Chromosome-level dairy goat genome reveals the regulatory landscape of lactation.

Goat milk is rich in various nutrients that are beneficial for human health. However, the genomic evolution and genetic basis underlying the nutritional value and unique flavor formation in dairy goats remain poorly understood. In the present study, we generate a chromosome-level genome assembly for dairy goats comprising 2.63 Gb with a contig N50 of 43 Mb and a scaffold N50 of 101 Mb. Genome quality comparisons revealed that the dairy goat genome has higher integrity and continuity than the published goat and sheep genomes. The identification of genes under positive selection in dairy goats highlights potential candidates to explain their high milk production. Comparative genomic analysis elucidates the adaptive evolutionary mechanisms of dairy goats such as strong disease resistance, broad adaptability, and unique milk flavor. Moreover, we demonstrate the conservation of the lactation gene network and identify new potential regulators associated with lipid metabolism. Additionally, we establish the regulatory landscape of lactation for the first time in dairy goats, revealing its unique gene regulatory characteristics. Hence, our study not only provides the first chromosome-level reference genome for dairy goat, but also offers potential research directions for dairy production and genetic improvement.

Genomic and transcriptomic landscape to decipher the genetic basis of hyperpigmentation in Lanping black-boned sheep (Ovis aries).

BACKGROUND: Lanping black-boned sheep (LPB) represent a distinctive mammalian species characterized by hyperpigmentation, resulting in black bone and muscle features, in contrast to their conventional counterparts exhibiting red muscle and white bone. The genetic basis underlying LPB hyperpigmentation has remained enigmatic. METHODS: In this study, we conducted whole-genome sequencing of 100 LPB and 50 Lanping normal sheep (LPN), and integrated this data with 421 sequenced datasets from wild and domestic sheep, shedding light on the genetic backdrop and genomic variations associated with LPB. Furthermore, we performed comparative RNA-Seq analysis using liver sample to pinpoint genes implicated in the pigmentation process. We generated a comprehensive dataset comprising 97,944,357 SNPs from 571 sheep, facilitating an in-depth exploration of genetic factors. RESULTS: Population genetic structure analysis revealed that the LPB breed traces its origin back to LPN, having evolved into a distinct breed. The integration of positively selected genes with differentially expressed genes identified two candidates, ERBB4 and ROR1, potentially linked to LPB hyperpigmentation. Comparative analysis of ERBB4 and ROR1 mRNA relative expression levels in liver, spleen, and kidney tissues of LPB, in comparison to Diqing sheep, revealed significant upregulation, except for ERBB4 in the liver. Gene expression heatmaps further underscored marked allelic frequency disparities in different populations. CONCLUSION: Our findings establish the evolutionary lineage of the LPB breed from LPN and underscore the involvement of ERBB4 and ROR1 genes in melanin synthesis. These results enhance our comprehension of the molecular basis of hyperpigmentation and contribute to a more comprehensive depiction of sheep diversity.

Application of Pan-Omics Technologies in Research on Important Economic Traits for Ruminants.

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.

Sirtuin 1 Inhibits Fatty Acid Synthesis through Forkhead Box Protein O1-Mediated Adipose Triglyceride Lipase Expression in Goat Mammary Epithelial Cells.

Sirtuin 1 (SIRT1) is a key upstream regulator of lipid metabolism; however, the molecular mechanisms by which SIRT1 regulates milk fat synthesis in dairy goats remain unclear. This study aimed to investigate the regulatory roles of SIRT1 in modulating lipid metabolism in goat mammary epithelial cells (GMECs) and its impact on the adipose triglyceride lipase (ATGL) promoter activity using RNA interference (RNAi) and gene overexpression techniques. The results showed that SIRT1 is significantly upregulated during lactation compared to the dry period. Additionally, SIRT1 knockdown notably increased the expressions of genes related to fatty acid synthesis (SREBP1, SCD1, FASN, ELOVL6), triacylglycerol (TAG) production (DGAT2, AGPAT6), and lipid droplet formation (PLIN2). Consistent with the transcriptional changes, SIRT1 knockdown significantly increased the intracellular contents of TAG and cholesterol and the lipid droplet abundance in the GMECs, while SIRT1 overexpression had the opposite effects. Furthermore, the co-overexpression of SIRT1 and Forkhead box protein O1 (FOXO1) led to a more pronounced increase in ATGL promoter activity, and the ability of SIRT1 to enhance ATGL promoter activity was nearly abolished when the FOXO1 binding sites (FKH1 and FKH2) were mutated, indicating that SIRT1 enhances the transcriptional activity of ATGL via the FKH element in the ATGL promoter. Collectively, our data reveal that SIRT1 enhances the transcriptional activity of ATGL through the FOXO1 binding sites located in the ATGL promoter, thereby regulating lipid metabolism. These findings provide novel insights into the role of SIRT1 in fatty acid metabolism in dairy goats.

Elucidating hydroxysafflor yellow A's multi-target mechanisms against alcoholic liver disease through integrative pharmacology.

BACKGROUND: Alcoholic liver disease (ALD) significantly contributes to global liver-related morbidity and mortality. Natural products play a crucial role in the prevention and treatment of ALD. Hydroxysafflor yellow A (HSYA), a unique and primary component of Safflower (Carthamus tinctorius l.), exhibits diverse pharmacological activities. However, the impact and mechanism of HSYA on ALD have not been fully elucidated. PURPOSE: The purpose of this study was to employ an integrative pharmacology approach to assess the multi-targeted mechanism of HSYA against ALD. METHODS: Network pharmacology and molecular docking techniques were used to analyze the potential therapeutic signaling pathways and targets of HSYA against ALD. An ALD model in zebrafish larvae was established. Larvae were pretreated with HSYA and then exposed to ethanol. Liver injury was measured by fluorescence expression analysis in the liver-specific transgenic zebrafish line Tg (fabp10a:DsRed) and liver tissue H&E staining. Liver steatosis was determined by whole-mount oil red O staining and TG level. Additionally, an ethanol-induced hepatocyte injury model was established in vitro to observe hepatocyte damage (cell viability, ALT level), lipid accumulation (oil red O staining, TC and TG), and oxidative stress (ROS, MDA, GPx and SOD) in HepG2 cells treated with or without HSYA. Finally, qRT-PCR combined with network pharmacology and molecular docking was employed to validate the effects of HSYA on targets. RESULTS: HSYA exhibited a significant, dose-dependent improvement in ethanol-induced liver injury in zebrafish larvae and HepG2 cells. Network pharmacology analysis revealed that HSYA may exert pharmacological effects against ALD through 341 potential targets. These targets are involved in various signaling pathways, including lipid metabolism and atherosclerosis, PI3K-Akt signaling pathway, MAPK signaling pathway, and ALD itself. Molecular docking studies displayed that HSYA had a strong binding affinity toward the domains of IL1B, IL6, TNF, PPARA, PPARG, HMGCR and ADH5. qRT-PCR assays demonstrated that HSYA effectively reversed the ethanol-induced aberrant gene expression of SREBF1, FASN, ACACA, CPT1A, PPARA, IL1B, IL6, TNFα, ADH5, and ALDH2 in vivo and in vitro. CONCLUSION: This study offers a comprehensive investigation into the anti-ALD mechanisms of HSYA using an integrative pharmacology approach. The potential targets of HSYA may be implicated in enhancing ethanol catabolism, reducing lipid accumulation, mitigating oxidative stress, and inhibiting inflammatory response.

Causal validation of the relationship between 35 blood and urine biomarkers and hyperthyroidism: a bidirectional Mendelian randomization study and meta-analysis.

Background: Hyperthyroidism is an endocrine disorder with a relatively low global prevalence but significantly higher incidence among females compared to males. The onset age primarily ranges from 30 to 50, although it is not limited to this age group. Challenges in the treatment of hyperthyroidism include individualized treatment plan formulation, management of side effects, and prediction of disease progression, necessitating comprehensive consideration to achieve more effective therapy and management. Mendelian randomization studies can reveal more precise therapeutic targets between blood and urine biomarkers and hyperthyroidism, providing more decadent treatment options for the condition. Methods: The study will build upon the omics Mendelian randomization (MR) framework by conducting MR analysis using 35 blood and urine biomarkers separately for two distinct databases of hyperthyroidism. Subsequently, the results will undergo meta-analysis and multiple corrections to ensure accuracy and reliability. Finally, positive findings will undergo reverse MR validation to verify causal relationships with hyperthyroidism. Results: In the British database, the MR analysis of Total bilirubin levels about hyperthyroidism yielded an odds ratio (OR) of 1.097 (95% CI: 0.951-1.265, P = 0.205). Conversely, in the Thyroid Omics Association database, the MR analysis revealed an OR of 1.283 (95% CI: 1.122-1.467, P = 0.0002) for the same relationship. Meta-analysis of the MR analysis results from both databases, following multiple corrections, resulted in an OR of 1.192 (95% CI: 1.081-1.314, P = 0.015). Additionally, the direction of beta values in the MR analysis results from both databases was consistent. Conclusion: The urine biomarker total bilirubin levels may contribute to an increased risk of hyperthyroidism and accelerate its progression, thus representing a risk factor for the condition.

Sub-regional Radiomics Analysis for Predicting Metastasis Risk in Clear Cell Renal Cell Carcinoma: A Multicenter Retrospective Study.

RATIONALE AND OBJECTIVES: Clear cell renal cell carcinoma (ccRCC) is the most common malignant neoplasm affecting the kidney, exhibiting a dismal prognosis in metastatic instances. Elucidating the composition of ccRCC holds promise for the discovery of highly sensitive biomarkers. Our objective was to utilize habitat imaging techniques and integrate multimodal data to precisely predict the risk of metastasis, ultimately enabling early intervention and enhancing patient survival rates. MATERIAL AND METHODS: A retrospective analysis was performed on a cohort of 263 patients with ccRCC from three hospitals between April 2013 and March 2021. Preoperative CT images, ultrasound images, and clinical data were comprehensively analyzed. Patients from two campuses of Qilu Hospital of Shandong University were assigned to the training dataset, while the third hospital served as the independent testing dataset. A robust consensus clustering method was used to classify the primary tumor space into distinct sub-regions (i.e., habitats) using contrast-enhanced CT images. Radiomic features were extracted from these tumor sub-regions and subsequently reduced to identify meaningful features for constructing a predictive model for ccRCC metastasis risk assessment. In addition, the potential value of radiomics in predicting ccRCC metastasis risk was explored by integrating ultrasound image features and clinical data to construct and compare alternative models. RESULTS: In this study, we performed k-means clustering within the tumor region to generate three distinct tumor subregions. We quantified the Hounsfiled Unit (HU) value, volume fraction, and distribution of high- and low-risk groups in each subregion. Our investigation focused on 252 patients with Habitat1 + Habitat3 to assess the discriminative power of these two subregions. We then developed a risk prediction model for ccRCC metastasis risk classification based on radiomic features extracted from CT and ultrasound images, and clinical data. The Combined model and the CT_Habitat3 model showed AUC values of 0.935 [95%CI: 0.902-0.968] and 0.934 [95%CI: 0.902-0.966], respectively, in the training dataset, while in the independent testing dataset, they achieved AUC values of 0.891 [95%CI: 0.794-0.988] and 0.903 [95%CI: 0.819-0.987], respectively. CONCLUSION: We have identified a non-invasive imaging predictor and the proposed sub-regional radiomics model can accurately predict the risk of metastasis in ccRCC. This predictive tool has potential for clinical application to refine individualized treatment strategies for patients with ccRCC.

Immunomodulatory effect of tibetan medicine compound extracts against ORFV in vitro by metabolomics.

Ovine contagious pustular dermatitis (ORF) is one of the main diseases of sheep and is a zoonotic disease caused by Ovine contagious pustular dermatitis virus (ORFV) infection, posing a significant constraint on sheep breeding industry and human health. The Tibetan medical formulation composed of Polygonum leucoides, Polygonum xanthoxylum and Acanthophora rotunda significantly regulated lymphocyte immune function following ORFV stimulation, although the mechanism remains unclear. In order to study the immunomodulatory effects and mechanism of three Tibetan medicinal extracts (Polygonum leucoides, Polygonum xanthoxylum, and Acanthophora rotunda) against ORFV in vitro, sheep peripheral blood lymphocytes were isolated in vitro and treated with different concentrations of Tibetan medicine compound extract solution after ORFV infection. The cytokine expression levels in lymphocytes were measured at 4 h, 8 h and 12 h. Additionally endogenous metabolites in lymphocytes at 0 h, 4 h, 8 h and 12 h were quantified by untargeted metabolomics method. The results showed that, the extracts could regulate the lymphocyte immune factors altered by ORFV, and regulate the lymphocyte immune function through cysteine and methionine metabolic pathways as well as the pyrimidine metabolic pathways, potentially alleviating the immune evasion induced by ORFV.

Diaminonaphthalene Boronic Acid (DANBA): New Approach for Peroxynitrite Sensing Site.

Selective detection of reactive oxygen species (ROS) is vital for studying their role in brain diseases. Fluorescence probes can distinguish ONOO- species from other ROS; however, their selectivity toward ONOO- species depends on the ONOO- recognition group. Aryl-boronic acids and esters, which are common ONOO- recognition groups, are not selective for ONOO- over H2O2. In this study, we developed a diaminonaphthalene (DAN)-protected boronic acid as a new ONOO- recognition group that selectively reacts with ONOO- over H2O2 and other ROS. Three DAN-protected boronic acid (DANBA)-based fluorophores that emit fluorescence over visible to near-infrared (NIR) regions, Cou-BN, BVP-BN, and HDM-BN, and their aryl-boronic acid-based counterparts (Cou-BO, BVP-BO, and HDM-BO), were developed. The DANBA-based probes exhibited enhanced selectivity toward ONOO- over that of their control group, as well as universality in MTT assays and in vitro experiments with PC12 cells. The NIR-emissive HDM-BN was optimized to delineate in vivo ONOO- levels in mouse brains with Parkinson's disease. This DAN-protected boronic acid belongs to a new generation of recognition groups for developing ONOO- probes, and this strategy could be extended to other common hydroxyl-containing dyes to detect ONOO- levels in complex biological systems and processes.

Application of GWAS and mGWAS in Livestock and Poultry Breeding.

In recent years, genome-wide association studies (GWAS) and metabolome genome-wide association studies (mGWAS) have emerged as crucial methods for investigating complex traits in animals and plants. These have played pivotal roles in research on livestock and poultry breeding, facilitating a deeper understanding of genetic diversity, the relationship between genes, and genetic bases in livestock and poultry. This article provides a review of the applications of GWAS and mGWAS in animal genetic breeding, aiming to offer reference and inspiration for relevant researchers, promote innovation in animal genetic improvement and breeding methods, and contribute to the sustainable development of animal husbandry.

Viola yedoensis Makino alleviates lipopolysaccharide-induced intestinal oxidative stress and inflammatory response by regulating the gut microbiota and NF-κB-NLRP3/ Nrf2-MAPK signaling pathway in broiler.

Viola yedoensis Makino (Vy) is a well-known traditional Chinese medicine widely used to treat inflammatory diseases. However, the regulatory effects of dietary Vy supplementation on lipopolysaccharide (LPS)-induced intestinal damage in broilers and the underlying molecular mechanisms remain unclear. In this study, broilers were intraperitoneally injected with 1 mg/kg LPS on days 17, 19 and 21 to induce intestinal damage. Vy supplementation at 0.5, 1.5 and 4.5 % in the diet was administered separately for 21 days to investigate the potential protective effects of Vy supplementation against LPS-induced intestinal impairment in broilers. Vy supplementation improved intestinal morphology and restored growth performance. Vy supplementation attenuated intestinal inflammation by regulating the nuclear factor kappa B (NF-κB) / NLR family pyrin domain-containing 3 (NLRP3) signaling pathway and inhibited its downstream pro-inflammatory factor levels. In addition, Vy supplementation relieved intestinal oxidative impairment by regulating the nuclear factor erythroid-2 related factor 2 (Nrf2) / mitogen-activated protein kinase (MAPK) signaling pathway and downstream antioxidant enzyme activity. Vy supplementation reduced LPS-induced mitochondrial damage and apoptosis. Furthermore, Vy supplementation alleviated LPS-induced intestinal inflammation and oxidative damage in chickens by increasing the abundance of protective bacteria (Lactobacillus and Romboutsia) and reducing the number of pathogenic bacteria (unclassified_f_Ruminococcaceae, unclassified_f_Oscillospiraceae and norank_f_norank_o_Clostridia_vadinBB60_group). Overall, Vy supplementation effectively ameliorated LPS-induced intestinal damage by regulating the NF-κB-NLRP3/Nrf2-MAPK signaling pathway and maintaining intestinal microbiota balance. Vy supplementation can be used as a dietary supplement to protect broilers against intestinal inflammation and oxidative damage.

Chromatin accessibility and transcriptional landscape in PK-15 cells during early exposure to Aflatoxin B1.

Aflatoxin B1 (AFB1) not only causes significant losses in livestock production but also poses a serious threat to human health. It is the most carcinogenic among known chemicals. Pigs are more susceptible to AFB1 and experience a higher incidence. However, the molecular mechanism of the toxic effect of AFB1 remains unclear. In this study, we used assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA-seq to uncover chromatin accessibility and gene expression dynamics in PK-15 cells during early exposure to AFB1. We observed that the toxic effects of AFB1 involve signaling pathways such as p53, PI3K-AKT, Hippo, MAPK, TLRs, apoptosis, autophagy, and cancer pathways. Basic leucine zipper (bZIP) transcription factors (TFs), including AP-1, Fos, JunB, and Fra2, play a crucial role in regulating the biological processes involved in AFB1 challenge. Several new TFs, such as BORIS, HNF1b, Atf1, and KNRNPH2, represent potential targets for the toxic mechanism of AFB1. In addition, it is crucial to focus on the concentration of intracellular zinc ions. These findings will contribute to a better understanding of the mechanisms underlying AFB1-induced nephrotoxicity and offer new molecular targets.

New perspectives on the therapeutic potential of quercetin in non-communicable diseases: Targeting Nrf2 to counteract oxidative stress and inflammation.

Non-communicable diseases (NCDs), including cardiovascular diseases, cancer, metabolic diseases, and skeletal diseases, pose significant challenges to public health worldwide. The complex pathogenesis of these diseases is closely linked to oxidative stress and inflammatory damage. Nuclear factor erythroid 2-related factor 2 (Nrf2), a critical transcription factor, plays an important role in regulating antioxidant and anti-inflammatory responses to protect the cells from oxidative damage and inflammation-mediated injury. Therefore, Nrf2-targeting therapies hold promise for preventing and treating NCDs. Quercetin (Que) is a widely available flavonoid that has significant antioxidant and anti-inflammatory properties. It modulates the Nrf2 signaling pathway to ameliorate oxidative stress and inflammation. Que modulates mitochondrial function, apoptosis, autophagy, and cell damage biomarkers to regulate oxidative stress and inflammation, highlighting its efficacy as a therapeutic agent against NCDs. Here, we discussed, for the first time, the close association between NCD pathogenesis and the Nrf2 signaling pathway, involved in neurodegenerative diseases (NDDs), cardiovascular disease, cancers, organ damage, and bone damage. Furthermore, we reviewed the availability, pharmacokinetics, pharmaceutics, and therapeutic applications of Que in treating NCDs. In addition, we focused on the challenges and prospects for its clinical use. Que represents a promising candidate for the treatment of NCDs due to its Nrf2-targeting properties.

Beef Cattle Genome Project: Advances in Genome Sequencing, Assembly, and Functional Genes Discovery.

Beef is a major global source of protein, playing an essential role in the human diet. The worldwide production and consumption of beef continue to rise, reflecting a significant trend. However, despite the critical importance of beef cattle resources in agriculture, the diversity of cattle breeds faces severe challenges, with many breeds at risk of extinction. The initiation of the Beef Cattle Genome Project is crucial. By constructing a high-precision functional annotation map of their genome, it becomes possible to analyze the genetic mechanisms underlying important traits in beef cattle, laying a solid foundation for breeding more efficient and productive cattle breeds. This review details advances in genome sequencing and assembly technologies, iterative upgrades of the beef cattle reference genome, and its application in pan-genome research. Additionally, it summarizes relevant studies on the discovery of functional genes associated with key traits in beef cattle, such as growth, meat quality, reproduction, polled traits, disease resistance, and environmental adaptability. Finally, the review explores the potential of telomere-to-telomere (T2T) genome assembly, structural variations (SVs), and multi-omics techniques in future beef cattle genetic breeding. These advancements collectively offer promising avenues for enhancing beef cattle breeding and improving genetic traits.

Effects of UV light on physicochemical changes in thermoplastic polyurethanes: Mechanism and disinfection byproduct formation.

The presence of microplastics (MPs) products and particles in the environment can significantly impact the human body. Most MPs that enter the environment also enter the water cycle. During sunlight light irradiation (especially ultraviolet (UV) part) or UV disinfection, many of these MPs, particularly those rich in surface functional groups like thermoplastic polyurethanes (TPU), undergo physicochemical changes that can affect the formation of disinfection byproducts (DBPs). This study investigates the physicochemical changes of TPU in water after exposure to UV irradiation and incubation in the dark, as well as the formation of DBPs after chlorination. The results show that TPU undergo chain breakage, oxidation, and cross-linking when exposed to UV irradiation in an aqueous system. This leads to fragmentation into smaller particles, which facilitates the synthesis of DBPs. Subsequent research has demonstrated that the TPU leaching solution produces a significantly higher DBP content than the chlorination of TPU MPs, particularly at high concentrations of CHCl3. Therefore, it is important to give greater consideration to the soluble DBP precursors released by TPU.

Invariant contexts reduce response time variability in visual search in an age-specific way: A comparison of children, teenagers, and adults.

Contextual cueing is a phenomenon in which repeatedly encountered arrays of items can enhance the visual search for a target item. This is widely attributed to attentional guidance driven by contextual memory acquired during visual search. Some studies suggest that children may have an immature ability to use contextual cues compared to adults, while others argue that contextual learning capacity is similar across ages. To test the development of context-guided attention, this study compared contextual cueing effects among three age groups: adults (aged 18-33 years, N = 32), teenagers (aged 15-17 years, N = 41), and younger children (aged 8-9 years, N = 43). Moreover, this study introduced a measure of response time variability that tracks fluctuations in response time throughout the experiment, in addition to the conventional analysis of response times. The results showed that all age groups demonstrated significantly faster responses in repeated than non-repeated search contexts. Notably, adults and teenagers exhibited smaller response time variability in repeated contexts than in non-repeated ones, while younger children did not. This implies that children are less efficient at consolidating contextual information into a stable memory representation, which may lead to less stable attentional guidance during visual search.

Acquired immune thrombotic thrombocytopenic purpura (TTP) associated with inactivated COVID-19 vaccine CoronaVac.

Corona virus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the whole world. Acquired thrombotic thrombocytopenic purpura (TTP) has been reported after administration of mRNA- or adenoviral vector-based COVID-19 vaccines, including Ad26.COV2-S, BNT162b2, mRNA-1273, and ChAdOx1 nCov-19. However, whether inactivated vaccines, such as CoronaVac, could cause TTP and whether the symptoms in TTPs caused by inactivated vaccines are different from previously reported cases are unknown. In this study, two cases were reported. Both cases developed TTP after the second CoronaVac vaccination shot, but not the first. They demonstrated symptoms of fever, neurological abnormalities, renal dysfunction, thrombocytopenia, and hemolysis. Both patients achieved complete remission through several sessions of plasma exchanges and immune suppression. The incidence of TTP in Nanjing area was analyzed. The number of patients with TTP was 12 in 2019, 6 in 2020, 16 in 2021, and 19 in 2022. To the authors' knowledge, this report is the first report of TTP associated with inactivated COVID-19 vaccine (CoronaVac). The rarity and delayed onset may be due to the relatively milder immune response caused by the inactivated vaccines than mRNA-based ones. Timely plasma exchange is a vital treatment for CoronaVac-related TTP, similar to activated vaccine-related TTP.

MicroRNA-505-3p mediates cell motility of epithelial ovarian cancer via suppressing PEAK1 expression.

MicroRNAs (miRNAs) are a class of small RNA genes with important roles in cancer biology regulation. There are considerable studies regarding the roles of microRNA-505-3p (miR-505-3p) in cancer development and progression, but the function of miR-505-3p in epithelial ovarian cancer (EOC) has not been fully clarified. Comparative analysis of miRNA expression data set was used to select differentially expressed miRNAs. Quantitative real-time polymerase chain reaction was applied to detect expression levels of RNAs, while western blot and immunofluorescence staining were performed to detect expression levels of proteins of interest. The motility of EOC cells was assessed by wound healing and transwell assays. The binding and regulating relationship between miRNA and its direct target gene was investigated by dual-luciferase assay. Our results show that miR-505-3p was upregulated in recurrent EOC, which significantly inhibits EOC cell motility via modulating cell epithelial-mesenchymal transition. Furthermore, our results indicated that PEAK1 expression was inhibited by direct binding of miR-505-3p into its 3'-URT in EOC cells. Importantly, knockdown of PEAK1 attenuated the effect of mi-505-3p inhibitor on EOC cell migration and invasion. In conclusion, our findings indicate that miRNA-505-3p inhibits EOC cell motility by targeting PEAK1.

Inhibition of ferroptosis rescues M2 macrophages and alleviates arthritis by suppressing the HMGB1/TLR4/STAT3 axis in M1 macrophages.

Ferroptosis is a type of programmed cell death driven by iron-dependent lipid peroxidation. The TNF-mediated biosynthesis of glutathione has been shown to protect synovial fibroblasts from ferroptosis in the hyperplastic synovium. Ferroptosis induction provides a novel therapeutic approach for rheumatoid arthritis (RA) by reducing the population of synovial fibroblasts. The beginning and maintenance of synovitis in RA are significantly influenced by macrophages, as they generate cytokines that promote inflammation and contribute to the destruction of cartilage and bone. However, the vulnerability of macrophages to ferroptosis in RA remains unclear. In this study, we found that M2 macrophages are more vulnerable to ferroptosis than M1 macrophages in the environment of the arthritis synovium with a high level of iron, leading to an imbalance in the M1/M2 ratio. During ferroptosis, HMGB1 released by M2 macrophages interacts with TLR4 on M1 macrophages, which in turn triggers the activation of STAT3 signaling in M1 macrophages and contributes to the inflammatory response. Knockdown of TLR4 decreased the level of cytokines induced by HMGB1 in M1 macrophages. The ferroptosis inhibitor liproxstatin-1 (Lip-1) started at the presymptomatic stage in collagen-induced arthritis (CIA) model mice, and GPX4 overexpression in M2 macrophages at the onset of collagen antibody-induced arthritis (CAIA) protected M2 macrophages from ferroptotic cell death and significantly prevented the development of joint inflammation and destruction. Thus, our study demonstrated that M2 macrophages are vulnerable to ferroptosis in the microenvironment of the hyperplastic synovium and revealed that the HMGB1/TLR4/STAT3 axis is critical for the ability of ferroptotic M2 macrophages to contribute to the exacerbation of synovial inflammation in RA. Our findings provide novel insight into the progression and treatment of RA.

Integrated mRNA-miRNA transcriptome profiling of blood immune responses potentially related to pulmonary fibrosis in forest musk deer.

Background: Forest musk deer (FMD, Moschus Berezovskii) is a critically endangered species world-widely, the death of which can be caused by pulmonary disease in the farm. Pulmonary fibrosis (PF) was a huge threat to the health and survival of captive FMD. MicroRNAs (miRNAs) and messenger RNAs (mRNAs) have been involved in the regulation of immune genes and disease development. However, the regulatory profiles of mRNAs and miRNAs involved in immune regulation of FMD are unclear. Methods: In this study, mRNA-seq and miRNA-seq in blood were performed to constructed coexpression regulatory networks between PF and healthy groups of FMD. The hub immune- and apoptosis-related genes in the PF blood of FMD were explored through Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Further, protein-protein interaction (PPI) network of immune-associated and apoptosis-associated key signaling pathways were constructed based on mRNA-miRNA in the PF blood of the FMD. Immune hub DEGs and immune hub DEmiRNAs were selected for experimental verification using RT-qPCR. Results: A total of 2744 differentially expressed genes (DEGs) and 356 differentially expressed miRNAs (DEmiRNAs) were identified in the PF blood group compared to the healthy blood group. Among them, 42 DEmiRNAs were negatively correlated with 20 immune DEGs from a total of 57 correlations. The DEGs were significantly associated with pathways related to CD molecules, immune disease, immune system, cytokine receptors, T cell receptor signaling pathway, Th1 and Th2 cell differentiation, cytokine-cytokine receptor interaction, intestinal immune network for IgA production, and NOD-like receptor signaling pathway. There were 240 immune-related DEGs, in which 186 immune-related DEGs were up-regulated and 54 immune-related DEGs were down-regulated. In the protein-protein interaction (PPI) analysis of immune-related signaling pathway, TYK2, TLR2, TLR4, IL18, CSF1, CXCL13, LCK, ITGB2, PIK3CB, HCK, CD40, CD86, CCL3, CCR7, IL2RA, TLR3, and IL4R were identified as the hub immune genes. The mRNA-miRNA coregulation analysis showed that let-7d, miR-324-3p, miR-760, miR-185, miR-149, miR-149-5p, and miR-1842-5p are key miRNAs that target DEGs involved in immune disease, immune system and immunoregulation. Conclusion: The development and occurrence of PF were significantly influenced by the immune-related and apoptosis-related genes present in PF blood. mRNAs and miRNAs associated with the development and occurrence of PF in the FMD.