ADAM9 promotes type I interferon-mediated innate immunity during encephalomyocarditis virus infection.

Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)-a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis.

Blockade of the ADAM8-Fra-1 complex attenuates neuroinflammation by suppressing the Map3k4/MAPKs axis after spinal cord injury.

BACKGROUND: Mechanical spinal cord injury (SCI) is a deteriorative neurological disorder, causing secondary neuroinflammation and neuropathy. ADAM8 is thought to be an extracellular metalloproteinase, which regulates proteolysis and cell adherence, but whether its intracellular region is involved in regulating neuroinflammation in microglia after SCI is unclear. METHODS: Using animal tissue RNA-Seq and clinical blood sample examinations, we found that a specific up-regulation of ADAM8 in microglia was associated with inflammation after SCI. In vitro, microglia stimulated by HMGB1, the tail region of ADAM8, promoted microglial inflammation, migration and proliferation by directly interacting with ERKs and Fra-1 to promote activation, then further activated Map3k4/JNKs/p38. Using SCI mice, we used BK-1361, a specific inhibitor of ADAM8, to treat these mice. RESULTS: The results showed that administration of BK-1361 attenuated the level of neuroinflammation and reduced microglial activation and recruitment by inhibiting the ADAM8/Fra-1 axis. Furthermore, treatment with BK-1361 alleviated glial scar formation, and also preserved myelin and axonal structures. The locomotor recovery of SCI mice treated with BK-1361 was therefore better than those without treatment. CONCLUSIONS: Taken together, the results showed that ADAM8 was a critical molecule, which positively regulated neuroinflammatory development and secondary pathogenesis by promoting microglial activation and migration. Mechanically, ADAM8 formed a complex with ERK and Fra-1 to further activate the Map3k4/JNK/p38 axis in microglia. Inhibition of ADAM8 by treatment with BK-1361 decreased the levels of neuroinflammation, glial formation, and neurohistological loss, leading to favorable improvement in locomotor functional recovery in SCI mice.

ADAM22 acts as a novel predictive biomarker for unfavorable prognosis and facilitates metastasis via PI3K/AKT signaling pathway in nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a type of epithelial malignancy known for its high likelihood of metastasizing to distant organs, which remains the primary obstacle in the treatment of NPC. The present study aimed to identify potential intervention target for NPC metastasis. METHODS: The differentially expressed genes (DEGs) were firstly analyzed and intersected across various NPC related datasets in the Gene Expression Omnibus database. Subsequently, various techniques including quantitative polymerase chain reaction (qPCR), western blotting, immunohistochemistry, migration and invasion assays, in conjunction with bioinformatics and prognostic modeling, were utilized to elucidate the role of candidate genes in NPC metastasis. RESULTS: We discerned the gene a disintegrin and metalloprotease 22 (ADAM22) as a distinct and significant factor in the progression and metastasis of NPC through five datasets. The elevated expression of ADAM22 was observed in clinical tissue and plasma samples with advanced NPC, as well as in high metastatic cells. Furthermore, we highlighted its essential role in a prognostic model that demonstrated strong prediction performance for NPC. Notably, overexpression of ADAM22 was found to enhance the aggressiveness and epithelial-mesenchymal transition (EMT) of low metastatic NPC cells, whereas the downregulation of ADAM22 resulted in suppressed effect in high metastatic cells. Delving into the mechanism, ADAM22 activated the PI3K/Akt signaling pathway through the mediation of Rac Family Small GTPase 2 (RAC2), thereby facilitating EMT and metastasis in NPC. CONCLUSIONS: The study provided pioneering insights that ADAM22 had the potential to act as an oncogene by promoting EMT and metastasis of NPC through the RAC2-mediated PI3K/Akt signaling pathway. Thus, ADAM22 could serve as a novel prognostic indicator in NPC.

Digital methylation-specific PCR: New applications for liquid biopsy.

Epigenetic analysis is a fundamental part of understanding pathophysiological processes with potential applications in diagnosis, prognosis, and assessment of disease susceptibility. Epigenetic changes have been widely studied in chronic obstructive pulmonary disease (COPD), but currently, there is no molecular marker used to improve the treatment of patients. Furthermore, this progressive disease is a risk factor for the development of more severe COVID-19. Methylation-specific polymerase chain reaction (MSP-PCR) plays an important role in the analysis of DNA methylation profiles, and it is one of the most widely used techniques. In this context, the combination of MSP-PCR with emerging PCR technologies, such as digital PCR (dPCR), results in more accurate analyses of the DNA methylation profile of the genes under study. In this study, we propose the application of the MSP-dPCR technique to evaluate the methylation profile of the ADAM33 gene from saliva samples and lung tissue biopsies of patients with COPD and COVID-19. MSP-dPCR generated a measurable prediction of gene methylation rate, with the potential application of this combined technology for diagnostic and prognostic purposes. It has also proven to be a powerful tool for liquid biopsy applications.

ADAM33's Role in Asthma Pathogenesis: An Overview.

Asthma is a complex chronic respiratory disease characterized by airway hyperresponsiveness, inflammation, and obstruction. Many genes have been identified as associated with asthma but none with such substantial significance as the ADAM33 gene due to its role in airway remodeling and bronchial hyperresponsiveness. This review summarizes the current knowledge on the genetic and functional aspects of ADAM33 in asthma pathogenesis. We highlight its genetic variants associated with asthma susceptibility and severity, as well as the functional effects of ADAM33 on airway remodeling, smooth muscle cell proliferation, and its interplay with environmental factors. Additionally, we discuss the potential clinical implications of ADAM33 as a therapeutic target for asthma management.

Multiple genes in the Pate5-13 genomic region contribute to ADAM3 processing†.

Sperm proteins undergo post-translational modifications during sperm transit through the epididymis to acquire fertilizing ability. We previously reported that the genomic region coding Pate family genes is key to the proteolytic processing of the sperm membrane protein ADAM3 and male fertility. This region contains nine Pate family genes (Pate5-13), and two protein-coding genes (Gm27235 and Gm5916), with a domain structure similar to Pate family genes. Therefore, in this study, we aimed to identify key factors by narrowing the genomic region. We generated three knockout (KO) mouse lines using CRISPR/Cas9: single KO mice of Pate10 expressed in the caput epididymis; deletion KO mice of six caput epididymis-enriched genes (Pate5-7, 13, Gm27235, and Gm5916) (Pate7-Gm5916 KO); and deletion KO mice of four genes expressed in the placenta and epididymis (Pate8, 9, 11, and 12) (Pate8-12 KO). We observed that the fertility of only Pate7-Gm5916 KO males was reduced, whereas the rest remained unaffected. Furthermore, when the caput epididymis-enriched genes, Pate8 and Pate10 remained in Pate7-Gm5916 KO mice were independently deleted, both KO males displayed more severe subfertility due to a decrease in mature ADAM3 and a defect in sperm migration to the oviduct. Thus, our data showed that multiple caput epididymis-enriched genes within the region coding Pate5-13 cooperatively function to ensure male fertility in mice.

Hsa_circ_0001583 fuels bladder cancer metastasis by promoting staphylococcal nuclease and tudor domain containing 1-mediated MicroRNA decay.

Muscle-invasive and metastatic bladder cancer indicates extra worse prognosis. Accumulating evidence roots for the prominent role of circular RNAs(circRNAs) in bladder cancer, while the mechanisms linking circRNAs and bladder cancer metastasis remain limitedly investigated. Here, we identified a significantly upregulated circRNA candidate, hsa_circ_0001583, from online datasets. Validated by qRT-PCR, PCR, sanger sequencing, actinomycin D and RNase R digestion experiments, hsa_circ_0001583 was proved to be a genuine circular RNA with higher expression levels in bladder cancer tissue. Through gain and loss of function experiments, hsa_circ_0001583 exhibited potent migration and invasion powers both in vitro and in vivo. The staphylococcal nuclease and Tudor domain containing 1 (SND1) was identified as an authentic binding partner for hsa_circ_0001583 through RNA pulldown and RIP experiments. Elevated levels of hsa_circ_0001583 could bind more to SND1 and protect the latter from degradation. Rescue experiments demonstrated that such interaction-induced increased in SND1 levels in bladder cancer cells enabled the protein to pump its endonuclease activity, leading to the degradation of tumor-suppressing MicroRNAs (miRNAs) including miR-126-3p, the suppressor of Disintegrin And Metalloproteinase Domain-Containing Protein 9 (ADAM9), ultimately driving cells into a highly migrative and invasive state. In summary, our study is the first to highlight the upregulation of hsa_circ_0001583 in bladder cancer and its role in downregulating miR-126-3p by binding to and stabilizing the SND1 protein, thereby promoting bladder cancer cell migration and invasion. This study adds hsa_circ_0001583 to the pool of bladder cancer metastasis biomarkers and therapeutic targets.

Whole-exome sequencing analysis of patent ductus arteriosus in a Japanese macaque (Macaca fuscata).

We performed whole-exome sequencing using a human exome capture kit to analyze the potential genetic factors related to patent ductus arteriosus in Japanese macaques. Compared with the reference sequences of other primates, we identified potential missense variants in five genes: ADAM15, AZGP1, CSPG4, TNFRSF13B, and EPOR.

Functional characteristics of DNA N6-methyladenine modification based on long-read sequencing in pancreatic cancer.

Abnormalities of DNA modifications are closely related to the pathogenesis and prognosis of pancreatic cancer. The development of third-generation sequencing technology has brought opportunities for the study of new epigenetic modification in cancer. Here, we screened the N6-methyladenine (6mA) and 5-methylcytosine (5mC) modification in pancreatic cancer based on Oxford Nanopore Technologies sequencing. The 6mA levels were lower compared with 5mC and upregulated in pancreatic cancer. We developed a novel method to define differentially methylated deficient region (DMDR), which overlapped 1319 protein-coding genes in pancreatic cancer. Genes screened by DMDRs were more significantly enriched in the cancer genes compared with the traditional differential methylation method (P < 0.001 versus P = 0.21, hypergeometric test). We then identified a survival-related signature based on DMDRs (DMDRSig) that stratified patients into high- and low-risk groups. Functional enrichment analysis indicated that 891 genes were closely related to alternative splicing. Multi-omics data from the cancer genome atlas showed that these genes were frequently altered in cancer samples. Survival analysis indicated that seven genes with high expression (ADAM9, ADAM10, EPS8, FAM83A, FAM111B, LAMA3 and TES) were significantly associated with poor prognosis. In addition, the distinction for pancreatic cancer subtypes was determined using 46 subtype-specific genes and unsupervised clustering. Overall, our study is the first to explore the molecular characteristics of 6mA modifications in pancreatic cancer, indicating that 6mA has the potential to be a target for future clinical treatment.

Long non-coding RNA LINC00565 regulates ADAM19 expression through sponging microRNA-532-3p, thereby facilitating clear cell renal cell carcinoma progression.

Proven by publications, long non-coding RNAs (lncRNAs) play critical roles in the development of clear cell renal cell carcinoma (ccRCC). Although lncRNA LINC00565 has been implicated in the progression of various cancers, its biological effects on ccRCC remain unknown. This study aimed to investigate the biological functions of LINC00565, as well as its potential mechanism in ccRCC. Here, the expression data of mature microRNAs (miRNAs) (normal: 71, tumor: 545), messenger RNAs (mRNAs), and lncRNAs (normal: 72, tumor: 539) of ccRCC were acquired from The Cancer Genome Atlas (TCGA) database and subjected to differential expression analysis. Quantitative reverse transcriptase polymerase chain reaction analyzed the expression levels of LINC00565, miR-532-3p, and ADAM19 mRNA. TCGA database, dual-luciferase report detection, and Argonaute 2 RNA immunoprecipitation were utilized to confirm the relationships between LINC00565 and miR-532-3p and between miR-532-3p and ADAM19, respectively. The progression of ccRCC cells was determined via CCK-8, colony formation, scratch healing, and transwell assays. Western blot was applied to detect the protein levels of epithelial-mesenchymal transition markers and ADAM19. We herein suggested that LINC00565 was prominently upregulated in ccRCC tissues and cells. Knockdown of LINC00565 repressed cell progression. We further predicted and validated miR-532-3p as a target of LINC00565, and miR-532-3p could target ADAM19. Knockdown of LINC00565 resulted in ADAM19 level downregulation in ccRCC cells and suppressed miR-532-3p could restore ADAM19 level. Thus, the three RNAs constructed a ceRNA network. Overexpressed ADAM19 could eliminate the anticancer effects caused by knocking down LINC00565 on ccRCC cells. In conclusion, LINC00565 upregulated ADAM19 via absorbing miR-532-3p, thereby facilitating the progression of ccRCC cells.

Novel ADAMTS13 mutations in a patient with congenital thrombotic thrombocytopenic purpura.

Congenital thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive genetic disorder caused by mutations in the ADAMTS13 gene. Approximately 200 mutations of the ADAMTS-13 gene have been identified, although only a few have been characterized through in vitro expression studies. We conducted an investigation on a male congenital TTP patient with reduced plasma levels of ADAMTS13 activity. DNA sequence analysis revealed two mutations on chromosome 9 (1.9q34.2) in the patient's ADAMTS13 gene. One mutation was a non-synonymous mutation (exon 5: c.A530G: p.Y177C), while the other was a nonsense mutation (exon 21: c.G2651A: p.W884X). Both mutations were found to be heterozygous. The patient's parents had no history of thrombocytopenia or neurological symptoms. DNA sequence analysis showed the patient's father was a heterozygote for the nonsense mutation of the ADAMTS13 gene (exon 21: c.G2651A: p.W884X), while the mother was a heterozygote for the non-synonymous mutation of the ADAMTS13 gene (exon 5: c.A530G: p.Y177C). To investigate the mechanism behind ADAMTS13 deficiency in this patient, wild type (WT), ADAMTS13 p.Y177C, and ADAMTS13 p.W884X were transiently expressed in 293-6E cells. Expression studies revealed a significant reduction in enzyme activity and secretion, although the protease was detected within the cells. The 3D structures of the natural and mutated ADAMTS-13 proteins were partially reconstructed using the Phyre2 web server. The mutation that replaces the tyrosine residue at amino acid position 177 with cysteine may result in decreased steric hindrance and a looser structure. This mutation affects the binding of calcium ions and the secretion of the enzyme from intracellular to extracellular compartments.

Hereditary Thrombotic Thrombocytopenic Purpura.

Hereditary thrombotic thrombocytopenic purpura (hTTP), also known as Upshaw-Schulman syndrome, is a rare genetic disorder caused by mutations in the ADAMTS13 gene that leads to decreased or absent production of the plasma von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13. The result is circulating ultra-large multimers of VWF that can cause microthrombi, intravascular occlusion and organ damage, especially at times of turbulent circulation. Patients with hTTP may have many overt or clinically silent manifestations, and a high index of suspicion is required for diagnosis. For the treatment of hTTP, the goal is simply replacement of ADAMTS13. The primary treatment is prophylaxis with plasma infusions or plasma-derived factor VIII products, providing sufficient ADAMTS13 to prevent acute episodes. When acute episodes occur, prophylaxis is intensified. Recombinant ADAMTS13, which is near to approval, will immediately be the most effective and also the most convenient treatment. In this review, we discuss the possible clinical manifestations of this rare disease and the relevant differential diagnoses in different age groups. An extensive discussion on prophylaxis and treatment strategies is also presented. Unique real patient cases have been added to highlight critical aspects of hTTP manifestations, diagnosis and treatment.

Gender-specific lncRNA-miRNA-mRNA regulatory network to reveal potential genes for primary open-angle glaucoma.

BACKGROUND: Investigation of biomarkers may facilitate understanding the mechanisms of primary open-angle glaucoma (POAG) and developing therapeutic targets. This study aimed to identify potential genes based on competing endogenous RNA (ceRNA) network for POAG. METHODS: Based on long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNAs (mRNAs) from the Gene Expression Omnibus (GEO) database, we identified differential expressed lncRNAs (DELs), differential expressed miRNAs (DEMis) and differential expressed mRNAs (DEMs) and then constructed a ceRNA network. Through weighted gene co-expression network analysis (WGCNA), we identified gender-specific genes for gender-associated ceRNA network construction, followed by the protein-protein interaction (PPI) network and functional enrichment analysis to screen hub genes and reveal their functions. The expression levels of hub genes were measured in steroid-induced ocular hypertension (SIOH) mice. RESULTS: A total of 175 DELs, 727 DEMs and 45 DEMis were screened between control and POAG samples. Seven modules were identified through WGCNA and one module was associated with gender of POAG patients. We discovered 41 gender-specific genes for gender-associated ceRNA construction and then identified 8 genes (NAV3, C1QB, RXRB, P2RY4, ADAM15, VAV3, ZNF207 and TOP1), which were enriched in cell cycle-related pathways and immune-related pathways. C1QB, RXRB, Top1 and ZNF207 were highly interacted with other proteins. The expression levels of NAV3 and C1QB were downregulated in SIOH, while the levels of RXRB, P2RY4, ADAM15, VAV3, ZNF207 and TOP1 were upregulated in SIOH. CONCLUSION: This study identifies hub genes associated with the pathogenesis of gender-specific POAG and provides potential biomarkers for POAG.

Loss of cancer cell-derived ADAM15 alters the tumor microenvironment in colorectal tumors.

Tumor progression and response to treatment are highly affected by interactions between cancer cells and the tumor microenvironment (TME). Many of the soluble factors and signaling receptors involved in this crosstalk are shed by a disintegrin and metalloproteinases (ADAMs). Upregulation of ADAM15 has been linked to worse survival in cancer patients and a tumor-promoting function both in vitro and in murine cancer models. Although ADAM15 has been involved in cell-cell and cell-extracellular matrix interactions, its role in the crosstalk between cancer cells and the TME in vivo remains unexplored. Therefore, we aimed to understand how ADAM15 regulates the cell composition of the TME and how it affects tumor progression. Here, we showed an upregulation of ADAM15 in tumor tissues from rectal cancer patients. Subcutaneous injection of wildtype and ADAM15-knockout CT26 colon cancer cells in syngeneic mice confirmed the protumorigenic role of ADAM15. Profiling of tumors revealed higher immune cell infiltration and cancer cell apoptosis in the ADAM15-deficient tumors. Specifically, loss of ADAM15 led to a reduced number of granulocytes and higher infiltration of antigen-presenting cells, including dendritic cells and macrophages, as well as more T cells. Using in vitro assays, we confirmed the regulatory effect of ADAM15 on macrophage migration and identified ADAM15-derived CYR61 as a potential molecular mediator of this effect. Based on these findings, we speculate that targeting ADAM15 could increase the infiltration of immune cells in colorectal tumors, which is a prerequisite for effective immunotherapy.

Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease.

BACKGROUND: Comorbidity exists between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), but the role of genetic factors is unclear. OBJECTIVE: We aim to investigate genetic correlation, causal relationship, and comorbid genes between ALS and PD. METHODS: Leveraging the largest genome-wide association study data (ALS: 27,205 cases, 110,881 controls; PDG: 33,674 cases, 449,056 controls), we used linkage disequilibrium score regression and Mendelian randomization analysis for genetic correlation and causal inference. We performed genome-wide cross-trait analysis via Multi-Trait Analysis of Genome-Wide Association Studies and Cross-Phenotype Association to identify specific single-nucleotide polymorphisms, followed by functional mapping and annotation. Integrating expression quantitative trait loci data from 13 brain regions, we conducted a transcriptome-wide association study via functional summary-based imputation and joint-tissue imputation to explore comorbid genes, followed by pathway enrichment analysis. RESULTS: We found that PD positively correlates with ALS (rg = 0.144, P = 0.026) and confers a causal effect (odds ratio = 1.09, 95% confidence interval: 1.03-1.15, P = 3.00 × 10-3 ). We identified nine single-nucleotide polymorphisms (eight new), associating with three risk loci (chromosomes 4, 10, and 17) and seven genes (TMEM175, MAPT, NSF, LRRC37A2, ARHGAP27, GAK, and FGFRL1). In transcriptome-wide association study analysis, we showed six previously unreported pleiotropic genes (KANSL1, ARL17B, EFNA1, WNT3, ERCC8, and ADAM15), and we found these candidate genes are mainly enriched in negative regulation of neuron projection development (GO:0010977). CONCLUSIONS: Our work demonstrates shared genetic architecture between ALS and PD, reports new pleiotropic genes, and sheds light on the comorbid mechanism. © 2023 International Parkinson and Movement Disorder Society.

Evaluation of the association between clinical parameters and ADAM33 and ORMDL3 asthma gene single-nucleotide polymorphisms with the severity of COVID-19.

BACKGROUND: Coronavirus Disease of 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients had varying clinical symptoms and disease severity (mild, moderate, severe, and critical). Several risk factors, including genetic polymorphisms, have been reported to be associated with disease risk and severity. This study aimed to investigate the association of two polymorphisms in the orosomucoid1-like 3 (ORMDL3) and a disintegrin and metalloprotease 33 (ADAM33) asthma-related genes with the severity of COVID-19. MATERIAL AND METHODS: The study included 116 COVID-19 patients with a positive polymerase chain reaction (PCR) test for the SARS-CoV-2 Delta variant. 58 patients with moderate symptoms, 28 patients with severe symptoms, and 30 outpatients with mild symptoms. Genotyping of rs7216389 in the ORMDL3 and rs2280091 in ADAM33 genes was performed by polymerase chain reaction-restriction fragment length polymorphism. Furthermore, records of patients were studied for hematological profiles and biochemical markers. RESULTS: No significant association was found between rs7216389 and rs2280091 and the severity of COVID-19 between different groups of COVID-19 patients. The serum levels of RBC and neutrophil-to-lymphocyte ratio were significantly increased; the erythrocyte sedimentation rate (ESR), and Aspartate transaminase (SGOT) were significantly decreased during treatment in intensive care unit (ICU) patients. The serum levels of red blood cells, Platelets, Urea, Alkaline phosphatase, ESR, Alanine transaminase (SGPT), and SGOT were significantly increased during treatment in hospitalized patients. The serum levels of inflammatory factors, including C-reactive protein (CRP), D-dimer, and Ferritin at the time of admission, were significantly higher in patients admitted to the ICU patients compared to the other group of patients. CONCLUSION: The two polymorphisms studied in this research are not suitable markers for predicting the severity of COVID-19. However, there are significant differences in the amounts of some blood factors in different groups of COVID-19 patients (P < 0.05) and these factors can be used as a marker for the disease severity prediction.

Genome-wide identification of bovine ADAMTS gene family and analysis of its expression profile in the inflammatory process of mammary epithelial cells.

ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS) are secreted, multi-domain matrix-related zinc endopeptidases that play a role in organogenesis, assembly and degradation of extracellular matrix (ECM), cancer and inflammation. Genome-wide identification and analysis of the bovine ADAMTS gene family has not yet been carried out. In this study, 19 ADAMTS family genes were identified in Bos taurus by genome-wide bioinformatics analysis, and they were unevenly distributed on 12 chromosomes. Phylogenetic analysis shows that the Bos taurus ADAMTS are divided into eight subfamilies, with highly consistent gene structures and motifs within the same subfamily. Collinearity analysis showed that the Bos taurus ADAMTS gene family is homologous to other bovine subfamily species, and many ADAMTS genes may be derived from tandem replication and segmental replication. In addition, based on the analysis of RNA-seq data, we found the expression pattern of ADAMTS gene in different tissues. Meanwhile, we also analyzed the expression profile of ADAMTS gene in the inflammatory response of bovine mammary epithelial cells (BMECs) stimulated by LPS by qRT-PCR. The results can provide ideas for understanding the evolutionary relationship and expression pattern of ADAMTS gene in Bovidae, and clarify the theoretical basis of the function of ADAMTS in inflammation.

ADAMTS Proteases: Importance in Animal Reproduction.

Many reproductive physiological processes, such as folliculogenesis, ovulation, implantation, and fertilization, require the synthesis, remodeling, and degradation of the extracellular matrix (ECM). The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) family genes code for key metalloproteinases in the remodeling process of different ECM. Several genes of this family encode for proteins with important functions in reproductive processes; in particular, ADAMTS1, 4, 5 and 9 are genes that are differentially expressed in cell types and the physiological stages of reproductive tissues. ADAMTS enzymes degrade proteoglycans in the ECM of the follicles so that the oocytes can be released and regulate follicle development during folliculogenesis, favoring the action of essential growth factors, such as FGF-2, FGF-7 and GDF-9. The transcriptional regulation of ADAMTS1 and 9 in preovulatory follicles occurs because of the gonadotropin surge in preovulatory follicles, via the progesterone/progesterone receptor complex. In addition, in the case of ADAMTS1, pathways involving protein kinase A (PKA), extracellular signal regulated protein kinase (ERK1/2) and the epidermal growth factor receptor (EGFR) might contribute to ECM regulation. Different Omic studies indicate the importance of genes of the ADAMTS family from a reproductive aspect. ADAMTS genes could serve as biomarkers for genetic improvement and contribute to enhance fertility and animal reproduction; however, more research related to these genes, the synthesis of proteins encoded by these genes, and regulation in farm animals is needed.

The rs16969968 Tobacco Smoking-Related Single-Nucleotide Variant Is Associated with Clinical Markers in Patients with Severe COVID-19.

Tobacco smoking is the leading risk factor for many respiratory diseases. Several genes are associated with nicotine addiction, such as CHRNA5 and ADAM33. This research aims to evaluate the association of the polymorphisms rs16969968 (CHRNA5) and rs3918396 (ADAM33) in patients who developed severe COVID-19. We included 917 COVID-19 patients hospitalized with critical disease and oxygenation impairment. They were divided into two groups, tobacco-smoking (n = 257) and non-smoker (n = 660) patients. The genotype and allele frequencies of two single nucleotide variants, the rs16969968 (CHRNA5) and rs3918396 (ADAM33), were evaluated. The rs3918396 in ADAM33 does not show a significative association. We analyzed the study population according to the rs16969968 genotype (GA + AA, n = 180, and GG, n = 737). The erythrocyte sedimentation rate (ESR) shows statistical differences; the GA + AA group had higher values than the GG group (p = 0.038, 32 vs. 26 mm/h, respectively). The smoking patients and GA or AA genotype carriers had a high positive correlation (p < 0.001, rho = 0.753) between fibrinogen and C-reactive protein. COVID-19 patients and smokers carriers of one or two copies of the risk allele (rs16969968/A) have high ESR and a positive correlation between fibrinogen and C-reactive protein.

Deep next-generation proteomics and network analysis reveal systemic and tissue-specific patterns in Fabry disease.

Fabry disease (FD) is an X-linked lysosomal rare disease due to a deficiency of α-galactosidase A activity. The accumulation of glycosphingolipids mainly affects the kidney, heart, and central nervous system, considerably reducing life expectancy. Although the accumulation of undegraded substrate is considered the primary cause of FD, it is established that secondary dysfunctions at the cellular, tissue, and organ levels ultimately give rise to the clinical phenotype. To parse this biological complexity, a large-scale deep plasma targeted proteomic profiling has been performed. We analyzed the plasma protein profiles of FD deeply phenotyped patients (n = 55) compared to controls (n = 30) using next-generation plasma proteomics including 1463 proteins. Systems biology and machine learning approaches have been used. The analysis enabled the identification of proteomic profiles that unambiguously separated FD patients from controls (615 differentially expressed proteins, 476 upregulated, and 139 downregulated) and 365 proteins are newly reported. We observed functional remodeling of several processes, such as cytokine-mediated pathways, extracellular matrix, and vacuolar/lysosomal proteome. Using network strategies, we probed patient-specific tissue metabolic remodeling and described a robust predictive consensus protein signature including 17 proteins CD200, SPINT1, CD34, FGFR2, GRN, ERBB4, AXL, ADAM15, PTPRM, IL13RA1, NBL1, NOTCH1, VASN, ROR1, AMBP, CCN3, and HAVCR2. Our findings highlight the pro-inflammatory cytokines' involvement in FD pathogenesis along with extracellular matrix remodeling. The study shows a tissue-wide metabolic remodeling connection to plasma proteomics in FD. These results will facilitate further studies to understand the molecular mechanisms in FD to pave the way for better diagnostics and therapeutics.