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Frontiers in Immunology 2024Sialic acids are found as terminal sugars on glycan structures on cellular surfaces. T cells carry these sialoglycans abundantly, and they are thought to serve multiple...
Sialic acids are found as terminal sugars on glycan structures on cellular surfaces. T cells carry these sialoglycans abundantly, and they are thought to serve multiple functions in cell adhesion, cell migration, and protection from complement attack. We studied the role of sialoglycans on T cells in a mouse model with a T cell-specific deletion of cytidine monophosphate-sialic acid synthase (CMAS), the enzyme that is crucial for the synthesis of sialoglycans. These mice showed a T-cell deficiency in peripheral lymphoid organs. Many T cells with an undeleted allele were found in the periphery, suggesting that they escaped the Cre-mediated deletion. The remaining peripheral T cells of T cell-specific KO mice had a memory-like phenotype. Additional depletion of the complement factor C3 could not rescue the phenotype, showing that the T-cell defect was not caused by a host complement activity. -deficient T cells showed a high level of activated caspase 3, indicating an ongoing apoptosis. In bone marrow chimeric cellular transfer experiments, we observed a strong competitive disadvantage of -deficient T cells compared to wild-type T cells. These results show that sialoglycans on the surface of T cells are crucial for T-cell survival and maintenance. This function has not been recognized before and is similar to the function of sialoglycans on B cells.
Topics: Animals; Mice; Mice, Knockout; T-Lymphocytes; Sialic Acids; Cell Survival; Mice, Inbred C57BL; Apoptosis; Complement C3; Mixed Function Oxygenases
PubMed: 38947328
DOI: 10.3389/fimmu.2024.1359494 -
Frontiers in Immunology 2024In the present study we investigated whether peptides derived from the entire SARS-CoV-2 proteome share homology to TAAs (tumor-associated antigens) and cross-reactive...
BACKGROUND
In the present study we investigated whether peptides derived from the entire SARS-CoV-2 proteome share homology to TAAs (tumor-associated antigens) and cross-reactive CD8+ T cell can be elicited by the BNT162b2 preventive vaccine or the SARS-CoV-2 natural infection.
METHODS AND RESULTS
Viral epitopes with high affinity (<100nM) to the HLA-A*02:01 allele were predicted. Shared and variant-specific epitopes were identified. Significant homologies in amino acidic sequence have been found between SARS-CoV-2 peptides and multiple TAAs, mainly associated with breast, liver, melanoma and colon cancers. The molecular mimicry of the viral epitopes and the TAAs was found in all viral proteins, mostly the Orf 1ab and the Spike, which is included in the BNT162b2 vaccine. Predicted structural similarities confirmed the sequence homology and comparable patterns of contact with both HLA and TCR α and β chains were observed. CD8+ T cell clones cross-reactive with the paired peptides have been found by MHC class l-dextramer staining.
CONCLUSIONS
Our results show for the first time that several SARS-COV-2 antigens are highly homologous to TAAs and cross-reactive T cells are identified in infected and BNT162b2 preventive vaccinated individuals. The implication would be that the SARS-Cov-2 pandemic could represent a natural preventive immunization for breast, liver, melanoma and colon cancers. In the coming years, real-world evidences will provide the final proof for such immunological experimental evidence. Moreover, such SARS-CoV-2 epitopes can be used to develop "multi-cancer" off-the-shelf preventive/therapeutic vaccine formulations, with higher antigenicity and immunogenicity than over-expressed tumor self-antigens, for the potential valuable benefit of thousands of cancer patients around the World.
Topics: Humans; SARS-CoV-2; COVID-19; Molecular Mimicry; CD8-Positive T-Lymphocytes; Cross Reactions; Epitopes, T-Lymphocyte; BNT162 Vaccine; Antigens, Viral; HLA-A2 Antigen; Neoplasms; Antigens, Neoplasm; COVID-19 Vaccines
PubMed: 38947322
DOI: 10.3389/fimmu.2024.1398002 -
MedRxiv : the Preprint Server For... Jun 2024Prioritization of HLA antigen-level matching in the US kidney allocation system intends to improve post-transplant survival but causes racial disparities and thus has...
BACKGROUND
Prioritization of HLA antigen-level matching in the US kidney allocation system intends to improve post-transplant survival but causes racial disparities and thus has been substantially de-emphasized. Recently, molecular matching based on eplets has been found to improve risk stratification compared to antigen matching.
METHODS
To assign eplets unambiguously, we utilized a cohort of 5193 individuals with high resolution allele-level HLA genotypes from the National Kidney Registry. Using repeated random sampling to simulate donor-recipient genotype pairings based on the ethnic composition of the historical US deceased donor pool, we profiled the percentage of well-matched donors for candidates by ethnicity.
RESULTS
The percentage of well-matched donors with zero-DR/DQ eplet mismatch was 3-fold less racially disparate for Black and Asian candidates than percentage of donors with zero-ABDR antigen mismatches, and 2-fold less racially disparate for Latino candidates. For other HLA antigen and eplet mismatch thresholds, the percentage of well-matched donors was more similar across candidate ethnic groups.
CONCLUSIONS
Compared to the current zero-ABDR antigen mismatch, prioritizing a zero-DR/DQ eplet mismatch in allocation would decrease racial disparities and increase the percentage of well-matched donors. High resolution HLA deceased donor genotyping would enable unambiguous assignment of eplets to operationalize molecular mismatch metrics in allocation.
KEY POINTS
What is the impact of prioritizing low molecular mismatch transplants on racial and ethnic disparities in US deceased-donor kidney allocation, compared to the current prioritization of antigen-level matching? The lowest-risk eplet mismatch approach decreases racial disparities up to 3-fold compared to lowest-risk antigen mismatch and identifies a larger number of the lowest allo-immune risk donors. Prioritizing eplet matching in kidney transplant allocation could both improve outcomes and reduce racial disparities compared to the current antigen matching.
PubMed: 38947023
DOI: 10.1101/2024.06.13.23290644 -
MedRxiv : the Preprint Server For... Jun 2024Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 gene coding for a membrane...
INTRODUCTION
Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 gene coding for a membrane component of adherens junctions is involved in response to infection, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as .
MATERIALS AND METHODS
We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor).
RESULTS
The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p<0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p<0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect.
CONCLUSION
This study reported a new causal relationship between pTau-181 and AD. We found that the association between rs6859 in the gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the gene and AD.
PubMed: 38947013
DOI: 10.1101/2024.06.21.24309310 -
MedRxiv : the Preprint Server For... Jun 2024Pharmacogenomics promises improved outcomes through individualized prescribing. However, the lack of diversity in studies impedes clinical translation and equitable...
Pharmacogenomics promises improved outcomes through individualized prescribing. However, the lack of diversity in studies impedes clinical translation and equitable application of precision medicine. We evaluated the frequencies of PGx variants, predicted phenotypes, and medication exposures using whole genome sequencing and EHR data from nearly 100k diverse All of Us Research Program participants. We report 100% of participants carried at least one pharmacogenomics variant and nearly all (99.13%) had a predicted phenotype with prescribing recommendations. Clinical impact was high with over 20% having both an actionable phenotype and a prior exposure to an impacted medication with pharmacogenomic prescribing guidance. Importantly, we also report hundreds of alleles and predicted phenotypes that deviate from known frequencies and/or were previously unreported, including within admixed American and African ancestry groups.
PubMed: 38946996
DOI: 10.1101/2024.06.12.24304664 -
Frontiers in Microbiology 2024The complex (Smc) has emerged as a significant nosocomial pathogen contributing to increased mortality rates, particularly in case of bloodstream infections.
BACKGROUND
The complex (Smc) has emerged as a significant nosocomial pathogen contributing to increased mortality rates, particularly in case of bloodstream infections.
METHODS
This study employed whole-genome sequencing (WGS) to assess the genetic diversity, antimicrobial resistance profiles, molecular epidemiology and frequencies of virulence genes among 55 isolates obtained from bacteremic cases over a 9-year period.
RESULTS
Based on the threshold of 95% average nucleotide identity (ANI) and 70% digital DNA-DNA hybridization (dDDH) for genospecies delineation, we classified 37 isolates into 6 known species, all belonging to the Smc. The remaining 18 isolates sequenced in this study were assigned to 6 new genomospecies. Among the 55 isolates, we identified 44 different sequence types (STs), comprising 22 known and 22 novel allele combinations. The resistance rate of Smc against trimethoprim-sulfamethoxazole (TMP/SMX) was found to be 3.6%, with the and class one integron integrase genes () detected in these isolates. All Smc isolates were susceptible to minocycline. Furthermore, all Smc strains harbored the genes. Genomospecies 1 (100%, = 9), (84.21%, = 19) and (71.43%, = 7) demonstrated a higher percentage of the gene, which was also associated with a higher separation rate. In addition to , , , genes, all strains (100%) contained , , , and genes, while all genomospecies 1 strains (100%) contained , , and genes.
CONCLUSION
Our study highlights the genetic diversity among Smc isolates from patients with bacteremia, revealing 22 novel ST types, 58 new alleles and 6 new genomospecies. and were found to carry more virulence factors, emphasizing the importance of accurate strain identification. Minocycline emerged as a promising alternative antibiotic for patients who were resistant to TMP/SMX.
PubMed: 38946894
DOI: 10.3389/fmicb.2024.1424241 -
Vavilovskii Zhurnal Genetiki I Selektsii Jun 2024Single-nucleotide polymorphisms (SNPs) can serve as reliable markers in genetic engineering, selection, screening examinations, and other fields of science, medicine,...
Single-nucleotide polymorphisms (SNPs) can serve as reliable markers in genetic engineering, selection, screening examinations, and other fields of science, medicine, and manufacturing. Whole-genome sequencing and genotyping by sequencing can detect SNPs with high specificity and identify novel variants. Nonetheless, in situations where the interest of researchers is individual specific loci, these methods become redundant, and their cost, the proportion of false positive and false negative results, and labor costs for sample preparation and analysis do not justify their use. Accordingly, accurate and rapid methods for genotyping individual alleles are still in demand, especially for verification of candidate polymorphisms in analyses of association with a given phenotype. One of these techniques is genotyping using TaqMan allele-specific probes (TaqMan dual labeled probes). The method consists of real-time PCR with a pair of primers and two oligonucleotide probes that are complementary to a sequence near a given locus in such a way that one probe is complementary to the wild-type allele, and the other to a mutant one. Advantages of this approach are its specificity, sensitivity, low cost, and quick results. It makes it possible to distinguish alleles in a genome with high accuracy without additional manipulations with DNA samples or PCR products; hence the popularity of this method in genetic association studies in molecular genetics and medicine. Due to advancements in technologies for the synthesis of oligonucleotides and improvements in techniques for designing primers and probes, we can expect expansion of the possibilities of this approach in terms of the diagnosis of hereditary diseases. In this article, we discuss in detail basic principles of the method, the processes that influence the result of genotyping, criteria for selecting optimal primers and probes, and the use of locked nucleic acid modifications in oligonucleotides as well as provide a protocol for the selection of primers and probes and for PCR by means of rs11121704 as an example. We hope that the presented protocol will allow research groups to independently design their own effective assays for testing for polymorphisms of interest.
PubMed: 38946890
DOI: 10.18699/vjgb-24-40 -
Andrology Jul 2024Cardiovascular disease induces erectile dysfunction modulated by endothelial nitric oxide synthase enzyme and an impaired ejection fraction that restricts penis vascular...
Erectile dysfunction in cardiovascular patients: A prospective study of the eNOS gene T-786C, G894T, and INTRON variable number of the tandem repeat functional interaction.
BACKGROUND
Cardiovascular disease induces erectile dysfunction modulated by endothelial nitric oxide synthase enzyme and an impaired ejection fraction that restricts penis vascular congestion. However, the mechanisms regulating endothelial dysfunction are not understood.
OBJECTIVES
Exploring the functional impact of endothelial nitric oxide synthase genetic polymorphisms on erectile dysfunction and drug therapy optimization in high-risk cardiovascular disease patients.
MATERIALS AND METHODS
Patients with erectile dysfunction symptoms and candidates for andrology therapy were included (n = 112). Clinical data and endothelial nitric oxide synthase rs1799983 (G894T) and rs2070744 (T-786C), genotyped by fluorescence polarization assays, were registered. The 27-bp variable number of the tandem repeat polymorphism in intron 4 (intron4b/a) was analyzed by polymerase chain reaction-restriction fragment length polymorphism. Association analyses were run with the R-3.2.0 software.
RESULTS
A significant association between endothelial nitric oxide synthase 786-TT (p = 0.005) and the aa/ac of intron 4 variable number of the tandem repeat (p = 0.02) with higher erectile dysfunction susceptibility was observed in cardiovascular disease patients (60 ± 9 years, 66% severe erectile dysfunction, 56% ejection fraction). After 3-months of phosphodiesterase type 5 inhibitors, erectile dysfunction (International Index of Erectile Function, 50 ± 16 scores, the International Index of Erectile Function-Erectile Function 21 ± 10 scores, p < 0.001) and sexual quality of life (modified Sexual Life Quality Questionnaire 55 ± 23 scores, p < 0.001) had significantly improved. The cardiovascular ejection fraction was influenced positively with better sexual quality of life (0.1941), and also in the endothelial nitric oxide synthase G894-T allele (p = 0.076) carriers, which could merit future analyses. Erectile dysfunction was present as the primary clinical manifestation in 62% of cases, with cardiovascular disease occurring concurrently. Only former smokers and obese subjects debuted prior to cardiovascular disease than to erectile dysfunction.
CONCLUSIONS
Our study provides comprehensive insights into the functional interaction linking endothelial nitric oxide synthase gene polymorphisms, erectile function, and ejection fraction in high-risk cardiovascular disease patients. Future therapeutic strategies could target endothelial nitric oxide synthase activity by including lifestyle changes and epigenetic modulations.
PubMed: 38946584
DOI: 10.1111/andr.13671 -
Clinical Toxicology (Philadelphia, Pa.) Jul 2024The opioid receptor mu1 is a protein coding gene that can have different codes for a protein and may have variations (polymorphisms) affecting how opioids work. The aim...
INTRODUCTION
The opioid receptor mu1 is a protein coding gene that can have different codes for a protein and may have variations (polymorphisms) affecting how opioids work. The aim of this study was to investigate the prevalence of the most common opioid receptor mu1 polymorphism () and any relationship between this polymorphism and features following tramadol overdose.
MATERIALS AND METHODS
This was a cross-sectional study of patients admitted with tramadol poisoning to an Iranian hospital. These patients were not taking any other drugs or medications and had no history of seizures.
RESULTS
The results showed that among the 83 patients included in the study, 57 (69 per cent) had the AA genotype, 25 (30 per cent) had the AG genotype, and one (1 per cent) had the GG genotype for the opioid receptor mu1 polymorphism. Nausea and/or vomiting occurred in nine (11 per cent) patients and dizziness in 38 (46 per cent) patients. Serious adverse events included seizures in 51 (60 per cent) patients and respiratory failure requiring mechanical ventilation in 21 (25 per cent) patients. However, there was no significant association between the opioid receptor mu1 polymorphism and these adverse events.
DISCUSSION
In our study, the frequency of the A allele was greater than the G allele, and the AA genotype was more prevalent than AG. The GG genotype was the least common among the polymorphisms of opioid receptor mu1 . There was no significant association between the opioid receptor mu1 polymorphism and symptoms in tramadol-poisoned patients. Although these allele proportions are similar to the results reported in other Caucasian populations, they are dissimilar to the findings in Chinese and Singaporean populations. In these Asian studies, the predominant allele was the G allele. It has been suggested that a mutated G allele will decrease the production of opioid receptor mu1-related messenger ribonucleic acid and related proteins, leading to fewer mu-opioid receptors in the brain.
CONCLUSIONS
This study found no significant association between the opioid receptor mu1 polymorphism and adverse outcomes in tramadol-poisoned patients. However, more research is needed to draw more definitive conclusions due to the limited evidence and variability of opioid receptor mu1 polymorphisms in different populations.
PubMed: 38946467
DOI: 10.1080/15563650.2024.2366921 -
Acta Dermatovenerologica Croatica : ADC Mar 2024The pro-inflammatory adipokine resistin is known to be related to obesity, insulin resistance, and inflammation. Resistin's significance in the etiology of inflammatory...
BACKGROUND
The pro-inflammatory adipokine resistin is known to be related to obesity, insulin resistance, and inflammation. Resistin's significance in the etiology of inflammatory illnesses, such as psoriasis, is explored herein. We examined the link between resistin gene polymorphisms (-420 C>G and +299 G>A) and psoriasis in the Turkish population.
METHODS
In this study, we examined 107 patients with psoriasis and 103 healthy controls. Resistin -420 C>G (rs1862513) and +299 G>A (rs3745367) gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
RESULTS
In patients with psoriasis, the frequency of the resistin -420 CG genotype was meaningfully lower than in the controls. In comparison with the controls, the resistin +299 GA genotype and A allele frequencies were significantly higher. The Resistin -420 CG genotype significantly reduced the risk of psoriasis incidence, while the resistin +299 GA genotype and A allele were found to be associated with a higher risk of psoriasis.
CONCLUSIONS
In the Turkish community, resistin gene polymorphisms at -420 C>G and +299 G>A may exert an important influence on psoriasis etiology and susceptibility.
Topics: Humans; Psoriasis; Resistin; Male; Female; Adult; Middle Aged; Genetic Predisposition to Disease; Turkey; Case-Control Studies; Genotype; Promoter Regions, Genetic; Gene Frequency; Polymorphism, Genetic; Polymorphism, Single Nucleotide
PubMed: 38946181
DOI: No ID Found