random forest (RF), gradient boosting machine (GBM), and extreme gradient boosting (XGB). Through 10-fold cross-validation, predictions were made for GEBV and phenotypes of pigs reaching weight milestones (100 kg and 115 kg) with adjustments for backfat and days to weight. The findings indicated that machine learning models exhibited higher accuracy in predicting GEBV compared to phenotypic traits. Notably, GBM demonstrated superior GEBV prediction accuracy, with values of 0.683, 0.710, 0.866, and 0.871 for B100, B115, D100, and D115, respectively, slightly outperforming other methods. In phenotype prediction, GBM emerged as the best-performing model for pigs with B100, B115, D100, and D115 traits, achieving prediction accuracies of 0.547, followed by DL at 0.547, and then XGB with accuracies of 0.672 and 0.670. In terms of model training time, RF required the most time, while GBM and DL fell in between, and XGB demonstrated the shortest training time. In summary, machine learning models obtained through automated techniques exhibited higher GEBV prediction accuracy compared to phenotypic traits. GBM emerged as the overall top performer in terms of prediction accuracy and training time efficiency, while XGB demonstrated the ability to train accurate prediction models within a short timeframe. RF, on the other hand, had longer training times and insufficient accuracy, rendering it unsuitable for predicting pig growth traits and GEBV.

α 2 -ADRENORECEPTOR ANTAGONIST AMELIORATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY SUPPRESSING NOREPINEPHRINE-MEDIATED FIBROBLAST DIFFERENTIATION VIA INHIBITING PKC ACTIVATION.

ABSTRACT: Pulmonary fibrosis is an important factor affecting the prognosis of severe septic patients with acute lung injury. The objective of this study was to explore the effect of norepinephrine (NE) and α 2 -adrenoreceptor (AR) on sepsis-associated pulmonary fibrosis and the mechanism underlying these effects. We found pulmonary fibrotic changes, and increased NE production and α 2A -AR expression in the pulmonary tissue of mice subjected to cecal ligation and puncture surgery. Reserpine and yohimbine alleviated pulmonary fibrosis in mice with sepsis by exhausting NE derived from the lung's adrenergic nerve and blocking α 2 -AR, respectively. There was no significant difference in the expression of the three α 1 -AR subtypes. The effect of NE on promoting pulmonary fibroblast differentiation in vitro was suppressed by yohimbine. Both the protein and mRNA expression levels of α 2A -AR were increased in pulmonary fibroblasts treated with LPS. Clonidine, a selective α 2 -AR agonist, enhanced LPS-induced differentiation in pulmonary fibroblasts, as indicated by the increase in α-smooth muscle actin and collagen I/III, which was mitigated by inhibiting PKC and p38. Further in vivo results indicated that yohimbine alleviated pulmonary fibrosis and inhibited the phosphorylation of PKC, p38, and Smad2/3 in lung tissue of mice exposed to LPS for 4 weeks. Clonidine showed the opposite effect to yohimbine, which aggravated LPS-induced pulmonary fibrosis. These findings demonstrated that the sepsis-induced increase in NE promoted fibroblast differentiation via activating α 2 -AR. Blockage of α 2 -AR effectively ameliorated sepsis-associated pulmonary fibrosis by abolishing NE-induced lung fibroblast differentiation and inhibiting the PKC-p38-Smad2/3 pathway.

Zilucoplan, a macrocyclic peptide inhibitor of human complement component 5, uses a dual mode of action to prevent terminal complement pathway activation.

Introduction: The complement system is a key component of the innate immune system, and its aberrant activation underlies the pathophysiology of various diseases. Zilucoplan is a macrocyclic peptide that binds and inhibits the cleavage/activation of human complement component 5 (C5). We present in vitro and ex vivo data on the mechanism of action of zilucoplan for the inhibition of C5 activation, including two clinically relevant C5 polymorphisms at R885. Methods: The interaction of zilucoplan with C5, including for clinical C5 R885 variants, was investigated using surface plasmon resonance (SPR), hemolysis assays, and ELISA. The interference of C5b6 formation by zilucoplan was investigated by native gel analysis and hemolysis assay. The permeability of zilucoplan in a reconstituted basement membrane was assessed by the partition of zilucoplan on Matrigel-coated transwell chambers. Results: Zilucoplan specifically bound human complement C5 with high affinity, competitively inhibited the binding of C5 to C3b, and blocked C5 cleavage by C5 convertases and the assembly of the cytolytic membrane attack complex (MAC, or C5b9). Zilucoplan fully prevented the in vitro activation of C5 clinical variants at R885 that have been previously reported to respond poorly to eculizumab treatment. Zilucoplan was further demonstrated to interfere with the formation of C5b6 and inhibit red blood cell (RBC) hemolysis induced by plasmin-mediated non-canonical C5 activation. Zilucoplan demonstrated greater permeability than a monoclonal C5 antibody in a reconstituted basement membrane model, providing a rationale for the rapid onset of action of zilucoplan observed in clinical studies. Conclusion: Our findings demonstrate that zilucoplan uses a dual mode of action to potently inhibit the activation of C5 and terminal complement pathway including wild-type and clinical R885 variants that do not respond to eculizumab treatment. These data may be relevant to the clinically demonstrated benefits of zilucoplan.

CYP24A1 is associated with fetal mummification in pigs.

Mummified piglets are among the leading causes of fertility loss and severely hamper reproductive performance in pigs. However, the contributions of genomic variation to the emergence of mummified piglets (MUM) have rarely been studied. This study aims to (1) elucidate the genetic architecture of MUM in sows of parity 1 - 3 using a single-step genome-wide association study (ssGWAS). The ssGWAS involved genotyping-by-sequencing of Large White and Landrace pig breeds. (2) Explore the biological role of the candidate genes at the cellular level. A total of 185 and 48 genome-wide significant SNPs are associated with MUM in Large White and Landrace pigs, explaining 0.01-36.52% genetic variance for different significant loci, respectively. All the significant SNPs are parity-specific, and the numerous, consecutive significant loci likely generated the nine significant peaks in different parities. Multiple candidate genes (including CYP24A1, FBXO30, and ARHGEF28) are associated with fetal congenital and maternal diseases. Collectively, CYP24A1 regulation contributes to steady-state levels of embryo development genes. CYP24A1 is involved in reproduction and, immune and gestational disorders. Thus, it is associated with known newborn death traits and MUM in Large White sows. Altogether, these results improve the current understanding of the genetic architecture of MUM and expand the knowledge on genetic variations for selecting against mummified piglets in pig breeding.

An Analysis of the COVID-19-Induced Flexible Grading Policy at a Public University.

To help students cope with the challenges of the COVID-19 pandemic, higher education institutions offered students flexible grading policies that blended traditional letter grades with alternative grading options such as the pass-fail or credit-no credit options. This study conducted an in-depth analysis of the flexible grading policy at a medium-sized university in the USA. We studied the differential selection of flexible grading options by course characteristics and students' sociodemographics and academic profiles between Spring 2020 and Spring 2021. We also examined the impacts of the policy on sequential courses. Our analysis utilized administrative and transcript data for undergraduate students at the study institution and employed a combination of descriptive statistics and regression models. The analysis revealed that the flexible grading policy was utilized differently depending on course characteristics, with core courses and subjects like mathematics, chemistry, and economics having higher rates of usage. Additionally, sociodemographic and academic profile factors led to varying degrees of utilization, with males, urban students, freshmen, and non-STEM majors using the policy more frequently. Furthermore, the analysis suggested that the policy may have disadvantaged some students as they struggled in subsequent courses after using the pass option. Several implications and directions for future research are discussed.

A single-cell transcriptome atlas of pig skin characterizes anatomical positional heterogeneity.

Different anatomical locations of the body skin show differences in their gene expression patterns depending on different origins, and the inherent heterogeneous information can be maintained in adults. However, highly resolvable cellular specialization is less well characterized in different anatomical regions of the skin. Pig is regarded as an excellent model animal for human skin research in view of its similar physiology to human. In this study, single-cell RNA sequencing was performed on pig skin tissues from six different anatomical regions of Chenghua (CH) pigs, with a superior skin thickness trait, and the back site of large white (LW) pigs. We obtained 233,715 cells, representing seven cell types, among which we primarily characterized the heterogeneity of the top three cell types, including smooth muscle cells (SMCs), endothelial cells (ECs), and fibroblasts (FBs). Then, we further identified several subtypes of SMCs, ECs, and FBs, and discovered the expression patterns of site-specific genes involved in some important pathways such as the immune response and extracellular matrix (ECM) synthesis in different anatomical regions. By comparing differentially expressed genes of skin FBs among different anatomical regions, we considered TNN, COL11A1, and INHBA as candidate genes for facilitating ECM accumulation. These findings of heterogeneity in the main skin cell types from different anatomical sites will contribute to a better understanding of inherent skin information and place the potential focus on skin generation, transmission, and transplantation, paving the foundation for human skin priming.

Dynamic chromatin architecture of the porcine adipose tissues with weight gain and loss.

Using an adult female miniature pig model with diet-induced weight gain/weight loss, we investigated the regulatory mechanisms of three-dimensional (3D) genome architecture in adipose tissues (ATs) associated with obesity. We generated 249 high-resolution in situ Hi-C chromatin contact maps of subcutaneous AT and three visceral ATs, analyzing transcriptomic and chromatin architectural changes under different nutritional treatments. We find that chromatin architecture remodeling underpins transcriptomic divergence in ATs, potentially linked to metabolic risks in obesity development. Analysis of chromatin architecture among subcutaneous ATs of different mammals suggests the presence of transcriptional regulatory divergence that could explain phenotypic, physiological, and functional differences in ATs. Regulatory element conservation analysis in pigs and humans reveals similarities in the regulatory circuitry of genes responsible for the obesity phenotype and identified non-conserved elements in species-specific gene sets that underpin AT specialization. This work provides a data-rich tool for discovering obesity-related regulatory elements in humans and pigs.

The E3 ubiquitin ligase CHIP protects against sepsis-induced myocardial dysfunction by inhibiting NF-κB-mediated inflammation via promoting ubiquitination and degradation of karyopherin-α 2.

Cardiac dysfunction has been recognized as a major contributor to mortality in sepsis, which is closely associated with inflammatory reactions. The carboxy terminus of Hsc70-interacting protein (CHIP), a U-box E3 ubiquitin ligase, defends against cardiac injury caused by other factors, but its role in sepsis-induced cardiac dysfunction has yet to be determined. The present study was designed to investigate the effects of CHIP on cardiac dysfunction caused by sepsis and the molecular mechanisms underlying these processes. We discovered that the CHIP level decreased gradually in the heart at different time points after septic model construction. The decline in CHIP expression of lipopolysaccharide (LPS)-stimulated cardiomyocytes was related to c-Jun activation that inhibited the transcription of CHIP. Functional biology experiments indicated that CHIP bound directly to karyopherin-α 2 (KPNA2) and promoted its degradation through polyubiquitination in cardiomyocytes. CHIP overexpression in cardiomyocytes obviously inhibited LPS-initiated release of TNF-α and IL-6 by promoting KPNA2 degradation, reducing NF-κB translocation into the nucleus. Consistent with the in vitro results, data obtained from animal experiments indicated that septic transgenic mice with heart-specific CHIP overexpression showed a weaker proinflammatory response and reduced cardiac dysfunction than septic control mice. Furthermore, we found that the therapeutic effect of compound YL-109 on cardiac dysfunction in septic mice was due to the upregulation of myocardial CHIP expression. These findings demonstrated that sepsis-initiated the activation of c-Jun suppressed CHIP transcription. CHIP directly promoted ubiquitin-mediated degradation of KPNA2, which reduced the production of proinflammatory cytokines by inhibiting the translocation of NF-κB from the cytoplasm into the nucleus in myocardium, thereby attenuating sepsis-induced cardiac dysfunction.

Whole-genome sequence association study identifies cyclin dependent kinase 8 as a key gene for the number of mummified piglets.

OBJECTIVE: Pigs, an ideal biomedical model for human diseases, suffer from about 50% early embryonic and fetal death, a major cause of fertility loss worldwide. However, identifying the causal variant remains a huge challenge. This study aimed to detect single nucleotide polymorphisms (SNPs) and candidate genes for the number of mummified (NM) piglets using the imputed whole-genome sequence (WGS) and validate the potential candidate genes. METHODS: The imputed WGS was introduced from genotyping-by-sequencing (GBS) using a multi-breed reference population. We performed genome-wide association studies (GWAS) for NM piglets at birth from a Landrace pig populatiGWAS peak located on SSC11: 0.10 to 7.11 Mbp (Top SNP, SSC11:1,889,658 bp; p = 9.98E-13) was identified in cyclin dependent kinase on. A total of 300 Landrace pigs were genotyped by GBS. The whole-genome variants were imputed, and 4,252,858 SNPs were obtained. Various molecular experiments were conducted to determine how the genes affected NM in pigs. RESULTS: A strong GWAS peak located on SSC11: 0.10 to 7.11 Mbp (Top SNP, SSC11:1,889,658 bp; p = 9.98E-13) was identified in cyclin dependent kinase 8 (CDK8) gene, which plays a crucial role in embryonic retardation and lethality. Based on the molecular experiments, we found that Y-box binding protein 1 (YBX1) was a crucial transcription factor for CDK8, which mediated the effect of CDK8 in the proliferation of porcine ovarian granulosa cells via transforming growth factor beta/small mother against decapentaplegic signaling pathway, and, as a consequence, affected embryo quality, indicating that this pathway may be contributing to mummified fetal in pigs. CONCLUSION: A powerful imputation-based association study was performed to identify genes associated with NM in pigs. CDK8 was suggested as a functional gene for the proliferation of porcine ovarian granulosa cells, but further studies are required to determine causative mutations and the effect of loci on NM in pigs.

Pituitary-Gland-Based Genes Participates in Intrauterine Growth Restriction in Piglets.

Intrauterine growth restriction (IUGR) is a major problem associated with piglet growth performance. The incidence of IUGR is widespread in Rongchang pigs. The pituitary gland is important for regulating growth and metabolism, and research has identified genes associated with growth and development. The pituitary gland of newborn piglets with normal birth weight (NBW group, n = 3) and (IUGR group, n = 3) was collected for transcriptome analysis. A total of 323 differentially expression genes (DEGs) were identified (|log2(fold-change)| > 1 and q value < 0.05), of which 223 were upregulated and 100 were downregulated. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that the DEGs were mainly related to the extracellular matrix, regulation of the multicellular organismal process, tissue development and angiogenesis, which participate in the growth and immune response in IUGR piglets. Moreover, 7 DEGs including IGF2, THBS1, ITGA1, ITGA8, EPSTI1, FOSB, and UCP2 were associated with growth and immune response. Furthermore, based on the interaction network analysis of the DEGs, two genes, IGF2 and THBS1, participated in cell proliferation, embryonic development and angiogenesis. IGF2 and THBS1 were also the main genes participating in the IUGR. This study identified the core genes involved in IUGR in piglets and provided a reference for exploring the effect of the pituitary gland on piglet growth.