The prevalence of autoimmune diseases (ADs) worldwide has rapidly increased over the past few decades. Thus, in addition to the classical risk factors for ADs, such as genetic polymorphisms, ...infections and smoking, environmental triggers have been considered. Recent sequencing-based approaches have revealed that patients with extra-intestinal ADs, such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus, have distinct gut microbiota compositions compared to healthy controls. Faecal microbiota transplantation or inoculation with specific microbes in animal models of ADs support the hypothesis that alterations of gut microbiota influence autoimmune responses and disease outcome. Here, we describe the compositional and functional changes in the gut microbiota in patients with extra-intestinal AD and discuss how the gut microbiota affects immunity. Moreover, we examine how the gut microbiota might be modulated in patients with ADs as a potential preventive or therapeutic approach.
Since the first half of the twentieth century, evolutionary theory has been dominated by the idea that mutations occur randomly with respect to their consequences
. Here we test this assumption with ...large surveys of de novo mutations in the plant Arabidopsis thaliana. In contrast to expectations, we find that mutations occur less often in functionally constrained regions of the genome-mutation frequency is reduced by half inside gene bodies and by two-thirds in essential genes. With independent genomic mutation datasets, including from the largest Arabidopsis mutation accumulation experiment conducted to date, we demonstrate that epigenomic and physical features explain over 90% of variance in the genome-wide pattern of mutation bias surrounding genes. Observed mutation frequencies around genes in turn accurately predict patterns of genetic polymorphisms in natural Arabidopsis accessions (r = 0.96). That mutation bias is the primary force behind patterns of sequence evolution around genes in natural accessions is supported by analyses of allele frequencies. Finally, we find that genes subject to stronger purifying selection have a lower mutation rate. We conclude that epigenome-associated mutation bias
reduces the occurrence of deleterious mutations in Arabidopsis, challenging the prevailing paradigm that mutation is a directionless force in evolution.
Objective: Through this work, we aimed to clarify the association between the severity of periodontitis and osteocalcin (OC) gene C298T polymorphismin Indonesian male subjects.Methods: DNA was ...extracted from blood serum samples of 100 consenting Indonesian men whose periodontitis was classified as mild, moderate,or severe. Polymerase chain reaction and restriction fragment length polymorphism techniques were applied to evaluate the status of OC (C298T)polymorphism using HindIII restriction enzyme and electrophoresis in agarose gel to separate the indicated fragments.Results: Although genotype distribution of the OC C298T polymorphism showed a trend for more frequent occurrence of genotype hh (and allele h)with increasing severity of periodontitis, this trend was not statistically significant in the tested sample population, in whom the HH genotypeappeared to be relatively rare.Conclusion: The results showed no significant association between the severity of periodontitis and OC C298T polymorphism in Indonesian malesubjects.
Antimicrobial peptides (AMPs) are essential components of immune defenses of multicellular organisms and are currently in development as anti-infective drugs. AMPs have been classically assumed to ...have broad-spectrum activity and simple kinetics, but recent evidence suggests an unexpected degree of specificity and a high capacity for synergies. Deeper evaluation of the molecular evolution and population genetics of AMP genes reveals more evidence for adaptive maintenance of polymorphism in AMP genes than has previously been appreciated, as well as adaptive loss of AMP activity. AMPs exhibit pharmacodynamic properties that reduce the evolution of resistance in target microbes, and AMPs may synergize with one another and with conventional antibiotics. Both of these properties make AMPs attractive for translational applications. However, if AMPs are to be used clinically, it is crucial to understand their natural biology in order to lessen the risk of collateral harm and avoid the crisis of resistance now facing conventional antibiotics.
•The Angiotensin system has been implicated in the pathogenesis of COVID-19.•Functional ACE/ACE2 polymorphisms might contribute to the outcome of COVID-19.•Severe COVID-19 was associated with ...hypertension, male gender, and ACE-DD genotype.•The ACE2 polymorphism was not associated with the disease outcome.•ACE2 showed no coding variants that could explain an increased risk of COVID-19.
The Angiotensin system is implicated in the pathogenesis of COVID-19. First, ACE2 is the cellular receptor for SARS-CoV-2, and expression of the ACE2 gene could regulate the individuaĺs susceptibility to infection. In addition, the balance between ACE1 and ACE2 activity has been implicated in the pathogenesis of respiratory diseases and could play a role in the severity of COVID-19. Functional ACE1/ACE2 gene polymorphisms have been associated with the risk of cardiovascular and pulmonary diseases, and could thus also contribute to the outcome of COVID-19.
We studied 204 COVID-19 patients (137 non-severe and 67 severe-ICU cases) and 536 age-matched controls. The ACE1 insertion/deletion and ACE2 rs2285666 polymorphism were determined. Variables frequencies were compared between the groups by logistic regression. We also sequenced the ACE2 coding nucleotides in a group of patients.
Severe COVID-19 was associated with hypertension male gender (p < 0.001), hypertension (p = 0.006), hypercholesterolaemia (p = 0.046), and the ACE1-DD genotype (p = 0.049). In the multiple logistic regression hypertension (p = 0.02, OR = 2.26, 95%CI = 1.12–4.63) and male gender (p = 0.002; OR = 3.15, 95%CI = 1.56–6.66) remained as independent significant predictors of severity. The ACE2 polymorphism was not associated with the disease outcome. The ACE2 sequencing showed no coding sequence variants that could explain an increased risk of developing COVID-19.
In conclusion, an adverse outcome of COVID-19 was associated with male gender, hypertension, hypercholesterolemia and the ACE1 genotype. Our work suggested that the ACE1-I/D might influence COVID-19 severity, but the effect was dependent on the hypertensive status. This result requires further validation in other large cohorts.
The aim
of the study was to analyze the genetic markers of Lyme disease pathogens, which can be used to specifically indicate maximum number of their strains and isolates.
Materials and methods.
The ...nucleotide sequences of various genes of
Borrelia garinii
,
B. afzelii
,
B. burgdorferi
were downloaded from the NCBI database (National Center for Biological Informatization). The occurrence of the analyzed nucleotide sequences in the genetic code of various organisms was determined in the nBLAST software utility. For the design of primers and probes, the Vector NTI 9.1.0 program (“Invitrogen Corporation”, Carlsbad, USA) was used. DNA was isolated using the MAGNO-sorb kit, version 100-200 (“AmpliSens”, Moscow, Russia), according to the manufacturer’s instructions. Primers and probes were synthesized at “Evrogen” company (Moscow, Russia). For PCR, reagents manufactured by “Synthol” company (Moscow, Russia) were applied.
Results and discussion.
In order to perform the reliable indication of pathogenic Borrelia, specific loci (genes) of
B. garinii
,
B. afzelii
,
B. burgdorferi
, which were significantly different from the genetic code of other representatives of the genus
Borrelia
and from the DNA of other organisms, have been determined by molecular-genetic methods. As a result of a preliminary determination of the analytical significance of the studied loci, the following genes and loci were selected for further work:
pepX
,
clpA
,
ospA
,
p83/100
,
ospC
and
flaB
, of which the
flaB
and
ospA
genes were selected for practical indication of pathogenic Borrelia DNA. The genetic markers of
B. burgdorferi
and
B. afzelii
are displayed during amplification of the
flaB
gene, while
B. garinii
and
B. afzelii
occur when the
ospA
gene is used as a genetic marker.
Our understanding of nonalcoholic fatty liver disease pathophysiology continues to advance rapidly. Accordingly, the field has moved from describing the clinical phenotype through the presence of ...nonalcoholic steatohepatitis (NASH) and degree of fibrosis to deep phenotyping with a description of associated comorbidities, genetic polymorphisms and environmental influences that could be associated with disease progression. These insights have fuelled a robust therapeutic pipeline across a variety of new targets to resolve steatohepatitis or reverse fibrosis, or both. Additionally, some of these therapies have beneficial effects that extend beyond the liver, such as effects on glycaemic control, lipid profile and weight loss. In addition, emerging therapies for NASH cirrhosis would have to demonstrate either reversal of fibrosis with associated reduction in portal hypertension or at least delay the progression with eventual decrease in liver-related outcomes. For non-cirrhotic NASH, it is the expectation that reversal of fibrosis by one stage or resolution of NASH with no worsening in fibrosis will need to be accompanied by overall survival benefits. In this Review, we summarize NASH therapies that have progressed to phase II and beyond. We also discuss some of the potential clinical challenges with the use of these new therapies when approved.
Non-alcoholic fatty liver disease (NAFLD) is projected to become the leading cause of hepatocellular carcinoma (HCC) in many countries. Many risk factors for NAFLD are also independently associated ...with HCC, including obesity, diabetes, Hispanic ethnicity and genetic polymorphisms in PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13. Steatosis-related lipotoxicity and oxidative DNA damage can induce hepatocarcinogenesis. These factors may explain the association between NAFLD and HCC, especially in the absence of cirrhosis. In fact, NAFLD/NASH is a leading cause of HCC in the absence of cirrhosis. Identifying patients with pre-cirrhotic NAFLD who have a high enough HCC risk to justify HCC screening represents one of the greatest clinical challenges in NAFLD. Validated models that combine multiple risk factors and fibrosis stage into “HCC risk calculators” are not yet available for patients with NAFLD. Development of such tools would enable risk stratification, identification of high-risk patients even in the absence of cirrhosis, and individualised (risk-based) surveillance strategies.
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