RESUMEN
Long or Post COVID-19 is a condition of collected symptoms persisted after recovery from COVID-19. Host genetic factors play a crucial role in developing Long COVID-19, and GWAS studies identified several SNPs/genes in various ethnic populations. In African-American population two SNPS, rs10999901 (C>T, p = 3.6E-08, OR = 1.39, MAF-0,27, GRCH38, chr10:71584799 bp) and rs1868001 (G>A, p = 6.7E-09, OR = 1.40, MAF-0.46, GRCH38, chr10:71587815 bp) and in Hispanic population, rs3759084 (A>C, p = 9.7E-09, OR = 1.56, MAF-0.17, chr12: 81,110,156 bp) are strongly associated with Long COVID-19. All these three SNPs reside in noncoding regions implying their regulatory function in the genome. In silico dissection suggests that rs10999901 and rs1868001 physically interact with the CDH23 and C10orf105 genes. Both SNPs act as distant enhancers and bind with several transcription factors (TFs). Further, rs10999901 SNP is a CpG that is methylated in CD4++ T cells and monocytes and loses its methylation due to transition from C>T. rs3759084 is located in the promoter (- 687 bp) of MYF5, acts as a distant enhancer, and physically interacts with PTPRQ. These results offer plausible explanations for their association and provide the basis for experiments to dissect the development of symptoms of Long COVID-19.
RESUMEN
An estimation of the proportion of nonsynonymous to synonymous mutation (dn/ds, ω) of the SARS-CoV-2 genome would indicate the evolutionary dynamics necessary to evolve into novel strains with increased infection, virulence, and vaccine neutralization. A temporal estimation of ω of the whole genome, and all twenty-nine SARS-CoV-2 genes of major virulent strains of alpha, delta and omicron demonstrates that the SARS-CoV-2 genome originally emerged (ω ~ 0.04) with a strong purifying selection (ω < 1) and reached (ω ~ 0.85) in omicron towards diversifying selection (ω > 1). A marked increase in the ω occurred in the spike gene from alpha (ω = 0.2) to omicron (ω = 1.97). The ω of the replication machinery genes including RDRP, NSP3, NSP4, NSP7, NSP8, NSP10, NSP13, NSP14, and ORF9 are markedly increased, indicating that these genes/proteins are yet to be evolutionary stabilized and are contributing to the evolution of novel virulent strains. The delta-specific maximum increase in ω in the immunomodulatory genes of NSP8, NSP10, NSP16, ORF4, ORF5, ORF6, ORF7A, and ORF8 compared to alpha or omicron indicates delta-specific vulnerabilities for severe COVID-19 related hospitalization and death. The maximum values of ω are observed for spike (S), NSP4, ORF8 and NSP15, which indicates that the gene-specific temporal estimation of ω identifies specific genes for its super-infectivity and virulency that could be targeted for drug development.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Evolución Molecular , Genoma Viral , SARS-CoV-2 , SARS-CoV-2/genética , SARS-CoV-2/patogenicidad , SARS-CoV-2/inmunología , Humanos , Vacunas contra la COVID-19/inmunología , COVID-19/virología , COVID-19/inmunología , Virulencia/genética , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Mutación , FilogeniaRESUMEN
G-quadruplex structure or Putative Quadruplex Sequences (PQSs) are abundant in human, microbial, DNA, or RNA viral genomes. These sequences in RNA viral genome play critical roles in integration into human genome as LTR (Long Terminal Repeat), genome replication, chromatin rearrangements, gene regulation, antigen variation (Av), and virulence. Here, we investigated whether the genome of SARS-CoV2, an RNA virus, contained such potential G-quadruplex structures. Using bioinformatic tools, we searched for such sequences and found thirty-seven (forward strand (twenty-five) + reverse strand (Twelve)) QGRSs (Quadruplex forming G-Rich Sequences)/PQSs in SARS-CoV2 genome. These sequences are dispersed mainly in the upstream of SARS-CoV2 genes. We discuss whether existing PQS/QGRS ligands could inhibit the SARS-CoV2 replication and gene transcription as has been observed in other RNA viruses. Further experimental validation would determine the role of these G-quadruplex sequences in SARS-CoV2 genome function to survive in the host cells and identify therapeutic agents to destabilize these PQSs/QGRSs.
Asunto(s)
COVID-19 , G-Cuádruplex , COVID-19/genética , ADN , Humanos , ARN Viral/química , ARN Viral/genética , SARS-CoV-2/genéticaRESUMEN
Diabetic Nephropathy (DN) is a debilitating consequence of both Type 1 and Type 2 diabetes affecting the kidney and renal tubules leading to End Stage Renal Disease (ESRD). As diabetes is a world epidemic and almost half of diabetic patients develop DN in their lifetime, a large group of people is affected. Due to the complex nature of the disease, current diagnosis and treatment are not adequate to halt disease progression or provide an effective cure. DN is now considered a manifestation of inflammation where inflammatory molecules regulate most of the renal physiology. Recent advances in genetics and genomic technology have identified numerous susceptibility genes that are associated with DN, many of which have inflammatory functions. Based on their role in DN, we will discuss the current aspects of developing biomarkers and molecular therapy for advancing precision medicine.
Asunto(s)
Biomarcadores/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/genética , Inflamación/genética , Terapia Molecular Dirigida , Animales , Autofagia/genética , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/patología , Humanos , Mutación/genéticaRESUMEN
Humans, throughout the life cycle, from birth to death, are accompanied by the presence of gut microbes. Environmental factors, lifestyle, age and other factors can affect the balance of intestinal microbiota and their impact on human health. A large amount of data show that dietary, prebiotics, antibiotics can regulate various diseases through gut microbes. In this review, we focus on the role of gut microbes in the development of metabolic, gastrointestinal, neurological, immune diseases and, cancer. We also discuss the interaction between gut microbes and the host with respect to their beneficial and harmful effects, including their metabolites, microbial enzymes, small molecules and inflammatory molecules. More specifically, we evaluate the potential ability of gut microbes to cure diseases through Fecal Microbial Transplantation (FMT), which is expected to become a new type of clinical strategy for the treatment of various diseases.
Asunto(s)
Dieta/efectos adversos , Disbiosis/terapia , Microbioma Gastrointestinal/efectos de los fármacos , Antibacterianos/efectos adversos , Disbiosis/etiología , Trasplante de Microbiota Fecal , Humanos , Prebióticos/efectos adversos , Probióticos/efectos adversosRESUMEN
Covid-19 has caused worldwide devastation. IFIH1 is a pattern recognition receptor that senses coronavirus RNA and triggers interferon production as a first line of viral immune defense. The role of IFIH1 polymorphism, rs1990760 (C>T; aaA946T) in the epidemiology of viral infection is well studied, and the minor allele T resists viral infection. Knock-in mice with mutated IFIH1 protein (946T) for this allele have enhanced interferon production and protection from lethal viral infection. The minor allele frequency (Tmaf) varies widely from Africans (0.06 to 0.35) to Chinese (0.19 to 0.23) to Caucasians (0.56 to 0.69). During the initial days of infection when the social restrictions were not imposed, I show that the infection rate in Italy was lower as expected from its higher Tmaf (0.56) than that in China (Tmaf for southern China, 0.23). The infection rate in the USA and Spain was intermediate between those two countries despite higher Caucasian overall Tmaf (0.69), perhaps due to a more admixed African population in these countries. These analyses suggest that African-Americans and Chinese with low Tmaf of rs1990760 are more vulnerable to SARS-COV2 infection, apart from other genetic factors or socioeconomic conditions in these population. Taken together, an IFN-beta supplement might aid in preventing COVID-19 infection and help in development of herd immunity.
Asunto(s)
Negro o Afroamericano/genética , Infecciones por Coronavirus/genética , Predisposición Genética a la Enfermedad , Helicasa Inducida por Interferón IFIH1/genética , Neumonía Viral/genética , Pueblo Asiatico , Betacoronavirus , COVID-19 , China , Frecuencia de los Genes , Genotipo , Humanos , Interferón beta , Italia , Pandemias , Polimorfismo de Nucleótido Simple , SARS-CoV-2 , Estados UnidosRESUMEN
Integrin alpha M (ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system. We previously identified a missense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecular mechanisms of this variant are incompletely understood. A meta-analysis of published and novel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10(-90), odds ratio (OR) = 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels in monocytes from patients with each rs1143679 genotype. We observed that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' < 'AG' < 'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10- to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. We found that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid- and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE.
Asunto(s)
Antígeno CD11b/genética , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Monocitos/metabolismo , ARN Mensajero/genética , Alelos , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Antígeno CD11b/metabolismo , Cromatina/metabolismo , Cromatina/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Fibrinógeno/genética , Fibrinógeno/metabolismo , Regulación de la Expresión Génica , Frecuencia de los Genes , Humanos , Autoantígeno Ku , Lupus Eritematoso Sistémico/etnología , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/patología , Masculino , Monocitos/patología , Subunidad p50 de NF-kappa B/genética , Subunidad p50 de NF-kappa B/metabolismo , Oportunidad Relativa , Polimorfismo Genético , Unión Proteica , ARN Mensajero/metabolismo , Grupos Raciales , Riesgo , Transactivadores/genética , Transactivadores/metabolismo , Transcripción Genética , Vitronectina/genética , Vitronectina/metabolismoRESUMEN
Recent reports have associated NCF2, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (P(EA) = 1.01 × 10(-54), PHS = 3.68 × 10(-10), P(AA) = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (PAA = 1.49 × 10(-9)), and rs13306575 in HS and KR (P(HS) = 7.04 × 10(-7), P(KR) = 3.30 × 10(-3)). In KR, a 3-SNP haplotype was significantly associated (P = 4.20 × 10(-7)), implying that SLE predisposing variants were tagged. Significant SNP-SNP interaction (P = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting in vivo enhancer function. Our results not only establish allelic heterogeneity within NCF2 associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance ('missing heritability') of complex diseases like SLE.
Asunto(s)
Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/etnología , Lupus Eritematoso Sistémico/genética , NADPH Oxidasas/genética , Negro o Afroamericano/genética , Asiático/genética , Biología Computacional , Heterogeneidad Genética , Variación Genética , Haplotipos , Hispánicos o Latinos/genética , Humanos , Modelos Moleculares , Polimorfismo de Nucleótido Simple , Población Blanca/etnología , Población Blanca/genéticaRESUMEN
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
Asunto(s)
Negro o Afroamericano/genética , ARN Helicasas DEAD-box/genética , Lupus Eritematoso Sistémico/genética , Alelos , Antígenos Nucleares/genética , Antígenos Nucleares/inmunología , Apoptosis/genética , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Mapeo Cromosómico , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Predisposición Genética a la Enfermedad , Genoma Humano , Haplotipos , Humanos , Inflamación/genética , Helicasa Inducida por Interferón IFIH1 , Autoantígeno Ku , Lupus Eritematoso Sistémico/inmunología , Polimorfismo de Nucleótido Simple , Unión Proteica , Población Blanca/genéticaRESUMEN
Acute Myocardial Infarction (AMI) after Percutaneous Coronary Intervention (PCI) often requires stent implantation leading to cardiovascular injury and cytokine release. Stent implantation induces cytokines production including TNFα, Hs-CRP, IL-1ß, IL2 receptor, IL6, IL8, and IL10, but their co-release is not extensively established. In 311 PCI patients with Drug-Eluting Stent (DES) implantation, we statistically evaluate the correlation of these cytokines release in various clinical conditions, stent numbers, and medications. We observed that TNFα is moderately correlated with IL-1ß (r2 = 0.59, p = 0.001) in diabetic PCI patients. Similarly, in NSTEMI (Non-ST Segment Elevation) patients, TNFα is strongly correlated with both IL-1ß (r2 = 0.97, p = 0.001) and IL8 (r2 = 0.82, p = 0.001). In CAD (Coronary Artery Disease)-diagnosed patients TNFα is highly correlated (r2 = 0.84, p = 0.0001) with IL8 release but not with IL-1ß. In patients with an increased number of stents, Hs-CRP is significantly coupled with IL8 > 5 pg/ml (t-statistic = 4.5, p < 0.0001). Inflammatory suppressor drugs are correlated as TNFα and IL8 are better suppressed by Metoprolol 23.75 (r2 = 0.58, p < 0.0001) than by Metoprolol 11.87 (r2 = 0.80, p = 0.5306). Increased TNFα and IL-1ß are better suppressed by the antiplatelet drug Brilinta (r2 = 0.30, p < 0.0001) but not with Clopidogrel (r2 = 0.87, p < 0.0001). ACI/ARB Valsartan 80 (r2 = 0.43, p = 0.0011) should be preferred over Benazepril 5.0 (r2 = 0.9291, p < 0.0001) or Olmesartan (r2 = 0.90, p = 0.0001). Thus, the co-release of IL-1ß, IL8 with TNFα, or only IL8 with TNFα could be a better predictor for the outcome of stent implantation in NSTEMI and CAD-diagnosed AMI patients respectively. Cytokine suppressive medications should be chosen carefully to inhibit further cardiovascular damage.
Asunto(s)
Stents Liberadores de Fármacos , Infarto del Miocardio , Infarto del Miocardio sin Elevación del ST , Intervención Coronaria Percutánea , Humanos , Intervención Coronaria Percutánea/efectos adversos , Infarto del Miocardio sin Elevación del ST/cirugía , Citocinas , Metoprolol , Factor de Necrosis Tumoral alfa , Antagonistas de Receptores de Angiotensina , Proteína C-Reactiva , Interleucina-8 , Resultado del Tratamiento , Inhibidores de la Enzima Convertidora de Angiotensina , Infarto del Miocardio/cirugía , Infarto del Miocardio/etiologíaRESUMEN
BACKGROUND: Omphalocele is a congenital birth defect characterised by the presence of internal organs located outside of the ventral abdominal wall. The purpose of this study was to identify the underlying genetic mechanisms of a large autosomal dominant Caucasian family with omphalocele. METHODS AND FINDINGS: A genetic linkage study was conducted in a large family with an autosomal dominant transmission of an omphalocele using a genome-wide single nucleotide polymorphism (SNP) array. The analysis revealed significant evidence of linkage (non-parametric NPL = 6.93, p=0.0001; parametric logarithm of odds (LOD) = 2.70 under a fully penetrant dominant model) at chromosome band 1p31.3. Haplotype analysis narrowed the locus to a 2.74 Mb region between markers rs2886770 (63014807 bp) and rs1343981 (65757349 bp). Molecular characterisation of this interval using array comparative genomic hybridisation followed by quantitative microsphere hybridisation analysis revealed a 710 kb duplication located at 63.5-64.2 Mb. All affected individuals who had an omphalocele and shared the haplotype were positive for this duplicated region, while the duplication was absent from all normal individuals of this family. Multipoint linkage analysis using the duplication as a marker yielded a maximum LOD score of 3.2 at 1p31.3 under a dominant model. The 710 kb duplication at 1p31.3 band contains seven known genes including FOXD3, ALG6, ITGB3BP, KIAA1799, DLEU2L, PGM1, and the proximal portion of ROR1. Importantly, this duplication is absent from the database of genomic variants. CONCLUSIONS: The present study suggests that development of an omphalocele in this family is controlled by overexpression of one or more genes in the duplicated region. To the authors' knowledge, this is the first reported association of an inherited omphalocele condition with a chromosomal rearrangement.
Asunto(s)
Duplicación Cromosómica , Cromosomas Humanos Par 1 , Variaciones en el Número de Copia de ADN , Genes Dominantes , Ligamiento Genético , Hernia Umbilical/genética , Hibridación Genómica Comparativa , Femenino , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Escala de Lod , Masculino , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
Background: Alzheimer's disease (AD) is the most common form of dementia, accounting for 80% of all cases. Mild cognitive impairment (MCI) is a transitional state between normal aging and AD. Early detection is crucial, as irreversible brain damage occurs before symptoms manifest. Objective: This study aimed to identify potential biomarkers for early detection of AD by analyzing urinary cytokine concentrations. We investigated 37 cytokines in AD, MCI, and cognitively normal individuals (NC), assessing their associations with AD development. Methods: Urinary cytokine concentrations were measured in AD (nâ=â25), MCI (nâ=â25), and NC (nâ=â26) patients. IL6ST and MMP-2 levels were compared between AD and NC, while TNFRSF8, IL6ST, and IL-19 were assessed in AD versus MCI. Diagnostic models distinguished AD from NC, and in-silico analysis explored molecular mechanisms related to AD. Results: Significant perturbations in IL6ST and MMP-2 concentrations were observed in AD urine compared to NC, suggesting their potential as biomarkers. TNFRSF8, IL6ST, and IL-19 differed significantly between AD and MCI, implicating them in disease progression. Diagnostic models exhibited promising performance (AUC: 0.59-0.79, sensitivity: 0.72-0.80, specificity: 0.56-0.78) in distinguishing AD from NC. In-silico analysis revealed molecular insights, including relevant non-coding RNAs, microRNAs, and transcription factors. Conclusion: This study establishes significant associations between urinary cytokine concentrations and AD and MCI. IL6ST, MMP-2, TNFRSF8, IL6ST, and IL-19 emerge as potential biomarkers for early detection of AD. In-silico analysis enhances understanding of molecular mechanisms in AD. Further validation and exploration of these biomarkers in larger cohorts are warranted to assess their clinical utility.
RESUMEN
Drug resistance in cancer is an overwhelming problem, because drug-resistant cancer cells are harder to kill with the same drug. The mechanism of drug resistance differs for various cancers based on the type of drug being used for its treatment. Most current drugs are shown to increase reactive oxygen species (ROS) in respective cancer cells that induces apoptosis, but continuous treatment with the same drug may reduce cellular ROS levels and may convert drug sensitive cancer cells into drug resistant cells. In addition, exogenous elevation of ROS in conjunction with drug resensitizes drug-resistant cancer cells. Thus, constant maintenance of higher ROS level in cancer cells may be a prerequisite for drug efficacy in certain type of cancer cells. Thus, modulation of ROS-mediated genetic pathway genes could be an efficient alternative to maintain higher ROS level in cancer cells for "combinational chemotherapy" with the drug. In this review, I discuss whether ROS reduction in drug-resistant cancer cells could be a general mechanism of drug resistance for most cancers with its specific drug, and whether elevation of ROS levels with the drug could be a valuable strategy for increasing drug efficacy in most cancers.
Asunto(s)
Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Estrés Oxidativo , Animales , HumanosRESUMEN
SARS-CoV2 is a novel respiratory coronavirus and, understanding its molecular mechanism is a prerequisite to developing effective treatment for covid-19. This RNA genome-carrying virus has a protein coat with spikes (S) that attaches to the ACE2 receptor at the cell surface of human cells. Several repurposed drugs are used to treat covid-19 patients that are proven to be largely unsuccessful or have limited success in reducing mortalities. Several vaccines are in use to reduce the viral load to prevent developing symptoms. Major challenges to their efficacy include the inability of antibody molecules to enter cells but remain effective in the bloodstream to kill the virus. The efficacy of vaccines also depends on their neutralizing ability to constantly evolve new virus strains due to novel mutations and evolutionary survival dynamics. Taken together, SARS-CoV2 antibody vaccines may not be very effective and other approaches based on genetic, genomic, and protein interactome could be fruitful to identify therapeutic targets to reduce disease-related mortalities.
RESUMEN
SARS-CoV2 virus is believed to be originated from a closely related bat Coronavirus RaTG13 lineage and uses its key entry-point residues in S1 protein to attach with human ACE2 receptor. SARS-CoV2 could enter human from bat with its poorly developed entry-point residues much before its known appearance with slower mutation rate or recently with efficiently developed entry-point residues with higher mutation rate or through an intermediate host. Temporal analysis of SARS-CoV2 genome shows that its nucleotide substitution rate is as low as 27nt/year with an evolutionary rate of 9×10-4/site/year, which is well within the range of other RNA virus (10-4 to 10-6/site/year). TMRCA of SARS-CoV2 from bat RaTG13 lineage appears to be in between 9 and 14 years. Evolution of a critical entry-point residue Y493Q needs two substitutions with an intermediate virus carrying Y493H (Y>H>Q) but has not been identified in known twenty-nine bat CoV virus. Genetic codon analysis indicates that SARS-CoV2 evolution during propagation in human disobeys neutral evolution as nonsynonymous mutations surpass synonymous mutations with the increase of ω (dn/ds). Taken together, genetic data suggests that SARS-CoV2 is originated long time back before its appearance in human in 2019. Increase of ω signifies that SARs-CoV2 evolution is approaching towards diversifying selection from purifying selection predictably for its infection power to evade multiple human organs.
Asunto(s)
COVID-19 , ARN Viral , Humanos , Mutación , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/químicaRESUMEN
Cardiomyopathy often leads to dilated cardiomyopathy (DCM) when caused by viral myocarditis. Apoptosis is long considered as the principal process of cell death in cardiomyocytes, but programmed necrosis or necroptosis is recently believed to play an important role in cardiomyocyte cell death. We investigated the role of necroptosis and its interdependency with other processes of cell death, autophagy, and apoptosis in a rat system of experimental autoimmune myocarditis (EAM). We successfully created a rat model system of EAM by injecting porcine cardiac myosin (PCM) and showed that in EAM, all three forms of cell death increase considerably, resulting in the deterioration of cardiac conditions with an increase in inflammatory infiltration in cardiomyocytes. To explore whether necroptosis occurs in EAM rats independent of autophagy, we treated EAM rats with a RIP1/RIP3/MLKL kinase-mediated necroptosis inhibitor, Necrostatin-1 (Nec-1). In Nec-1 treated rats, cell death proceeds through apoptosis but has no significant effect on autophagy. In contrast, autophagy inhibitor 3-Methyl Adenine (3-MA) increases necroptosis, implying that blockage of autophagy must be compensated through necroptosis. Caspase 8 inhibitor zVAD-fmk blocks apoptosis but increases both necroptosis and autophagy. However, all necroptosis, apoptosis, and autophagy inhibitors independently reduce inflammatory infiltration in cardiomyocytes and improve cardiac conditions. Since apoptosis or autophagy is involved in many important cellular aspects, instead of suppressing these two major cell death processes, Nec1 can be developed as a potential therapeutic target for inflammatory myocarditis.
RESUMEN
Long noncoding RNAs have gained widespread attention in recent years for their crucial role in biological regulation. They have been implicated in a range of developmental processes and diseases including cancer, cardiovascular, and neuronal diseases. However, the role of long noncoding RNAs (lncRNAs) in left ventricular noncompaction (LVNC) has not been explored. In this study, we investigated the expression levels of lncRNAs in the blood of LVNC patients and healthy subjects to identify differentially expressed lncRNA that develop LVNC specific biomarkers and targets for developing therapies using biological pathways. We used Agilent Human lncRNA array that contains both updated lncRNAs and mRNAs probes. We identified 1,568 upregulated and 1,141 downregulated (log fold-change > 2.0) lncRNAs that are differentially expressed between LVNC and the control group. Among them, RP11-1100L3.7 and XLOC_002730 are the most upregulated and downregulated lncRNAs. Using quantitative real-time reverse transcription polymerase chain reaction (RT-QPCR), we confirmed the differential expression of three top upregulated and downregulated lncRNAs along with two other randomly picked lncRNAs. Gene Ontology (GO) and KEGG pathways analysis with these differentially expressed lncRNAs provide insight into the cellular pathway leading to LVNC pathogenesis. We also identified 1,066 upregulated and 1,017 downregulated mRNAs. Gene set enrichment analysis (GSEA) showed that G2M, Estrogen, and inflammatory pathways are enriched in differentially expressed genes (DEG). We also identified miRNA targets for these differentially expressed genes. In this study, we first report the use of LncRNA microarray to understand the pathogenesis of LVNC and to identify several lncRNA and genes and their targets as potential biomarkers.
RESUMEN
PURPOSE: It was hypothesised that the coding variant (R77H), rs1143679, within ITGAM could predict specific clinical manifestations associated with systemic lupus erythematosus (SLE). METHOD: To assess genetic association, 2366 patients with SLE and 2931 unaffected controls with European ancestry were analysed. The patients with SLE were coded by the presence or absence of individual American College of Rheumatology criteria. Logistic regression and Pearson chi(2) tests were used to assess statistical significance. RESULTS: For overall case-control analysis, a highly significant association was detected (p=2.22x10-21, OR 1.73). Using case-only analysis, a significant association was detected with renal criteria (p=0.0003), discoid rash (p=0.02) and immunological criteria (p=0.04). When patients with SLE were compared with healthy controls, the association became stronger for renal (p=4.69x10-22, OR 2.15), discoid (p=1.77x10-14, OR 2.03) and immunological (p=3.49x10-22, OR 1.86) criteria. Risk allele frequency increased from 10.6% (controls) to 17.0% (SLE), 20.4% (renal), 18.1% (immunological) and 19.5% (discoid). CONCLUSION: These results show a strong association between the risk allele (A) at rs1143679 and renal disease, discoid rash and immunological manifestations of SLE.
Asunto(s)
Antígeno CD11b/genética , Lupus Eritematoso Discoide/genética , Lupus Eritematoso Sistémico/genética , Autoanticuerpos/sangre , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lupus Eritematoso Discoide/inmunología , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/genética , Nefritis Lúpica/inmunología , MasculinoRESUMEN
OBJECTIVES: Recently, a non-synonymous (Gly307Ser) variant, rs763361, in the CD226 gene was shown to be associated with multiple autoimmune diseases (ADs) in European Caucasian populations. However, shared autoimmunity with CD226 has not been evaluated in non-European populations. The aim of the present study is to assess the association of this single nucleotide polymorphism (SNP) with ADs in non-European populations. METHODS: To replicate this association in non-European populations, we evaluated case-control association between rs763361 and coeliac disease (CED) samples from Argentina; SLE, RA, type-1 diabetes (T1D) and primary SS (pSS) from Colombia; and SLE samples from China and Japan. We genotyped rs763361 and evaluated its genetic association with multiple ADs, using chi(2)-test. For each association, odds ratio (OR) and 95% CI were calculated. RESULTS: We show that rs763361 is significantly associated with Argentinean CED (P = 0.0009, OR = 1.60). We also observed a trend of possible association with Chinese SLE (P = 0.01, OR = 1.19), RA (P = 0.047, OR = 1.25), SLE (P = 0.0899, OR = 1.24) and pSS (P = 0.09, OR = 1.33) in Colombians. Meta-analyses for SLE (using our three populations) and T1D (our population and three published populations) yielded significant association with rs763361, P = 0.009 (OR = 1.16) and P = 1.1.46 x 10(-9) (OR = 1.14), respectively. CONCLUSIONS: Our results demonstrate that the coding variant rs763361 in CD226 gene is associated with multiple ADs in non-European populations.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/genética , Enfermedades Autoinmunes/genética , Predisposición Genética a la Enfermedad/genética , Argentina , Pueblo Asiatico/genética , Estudios de Casos y Controles , Colombia , Frecuencia de los Genes , Genotipo , Humanos , Estadística como Asunto , Población Blanca/genéticaRESUMEN
Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by swollen, painful, inflamed lesions in the axillae, groin, armpits and other parts of the body that contain apocrine glands. The aetiology of HS is unknown, and earlier reports indicate genetic locus responsible for this phenotype on chromosome 1p21.1-1q25.3, but no causative gene(s) have yet been identified. We studied two large multigeneration pedigrees (UR251 and UR252), in which the condition appeared to segregate as an autosomal dominant trait with 100% penetrance. No skipping of generations was observed in either family. Pedigrees consist of 96 individuals, including 25 affected individuals. Because of squamous cell carcinoma, a few deaths were reported in family UR0251. The locus on chromosome 1p21.1-1p25.3, known from previous studies is associated with HS, was excluded in both families by linkage and haplotype analyses. Further studies are in progress to identify the region that is associated with the phenotype in these families.