Protein Polymorphisms Research Articles

Contrasting sequence polymorphism and structural basis patterns of Plasmodium falciparum histidine-rich proteins 2/3 in Cameroon and India

Contrasting sequence polymorphism and structural basis patterns of Plasmodium falciparum histidine-rich proteins 2/3 in Cameroon and India

Molecular basis for shifted receptor recognition by an encephalitic arbovirus.

After decades of inactivity throughout the Americas, western equine encephalitis virus (WEEV) recently re-emerged in South America, causing a large-scale outbreak in humans and horses. WEEV binds protocadherin 10 (PCDH10) as a receptor; however, nonpathogenic strains no longer bind human or equine PCDH10 but retain the ability to bind avian receptors. Highly virulent WEEV strains can also bind the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) as alternative receptors. Here, by determining cryo-electron microscopy structures of WEEV strains isolated from 1941-2005 bound to mammalian receptors, we identify polymorphisms in the WEEV spike protein that explain shifts in receptor dependencies and that can allow nonpathogenic strains to infect primary cortical neurons. We predict the receptor dependencies of additional strains and of a related North American alphavirus. Our findings have implications for outbreak preparedness and enhance understanding of arbovirus neurovirulence through virus receptor binding patterns.

Ongoing Evolution of Middle East Respiratory Syndrome Coronavirus, Saudi Arabia, 2023-2024.

Middle East respiratory syndrome coronavirus (MERS-CoV) circulates in dromedary camels in the Arabian Peninsula and occasionally causes spillover infections in humans. MERS-CoV diversity is poorly understood because of the lack of sampling during the COVID-19 pandemic. We collected 558 swab samples from dromedary camels in Saudi Arabia during November 2023-January 2024. We found 39% were positive for MERS-CoV RNA by reverse transcription PCR. We sequenced 42 MERS-CoVs and 7 human 229E-related coronaviruses from camel swab samples by using high-throughput sequencing. Sequences from both viruses formed monophyletic clades apical to recently available genomes. MERS-CoV sequences were most similar to B5 lineage sequences and harbored unique genetic features, including novel amino acid polymorphisms in the spike protein. Further characterization will be required to understand their effects. MERS-CoV spillover into humans poses considerable public health concerns. Our findings indicate surveillance and phenotypic studies are needed to identify and monitor MERS-CoV pandemic potential.

Comprehensive in silico analysis of single nucleotide polymorphism and molecular dynamics simulation of human GATA6 protein in ventricular septal defect

Congenital heart disease (CHD) represents nearly one-third of congenital birth defects annually, with ventricular septal defect (VSD) being the most common type. The aim of this study was to explore the role of specific GATA binding protein 6 gene (GATA6) mutations as a potential etiological factor in the development of VSD through an in silico approach. Data were collected from the human gene databases: DisGeNET and GeneCards, with protein-protein interaction networks constructed via STRING and Cytoscape. Gene ontology and pathway enrichment analyses were conducted using DAVID, with data analysis in R with significance set at FDR p<0.05. Target single nucleotide polymorphisms (SNPs) of GATA6 were obtained from NCBI dbSNP, and non-synonymous single nucleotide polymorphism (nsSNP) effects were predicted using SIFT, PolyPhen-2, I-Mutant 2.0, Fathmm, MutPred 2.0, SNP&GO, and PON-P2. Conserved regions of GATA6 were analyzed using ConSurf, with functional classification, variant conservation, and stability changes evaluated in Google Colab. Multiple sequence alignment was performed using ClustalW. Mutation modeling and molecular dynamics analysis, using GROMACS, revealed that among 87 intersecting genes, 16 proteins were interconnected with GATA6, showing a centrality value of 0.4378. Gene ontology analysis highlighted atrioventricular canal development, protein-DNA complexes, and transcription factor regulation as key processes for cardiac development, especially in the ventricular septum. NsSNP and molecular dynamics analyses identified rs387906818 and rs387906820 as having the highest pathogenic potential for VSD due to amino acid structural changes.

Role of route of delivery on Chlamydia abortus vaccine-induced immune responses and genital tract immunity in mice.

We investigated if the efficacy of a Chlamydia abortus (Cab) subunit vaccine is influenced by route of administration. Thus, female CBA/J mice were immunized either by mucosal or systemic routes with Vibrio cholerae ghost (VCG)-based vaccine expressing T and B cell epitopes of Cab polymorphic membrane protein (Pmp) 18D, termed rVCG-Pmp18.3. Vaccine evaluation revealed that all routes of vaccine delivery induced a Th1-type antibody response after a prime boost or three-dose immunization regimen. Also, the intranasal and rectal mucosal and intramuscular systemic routes induced cross-reactive neutralizing antibodies against homologous and heterologous Cab strains. Irrespective of the route of immunization, the vaccine elicited a Th1-type cytokine response (IFN-γ/IL-4 >1) in immunized mice. Analysis of reduction in genital Cab burden as an index of protection showed that immunization induced substantial degrees of protection against infection, irrespective of route of delivery with the intranasal and rectal mucosal routes showing superior levels of protection 12 days postchallenge. Furthermore, there was correlation between the humoral and cellular immune response and protection was associated with the Cab-specific serum IgG antibody avidity and IFN-γ. Thus, while route of administration impacts vaccine efficacy, the rVCG-Pmp18.3-induced protective immunity against Cab respiratory infection can be accomplished by both mucosal and systemic immunization.

CspZ variant-specific interaction with factor H incorporates a metal site to support Lyme borreliae complement evasion.

Polymorphic microbial immune evasion proteins dictate the pathogen species- or strain-specific virulence. Metals can impact how microbial proteins confer host-pathogen interactions, but whether this activity can be allelically variable is unclear. Here, we investigate the polymorphic CspZ protein of Lyme disease spirochete bacteria to assess the role of metals in protein-protein interaction. CspZ facilitates evasion of the complement system, the first line of immune defense through binding to the complement regulator factor H (FH). By obtaining a high-resolution cocrystal CspZ-FH structure, we identified a zinc coordinating the binding of FH SCR6-7 domains to a Glu65 on a loop from CspZ of Borrelia burgdorferi B31. However, zinc is dispensable for human FH binding for CspZ orthologs with a different loop orientation and/or lacking this glutamate. Phylogenetic analysis of all known human FH-binding CspZ variants further grouped the proteins into three unique lineages correlating with loop sequences. This suggests multiple FH-binding mechanisms evolved through Lyme disease spirochete-host interactions. Overall, this multidisciplinary work elucidates how the allelically specific immune evasion role of metals is impacted by microbial protein polymorphisms.

Broadly inhibitory antibodies to severe malaria virulence proteins.

Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels1. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins of the parasite. A subset of PfEMP1 variants that bind to human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis2. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here we describe two broadly reactive and inhibitory human monoclonal antibodies to CIDRα1. The antibodies isolated from two different individuals exhibited similar and consistent EPCR-binding inhibition of diverse CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins, as well as parasite sequestration in bioengineered 3D human brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with three different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies are likely to represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.

Variations in Bovine Milk Proteins and Processing Conditions and Their Effect on Protein Digestibility in Humans: A Review of In Vivo and In Vitro Studies.

Bovine milk proteins account for 10% of the global protein supply, which justifies the importance of thoroughly understanding their digestive processes. Extensive research on digestion is being conducted both in vivo and in vitro. However, interpretations and comparisons across different studies require a thorough understanding of the methodologies used. Both the rate and extent of milk protein digestion can be affected by several intrinsic and extrinsic factors with potential implications for overall digestibility and physiological responses. Among intrinsic factors, the impact of genetic variants in native milk proteins has emerged as a growing research area. To these, further complexity is added by the processing conditions frequently applied to milk prior to consumption. The main aim of this work is to provide an overview of the current knowledge on the impact of variations in milk protein profiles (particularly whey: casein ratio and protein polymorphisms), the treatments applied during processing (pasteurisation, homogenisation) and consumption (temperature changes) on protein digestion. To support the interpretation of the current literature, this manuscript also presents a historical perspective into research in this field and summarizes the protocols that are most frequently used, presently, on in vitro digestion studies.

Potentiality of Amaranthus viridis (L.) to accumulation of heavy metals and its relation to protein profile

The present study was undertaken to assess the levels of heavy metals (Cd, Fe, Ni and Zn) in soil and plant parts. The phytoremediation potential of Amaranthus viridis (amaranth) was determined by calculating the bioconcentration factor (BCF) and translocation factor (TF). Soil and plant samples were collected from eight different sites in their native habitats, distributed along Ismailia irrigation canal located in the east of the Nile Delta region, Egypt. Roots of amaranth had the higher concentrations of Cd, Fe and Ni means which were 2.75, 547.3 and 7.25 mg g-1 DW at sites SH8, SH6 and SH4 respectively, as compared to the other sampling sites. Whereas, shoots had the higher concentrations of Zn (283.6 mg g-1 DW) at site SH5. All sites were found with BCF more than 1 for all heavy metals. Except for Zn, TF values of Cd, Fe and Ni at all sites were lower than one. Depending on BCF and TF results, amaranth showed significant potential for phytostabilization of Cd, Fe and Ni and phytoextraction of Zn as well. Moreover, the protein profile showed different bands with varied molecular weights. Both relationships between studied accessions and similarity were elucidated, with high similarity (96% between SH2 and SH3 accessions), lowest similarity (72% between SH4 and SH8) and degree of polymorphism calculated as 62.5%. The variation in the similarity index may be due to the induction of a variety of proteins under heavy metal stress and also ecological features in various sites that cause protein polymorphism.

Variability of non-structural proteins of HIV-1 sub-subtype A6 (Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus-1, sub-subtype A6) variants circulating in different regions of the Russian Federation.

HIV-1 non-structural proteins are promising targets for vaccine development and for creating approaches to personalized medicine. HIV-1 sub-subtype A6 has become the dominating strain in Russia. However, the geographic, economic and demographic characteristics of the country can contribute to the formation of differences between A6 variants circulating in different regions. The aim of the study is a comparative analysis of the consensus sequences of non-structural proteins in A6 variants circulating in the Amur Region, in Arkhangelsk, Irkutsk and Murmansk. 48 whole blood samples obtained from HIV-infected patients without experience of therapy observed at the AIDS Centers in Arkhangelsk, Irkutsk, Murmansk and Amur Region were analyzed. HIV-1 whole-genome nucleotide sequences were obtained and were subtyped. Consensus sequences of sub-subtype A6 variants non-structural proteins for each analyzed region were formed. Furthermore, reference sequences of sub-subtype A6 non-structural proteins were formed based on whole-genome sequences retrieved from the international Los Alamos database. Comparison of consensus sequences and references was performed using the MEGA v.10.2.2 and the PSIPRED programs. Vif, Vpr and Nef reference sequences have been obtained for HIV-1 sub-subtype A6. There was not difference in consensus sequences of Vpr in different regions. Characteristic features were found for consensus sequences of Tat, Rev, Vpu, Vif and Nef proteins in different regions. A limitation of the study is a small sample size. Overall, the results demonstrate the existing diversity of non-structural proteins in sub-subtype A6 variants in different regions and indicate the relevance of studying the polymorphism of non-structural proteins of virus variants in different regions.

The Role of Pharmacogenetic-Based Pharmacokinetic Analysis in Precise Breast Cancer Treatment.

Given the high prevalence of breast cancer and the diverse genetic backgrounds of patients, a growing body of research emphasizes the importance of pharmacogenetic-based pharmacokinetic analysis in optimizing treatment outcomes. The treatment of breast cancer involves multiple drugs whose metabolism and efficacy are influenced by individual genetic variations. Genetic polymorphisms in drug-metabolizing enzymes and transport proteins are crucial in the regulation of pharmacokinetics. Our review aims to investigate the opportunities and challenges of pharmacogenomic-based pharmacokinetic analysis as a precision medicine tool in breast cancer management.

Association of CETP gene polymorphisms and haplotypes with acute heart rate response to exercise

Abstract Background Polymorphisms in the cholesteryl ester transfer protein (CETP) gene are known to be strongly associated with increased cardiovascular risk, primarily through their effects on the lipid profile, and consequently on atherosclerotic risk. The acute heart rate response (AHRR) to physical activity is closely related to individual cardiovascular fitness. This study aimed to investigate the effect of CETP gene polymorphisms on AHRR. Methods Our analysis examines the association of five single nucleotide polymorphisms (SNPs; rs1532624, rs5882, rs708272, rs7499892 and rs9989419) and their haplotypes (H) known to be associated with cardiovascular risk in the CETP gene with AHRR in 607 individuals from the Hungarian population. Individual AHRR in the present study was assessed using the YMCA 3-minute step test and was measured as the difference between resting and post-exercise heart rate, i.e. delta heart rate (ΔHR). To exclude the direct confounding effect of the CETP gene on the lipid profile, adjustments for TG and HDL-C levels were applied in the statistical analyses. Results Among the five SNPs examined, two showed a significant association with lower ΔHR (rs1532624-Cdom: B = -8.15, p < 0.001; rs708272-Gdom: B = -8.09, p < 0.001) and reduced the risk of adverse AHRR (rs1532624-A: OR = 2.26, p < 0.001; rs708272-A: OR = 2.17, p < 0.001). Among the ten haplotypes, two showed significant association with lower ΔHR (H3 - CAGCA: B = -6.79, p = 0.003; H9 - CGGCG: B = -14.79, p = 0.014) and lower risk of adverse AHRR (H3 - CAGCA: OR = 0.58, p = 0.038; H9 - CGGCG: OR = 0.05, p = 0.008) compared to the reference haplotype (H1 - AGACG). Conclusions Our study is the first to report a significant association between polymorphisms and their haplotypes in the CETP gene and AHRR. It also confirms that the effect of the CETP gene on cardiovascular risk is expressed through the acute heart rate response to physical activity, in addition to its effect on the lipid profile. Key messages • Certain polymorphisms and haplotypes in the CETP gene show a significant association with AHRR. • The CETP gene polymorphisms exert their effect on cardiovascular risk not only by altering the lipid profile, but also by modifying the heart rate response to physical activity.

Genetic polymorphism of merozoite surface protein 1 and merozoite surface protein 2 in the Vietnam Plasmodium falciparum population

BackgroundPlasmodium falciparum merozoite surface proteins 1 (PfMSP1) and 2 (PfMSP2) are potential candidates for malaria vaccine development. However, the genetic diversity of these genes in the global P. falciparum population presents a significant challenge in developing an effective vaccine. Hence, understanding the genetic diversity and evolutionary trends in the global P. falciparum population is crucial.MethodsThis study analyzed the genetic variations and evolutionary changes of pfmsp1 and pfmsp2 in P. falciparum isolates from the Central Highland and South-Central regions of Vietnam. DNASTAR and MEGA7 programs were utilized for analyses. The polymorphic nature of global pfmsp1 and pfmsp2 was also investigated.ResultsA total of 337 sequences of pfmsp1 and 289 sequences of pfmsp2 were obtained. The pfmsp1 and pfmsp2 from Vietnam revealed a higher degree of genetic homogeneity compared to those from other malaria-endemic countries. Remarkably, the allele diversity patterns of Vietnam pfmsp1 and pfmsp2 differed significantly from those of neighboring countries in the Greater Mekong Subregion. Declines in allele diversity and polymorphic patterns of Vietnam pfmsp1 and pfmsp2 were observed.ConclusionsThe Vietnam P. falciparum population might be genetically isolated from the parasite populations in other neighboring GMS countries, likely due to geographical barriers and distinct evolutionary pressures. Furthermore, bottleneck effects or selective sweeps may have contributed to the genetic homogeneity of Vietnam pfmsp1 and pfmsp2.

Correction for Welsh et al., "Sequence polymorphisms in the reovirus σ1 attachment protein modulate encapsidation efficiency and replication in mice".

Correction for Welsh et al., "Sequence polymorphisms in the reovirus σ1 attachment protein modulate encapsidation efficiency and replication in mice".

Utilizing Arthrospira platensis for the fabrication of zinc oxide nanoparticles: Analysis and assessment for enhancing drought tolerance in Sub1A QTL bearing rice seedlings

In the present study, the underlying pathways for zinc oxide nanoparticles (ZnO-NPs) mediated modulation of oxidative stress under drought were evaluated in rice seedlings. Principally, rice cultivar (cv. Swarna Sub1) was used to assess the potential of the Sub1A QTL for its drought sensitivity in response to bio-fabricated ZnO-NPs. ZnO-NPs were synthesized from algal (Arthrospira platensis) extract and characterized for their opto-physical properties, confirming size (54 nm), hydrodynamicity (-18.54), amorphous-cubic shape and others features. Fifteen-day-old rice seedlings were primed with 25 ppm ZnO-NPs and exposed to 12 % polyethylene glycol (PEG) mediated drought stress (DS) for 7-days under laboratory conditions. Primarily, Sub1A QTL responded to drought-induced anoxic stress with a significant increase in the activities of alcohol dehydrogenase (447.41 %) and pyruvate decarboxylase (96.51 %) through ZnO-NPs sensitization. Plants recorded a significant reduction in root growth, which regained 89.25 % with ZnO-NPs treatments. ZnO-NPs also recovered relative water content (49 %), proline (99.2 %), and improved chlorophyll fluorescence (90.9 %) under stress. Furthermore, drought-induced membrane leakage was stabilized by reducing ionic conductivity through the distribution of wall-bound polyamines. A characteristic feature of fluorescence also reinforced the sustenance of photosynthetic activities by ZnO-NPs under drought. Alternatively, rice seedlings showed regulation of oxidative stress, where lipid peroxidation and protein carbonylation were reduced by 270 % and 178.2 %, respectively. This was observed with the minimization of superoxide and hydrogen peroxide concentrations by regulating apoplastic oxidase activity (117.64 %) with distinct polymorphisms in proteins. These observations suggest that ZnO-NPs can ameliorate drought-induced oxidative stress in rice, providing insights for improved nano-fertigation.

Effect of protein polymorphisms on milk composition, coagulation properties, and protein profile in dairy sheep

The objective of this study was to quantify the effect of protein polymorphisms on milk composition, coagulation properties, and protein profile in dairy sheep from a New Zealand flock. A total of 470 test-day records, from 147 lactating ewes, were used in the statistical analyses. Protein polymorphisms observed in the RP-HPLC were self-named for purposes of the present study. Data were analyzed using a mixed linear model, including the fixed effects of ewe age, litter size, coat-colour, and stage of lactation, and, as a covariate, deviation from the median lambing date of the flock. The effects of protein polymorphisms were added to the model, one at a time. Protein polymorphisms were significantly (p < 0.05) associated with milk composition and protein profile. Polymorphisms of β-lactoglobulin were significantly associated with milk heat stability, being AB type more heat stable than AA. The other processability traits were not significantly affected by protein polymorphisms. Further studies are required to confirm the protein variants and the properties of individual protein polymorphisms.

Polymorphism detection and characterization of sperm cells chromatin remodeling associated genes in Murrah buffalo.

Seasonal variations significantly impact buffalo bull semen production and quality, particularly during the summer months. Understanding the genetic basis of these changes is important for managing bull fertility and improving sperm quality. The present study focused on characterizing and identifying polymorphisms in chromatin remodeling genes, protamines (PRMs) and Transition Nuclear Proteins (TNPs) in Murrah buffalo bulls with varying semen quality due to seasonal effects. Our findings revealed none of the coding region variation in PRM1, PRM2, TNP1, and TNP2, these genes are highly conserved in buffalo. Two intronic variants were identified, including G16C in PRM1 intron 1 and intronic SNP in PRM2 intron 1(G96A). The complete CDS of consensus sequence of bubaline PRM1 was 86.3% identical and 94.1% similar to the bovine PRM1. Whereas the complete CDS of consensus sequence of bubaline TNP2 was 78.2% identical and 91.0% similar to bovine TNP2. Further, no statistically significant differences in the fold change of TNP1, TNP2, PRM1, and PRM2 levels between the hot summer SNA and SA groups and the winter SNA and SA groups This study represents the first comprehensive report on the characterization of bubaline PRM1 (complete CDS), PRM2 (partial CDS), TNP1 (partial CDS), and TNP2 (complete CDS) genes in buffalo sperm cells. Results of the study, clearly indicate that the genes associated with protamine (PRM1 and TNP2) are highly conserved in Bubalus bubalis. Understanding these genetic underpinnings can have implications for improving buffalo bull fertility and semen quality.

Clustering of Polymorphic Membrane Protein E Clade in Chlamydia trachomatis Lineages from Men Who Have Sex with Men.

Several Chlamydia trachomatis lineages identified through outer membrane protein A genotyping or multilocus sequence typing have been circulating worldwide among men who have sex with men. In a study in Tokyo, Japan, we demonstrate that such lineages commonly belong to a specific polymorphic membrane protein E clade across genotypes.

TLR4 and TNF-α single nucleotide polymorphisms in patients with brucellosis: Association with infection complications

ObjectivesTo investigate associations of the carriage of single nucleotide polymorphisms (SNPs) of proteins involved in the immune response of patients with brucellosis. MethodsA case control study of patients with brucellosis upon WHO criteria. Blood genomic analysis was performed by RFLP- PCR for the detection of SNPs: i) at promoters -376 G > A (rs1800750); -308 G > A (rs 1,800,629); -238 G > A (rs361525) of the TNF gene, ii) at -896 A > G Asp299Gly (rs4986790) and -1196 C > T Thr399Ile (rs4986791) positions of the TLR-4 gene. Logistic regression analysis of factors related to brucellar spondylodiscitis was performed. ResultsPatients with brucellosis (n = 105) were male (n = 67, 63.8 %); mean age (SD): 49.51(18.31); spondylodiscitis (n = 30), sacral osteomyelitis (n = 21). Carriage of the minor frequency A alleles at -238 of the promoter region of TNF was greater in patients than in controls (11.4% vs 2.6 %, p < 0.001). In a stepwise regression model including host variables and TNF-238 G A-1 genotype, only the last one was associated with brucellar spondylodiscitis [OR 2.91 (CI95 % 1.02–8.31), p = 0.047]. ConclusionsIn our cohort, the association of one TNF SNP of patients with brucellosis, in particular spondylodiscitis, might be prognostic whereas further investigation of the exact role in the host immune response is required.

Genetic polymorphism of Duffy binding protein in Pakistan Plasmodium vivax isolates

Plasmodium vivax Duffy binding protein (PvDBP) is crucial for erythrocyte invasion, interacting with the Duffy Antigen Receptor for Chemokines (DARC) on the erythrocyte surface. The amino-terminal cysteine-rich region II of PvDBP (PvDBPII) is a promising blood stage vaccine candidate, yet the genetic polymorphisms of this protein in global P. vivax isolates complicate the design of effective vaccines against vivax malaria. This study analyzed the genetic polymorphism of PvDBPII in Pakistan P. vivax isolates. A total of 29 single nucleotide polymorphisms (SNPs), including 22 nonsynonymous SNPs, were identified in 118 Pakistan PvDBPII. Most amino acid substitutions occurred in subdomains II and III, with six commonly observed in the global PvDBPII population. The amino acid change patterns in Pakistan PvDBPII generally mirrored those in global PvDBPII, although the frequencies of amino acid changes varied by country. Nucleotide diversity in Pakistan PvDBPII was comparable to that found in global PvDBPII. Evidence of natural selection and recombination in Pakistan PvDBPII aligned with observations in global PvDBPII. Analysis of the haplotype network of global PvDBPII revealed a complexed network of 167 haplotypes, but no geographical clustering was observed. The findings are crucial for understanding the genetic characteristics of Pakistan PvDBPII. A comprehensive analysis of nucleotide diversity and evolutionary trends in the global PvDBPII population offers valuable insights for the development of vivax malaria vaccines based on this antigen.