Variation In Pathogenesis Research Articles

High-mortality epizootic Mycobacterium ulcerans ecovar Liflandii in a colony of Zaire Dwarf Clawed Frogs (Hymenochirus boettgeri).

Mycobacterium ulcerans ecovar Liflandii (MuLiflandii) was identified as the causative agent of mycobacteriosis in a research colony of Zaire dwarf clawed frogs (Hymenochirus boettgeri) at the University of Michigan. Clinical presentation included lethargy, generalized septicemia, cutaneous granulomas, coelomic effusion, and acute mortality. Identification of the mycobacterial species was based on molecular, microbiological, and histopathologic characteristics. These findings indicate that MuLiflandii is a primary cause of morbidity and mortality in Zaire dwarf clawed frogs and should be considered in the differential diagnosis of sepsis and coelomic effusion in amphibians. Mycobacterial speciation is important given the variability in pathogenesis within the family Mycobacteriaceae and the implications for both animal and human health as potential zoonoses. The Zaire dwarf clawed frog is a species common in the pet trade, and these findings provide consideration for this pathogen as a potentially important public health concern. This is the first report of MuLiflandii infection in the genus Hymenochirus and illustrates the diagnostic challenges of differentiating among both mycolactone-producing mycobacteria and Mycobacterium marinum. Furthermore, we demonstrate the utility of environmental sampling for this pathogen within the tank system, suggesting this mode of sampling could replace the need for direct frog surveillance.

Neurobehavioral Testing as Cognitive Function Evaluation tool in Experimentally Induced Neurodegeneration in Mice

Neurodegeneration is a complex and multifactorial process presenting one of the major issues of fundamental science and clinical medicine due to its high prevalence, multiple nosological entities, and variations in pathogenesis. Translational research contributes to the study of neurodegenerative diseases, with modeling of such pathologies being an important part of this research. Behavioral testing in various animal models of neurodegenerative diseases allows to assess the model validity and reliability, as well as to investigate the potential efficacy of pharmacotherapy and other management approaches. In this overview we present test batteries that evaluate behavior, cognitive performance, and emotional states in animals with experimentally induced neurodegeneration.

The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and is divided into two distinct subtypes, clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC). Although many treatments exist for RCC, these are largely based on clinical trials performed in ccRCC and there are limited studies on the management of nccRCC. Non-clear cell RCC consists of multiple histological subtypes: papillary, chromophobe, translocation, medullary, collecting duct, unclassified, and other rare histologies. Due to variations in pathogenesis and therapeutic response, therapy should be tailored to specific variant histologies. For patients with localized nccRCC, surgical resection remains the gold standard. In the metastatic setting, the standard of care has yet to be clearly defined, and most guidelines recommend clinical trial participation. General therapeutic options include immunotherapy, either as monotherapy or in combination, targeted therapies such as vascular endothelial growth factor tyrosine kinase inhibitors and MET inhibitors, and chemotherapy in certain subtypes. Here we present a review of the incidence and pathogenesis of the various subtypes, as well as available clinical data to support therapeutic recommendations for these subtypes. We also highlight currently available clinical trials in nccRCC and future directions in investigating novel treatment modalities tailored to patients with variant histology.

HIV-1 Vif protein sequence variations in South African people living with HIV and their influence on Vif-APOBEC3G interaction

PurposeDespite extensive research, HIV-1 remains a global epidemic with variations in pathogenesis across regions and subtypes. The Viral Infectivity Factor (Vif) protein, which neutralizes the host protein APOBEC3G, has been implicated in differences in clinical outcomes among people living with HIV (PLHIV). Most studies on Vif sequence diversity have focused on subtype B, leaving gaps in understanding Vif variations in HIV-1C regions like South Africa. This study aimed to identify and compare Vif sequence diversity in a cohort of 51 South African PLHIV and other HIV-1C prevalent regions.MethodsSanger sequencing was used for Vif analysis in the cohort, and additional sequences were obtained from the Los Alamos database. Molecular modeling and docking techniques were employed to study the influence of subtype-specific variants on Vif-APOBEC3G binding affinity.ResultsThe findings showed distinct genetic variations between Vif sequences from India and Uganda, while South African sequences had wider distribution and closer relatedness to both. Specific amino acid substitutions in Vif were associated with geographic groups. Molecular modeling and docking analyses consistently identified specific residues (ARGR19, LYS26, TYR30, TYR44, and TRP79) as primary contributors to intermolecular contacts between Vif and APOBEC3G, essential for their interaction. The Indian Vif variant exhibited the highest predicted binding affinity to APOBEC3G among the studied groups.ConclusionsThese results provide insights into Vif sequence diversity in HIV-1C prevalent regions and shed light on differential pathogenesis observed in different geographical areas. The identified Vif amino acid residues warrant further investigation for their diagnostic, prognostic, and therapeutic potential.

Advances in Research on Type 2 Diabetes Mellitus Targets and Therapeutic Agents.

Diabetes mellitus is a chronic multifaceted disease with multiple potential complications, the treatment of which can only delay and prolong the terminal stage of the disease, i.e., type 2 diabetes mellitus (T2DM). The World Health Organization predicts that diabetes will be the seventh leading cause of death by 2030. Although many antidiabetic medicines have been successfully developed in recent years, such as GLP-1 receptor agonists and SGLT-2 inhibitors, single-target drugs are gradually failing to meet the therapeutic requirements owing to the individual variability, diversity of pathogenesis, and organismal resistance. Therefore, there remains a need to investigate the pathogenesis of T2DM in more depth, identify multiple therapeutic targets, and provide improved glycemic control solutions. This review presents an overview of the mechanisms of action and the development of the latest therapeutic agents targeting T2DM in recent years. It also discusses emerging target-based therapies and new potential therapeutic targets that have emerged within the last three years. The aim of our review is to provide a theoretical basis for further advancement in targeted therapies for T2DM.

Associations among the genome, rumen metabolome, ruminal bacteria, and milk production in early-lactation Holsteins

A multicenter observational study to evaluate genome-wide association was conducted in early-lactation Holstein cows (n = 293) from 36 herds in Canada, the USA, and Australia. Phenotypic observations included rumen metabolome, acidosis risk, ruminal bacterial taxa, and milk composition and yield measures. Diets ranged from pasture supplemented with concentrates to total mixed rations (nonfiber carbohydrates = 17 to 47, and neutral detergent fiber = 27 to 58% of dry matter). Rumen samples were collected <3 h after feeding and analyzed for pH, ammonia, d- and l-lactate, volatile fatty acid (VFA) concentrations, and abundance of bacterial phyla and families. Eigenvectors were produced using cluster and discriminant analyses from a combination of pH and ammonia, d-lactate, and VFA concentrations, and were used to estimate the probability of the risk of ruminal acidosis based on proximity to the centroid of 3 clusters, termed high (24.0% of cows), medium (24.2%), and low risk (51.8%) for acidosis. DNA of sufficient quality was successfully extracted from whole blood (218 cows) or hair (65 cows) collected simultaneously with the rumen samples and sequenced using the Geneseek Genomic Profiler Bovine 150K Illumina SNPchip. Genome-wide association used an additive model and linear regression with principal component analysis (PCA) population stratification and a Bonferroni correction for multiple comparisons. Population structure was visualized using PCA plots. Single genomic markers were associated with milk protein percent and the center logged ratio abundance of the phyla Chloroflexi, SR1, and Spirochaetes, and tended to be associated with milk fat yield, rumen acetate, butyrate, and isovalerate concentrations and with the probability of being in the low-risk acidosis group. More than one genomic marker was associated or tended to be associated with rumen isobutyrate and caproate concentrations, and the center log ratio of the phyla Bacteroidetes and Firmicutes and center log ratio of the families Prevotellaceae, BS11, S24-7, Acidaminococcaceae, Carnobacteriaceae, Lactobacillaceae, Leuconostocaceae, and Streptococcaceae. The provisional NTN4 gene, involved in several functions, had pleiotropy with 10 bacterial families, the phyla Bacteroidetes and Firmicutes, and butyrate. The ATP2CA1 gene, involved in the ATPase secretory pathway for Ca2+ transport, overlapped for the families Prevotellaceae, S24-7, and Streptococcaceae, the phylum Bacteroidetes, and isobutyrate. No genomic markers were associated with milk yield, fat percentage, protein yield, total solids, energy-corrected milk, somatic cell count, rumen pH, ammonia, propionate, valerate, total VFA, and d-, l-, or total lactate concentrations, or probability of being in the high- or medium-risk acidosis groups. Genome-wide associations with the rumen metabolome, microbial taxa, and milk composition were present across a wide geographical and management range of herds, suggesting the existence of markers for the rumen environment but not for acidosis susceptibility. The variation in pathogenesis of ruminal acidosis in the small population of cattle in the high risk for acidosis group and the dynamic nature of the rumen as cows cycle through a bout of acidosis may have precluded the identification of markers for acidosis susceptibility. Despite a limited sample size, this study provides evidence of interactions between the mammalian genome, the rumen metabolome, ruminal bacteria, and milk protein percentage.

Stress, cerebrovascular pathology and vascular dementia: from the diversity of pathogenesis — to multimodal pharmacotherapy

Stress, cerebrovascular pathology and vascular dementia: from the diversity of pathogenesis — to multimodal pharmacotherapy

LBMON234 Ultrasonographic Criteria In The Diagnosis Of Polycystic Ovary Syndrome: A Systematic Review And Meta Analysis

Abstract Ultrasonographic evaluation of polycystic ovarian morphology (PCOM) is part of the diagnostic evaluation of polycystic ovarian syndrome (PCOS). The relevance of PCOM as a diagnostic criterion for PCOS was reaffirmed in the most recent International Evidence-Based Guideline for the Assessment and Management of PCOS. However, there remains a lack of clarity regarding the best practices and specific ultrasonographic markers to define PCOM. We synthesized evidence on diagnostic test accuracy of ovarian ultrasound features to comprehensively determine the most suitable markers to diagnose PCOS. The primary outcome was diagnostic accuracy measures (e. g., thresholds, sensitivity, specificity) for PCOS using the following ovarian markers: follicle number per ovary (FNPO) or per single cross-section (FNPS), ovarian volume (OV), and stromal features. Databases of PubMed, Web of Science, Scopus, CINAHL, and CENTRAL were searched until 7 November 2021 to identify studies that compared ultrasound markers between women with PCOS to those without PCOS. Risk of bias and applicability assessment for diagnostic test accuracy studies were determined using the QUADAS-2 and QUADAS-C tool for a single index test or between multiple index tests, respectively. From a total of 1869 records initially identified, 22 studies were included and 18 (N=6,337; [n=2991 PCOS; n= 3346 Control]) were pooled for meta-analysis. FNPO was the most accurate diagnostic marker (sensitivity: 84%, CI: 81% to 87%; specificity: 91%, CI: 87% to 94%). OV and FNPS had similar but inferior pooled sensitivity (OV: 81%, CI: 75% to 86%; FNPS: 81%, CI: 70% to 89%) and specificity (OV: 79%, CI: 73% to 84%; FNPS: 83%, CI: 75% to 88%) compared to FNPO. Majority of studies had high risk of bias for patient selection and index test methodology across all markers. Subgroup analysis indicated that stratification based on age, body mass index (BMI), and previously proposed thresholds did not account for the heterogeneity in diagnostic accuracy observed across studies. For FNPO, studies that used a transducer frequency &amp;lt;8MHz or the Rotterdam criteria had improved positive likelihood ratio (+LR) and sensitivity, respectively. European studies had improved diagnostic accuracy (specificity, diagnostic odds ratio, +LR) compared to North American studies for FNPO, potentially due to BMI differences between PCOS populations (North America: 30.29 ± 0.61kg/m2, Europe: 27.62 ± 0.73kg/m2). Our findings support the use of FNPO as the gold standard in the ultrasonographic diagnosis of PCOS, with OV and FNPS as robust alternatives if total antral follicle counts cannot be obtained. These findings also identify avenues for future research to refine the ultrasonographic definition of PCOM for timely diagnosis of PCOS and investigations into phenotypic variations in pathogenesis and response to treatment in this condition (PROSPERO ID: CRD42021259118). Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Constitutional markers of urticaria and their prognostic significance (analysis of scientific literature)

Annotation. The purpose of the work is to analyze the scientific literature regarding the constitutional markers of urticaria and their prognostic significance. The analysis of modern scientific literature in the scientometric databases PubMed and MEDLINE is carried out. A review of the literature indicates that significant progress has been made in understanding the etiopathogenesis of urticaria in recent decades, with some clinical and anamnestic signs suggestive of adverse outcomes. However, identifying patients with the highest risk of complications remains an unresolved issue. In connection with the development and implementation in clinical practice of methods of genetic typing, much attention is paid to the search for genetic predictors of adverse course of this dermatosis. To date, phenotypic marker profiles that have been little modified over a lifetime and available for visualization in everyday clinical practice have not been properly considered in assessing the risk of urticaria. Modern anthropocentric approach to solving the problem of risk prediction in urticaria opens up the prospect of taking into account constitutional (personality-typological, somato-typological) and genetic factors that are the basis of psychobiological reactivity of the individual, determining individual variability of pathogenesis and clinical manifestations, patterns severity and frequency of complications.

Inherited GATA3 genetic Variants Are Associated With Childhood BCR-ABL1-Like Acute Lymphoblastic Leukemia and Increased Risk Of Relapse

Recent genomic profiling of acute lymphoblastic leukemia (ALL) has identified a novel high-risk subtype with a gene expression signature similar to that of BCR-ABL1-positive (Ph+) ALL and a poor prognosis. This novel BCR-ABL1-like ALL subtype is characterized by genomic aberrations targeting lymphoid development, cytokine receptor, and tyrosine kinase signaling pathways, e.g., IKZF1 deletion, CRLF2 rearrangements, and JAK mutations. However, the role of the inherited genetic variation in the pathogenesis of BCR-ABL1-like ALL remains unknown.Taking a genome-wide association study (GWAS) approach, we sought to examine germline single-nucleotide polymorphisms (SNPs) for their association with the predisposition to BCR-ABL1-like ALL. In the discovery GWAS, we compared germline SNP genotype frequencies between ALL cases with (N=75) vs. without (N=436) the BCR-ABL1-like expression signature enrolled on the high risk Children's Oncology Group (COG) AALL0232 protocol, and between BCR-ABL1-like ALL (N=75) vs. non-ALL controls (N=6,661). BCR-ABL1-like ALL was identified by prediction analysis of microarrays. After adjusting for genetic ancestry, we observed a single susceptibility locus on 10p14 signified by two SNPs within the GATA3 gene with genome-wide significant association (P=1.05×10-8 and P=2.62×10-7 [BCR-ABL1-like ALL vs. non-BCR-ABL1-like ALL]; P=2.17×10-14 and P=4.94×10-12 [BCR-ABL1-like ALL vs. non-ALL controls]). In a replication cohort of high-risk ALL, namely COG P9906, the disease risk alleles at both GATA3 polymorphisms were consistently over-represented in BCR-ABL1-like ALL (N=32) compared with 139 non-BCR-ABL1-like ALL (P=0.01 and P=0.004, respectively) and compared with an independent set of 5,755 non-ALL controls (P=3.69×10-5 and P=0.0001, respectively). This GATA3 SNP was also associated with GATA3 expression in lymphoblastoid cell lines (N=56, P=0.034) and in primary ALL blasts (COG AALL0232, N=511, P=9.2×10-8; COG P9906, N=173, P=3.6×10-6), indicating that this variant may function as a cis-acting element regulating GATA3 transcription. Ectopic overexpression of GATA3 in ALL cell lines led to global changes in gene expression, with a particular enrichment of genes within the BCR-ABL1-like ALL expression signature.In the discovery cohort (COG AALL0232), the GATA3 SNP was also significantly associated with CRLF2 rearrangements (P=9.64×10-7), JAK mutations (P=2.06×10-5), and IKZF1 deletion (P=0.0002), which was validated in COG P9906 (P=0.08, 0.008, and 0.002, respectively) and in a third independent cohort, COG P9905 (P=0.009, 0.05, and 0.0002, respectively). The GATA3 risk allele was further enriched among patients with multiple “BCR-ABL1-like ALL-related” lesions concurrently, with the highest frequency observed in cases with three genomic lesions, followed by those with one or two lesions, and lowest among patients without any of the three lesions (COG AALL0232, P=6.09×10-5; COG P9906, P=0.0005; and COG P9905, P=7.6×10-5). Interestingly, the association of the GATA3 SNP with BCR-ABL1-likeness remained significant after adjusting for all three genomic lesions (P=0.001).We further examined the relationships between GATA3 SNP genotype and ALL relapse. In the COG P9906 cohort, the GATA3 allele linked to BCR-ABL1-like ALL was associated with a higher risk of relapse (N=222, P=0.002) and poor early treatment response as measured by minimal residual disease (N=193, P=9.8×10-5), which was validated in COG P9905 (N=777, P=0.007 and N=710, P=0.039, respectively). Of interest, the GATA3 allele associated with relapse and BCR-ABL1-like ALL was more frequent in Hispanics (40%) than in populations of European descent (12%), consistent with the inferior treatment outcome for Hispanic children with ALL.In conclusion, we have identified common GATA3 germline variants associated with BCR-ABL1-like ALL, somatic molecular lesions characteristic of this subtype, and importantly the risk of ALL relapse. These results suggest plausible interactions between host and tumor genomic variations in ALL pathogenesis and drug response. Disclosures:Evans:St. Jude: In accordance with institutional policy, St. Jude allocates a portion of the income it receives from licensing inventions and tangible research materials to those researchers responsible for creating this intellectual property. Patents & Royalties, Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics., Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Other. Relling:St. Jude: In accordance with institutional policy, St. Jude allocates a portion of the income it receives from licensing inventions and tangible research materials to those researchers responsible for creating this intellectual property. Patents & Royalties, Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics., Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Other.

Dysbiosis and Gut Microbiota Modulation in Systemic Sclerosis.

Gastrointestinal (GI) involvement is an early manifestation in systemic sclerosis (SSc), affecting more than 90% of patients, and severe GI disease is a marker of poor prognosis and mortality. Recent studies have hypothesized that alterations of the intestinal microbiota, known as dysbiosis, may represent 1 of the possible environmental factors influencing SSc disease status. In addition, specific microorganisms may be associated with SSc pathogenesis, progression, and GI manifestations. Therapeutic approaches aiming to modulate the intestinal microbiota have emerged, as alternatives to treat GI symptoms, and dietary interventions, probiotic administration, and fecal microbiota transplantation are potential therapies for SSc patients. However, given the complexity and variability of pathogenesis and clinical manifestations in SSc, these therapies need to be combined with additional interventions that target other disease components. Here, we summarize studies addressing intestinal dysbiosis in SSc and discuss the potential of microbiota modulators to treat SSc-related GI disorders.

Heterologous Inferential Analysis (HIA) and Other Emerging Concepts: In Understanding Mitochondrial Variation In Pathogenesis: There is no More Low-Hanging Fruit.

Here we summarize our latest efforts to elucidate the role of mtDNA variants affecting the mitochondrial translation machinery, namely variants mapping to the mt-rRNA and mt-tRNA genes. Evidence is accumulating to suggest that the cellular response to interference with mitochondrial translation is different from that occurring as a result ofmutations in genes encodingOXPHOS proteins. As a result, it appears safe to state that a complete view of mitochondrial disease will not be obtained until we understand the effect of mt-rRNA and mt-tRNA variants on mitochondrial protein synthesis. Despite the identification of a large number of potentially pathogenic variants in the mitochondrially encoded rRNA (mt-rRNA) genes, we lack direct methods to firmly establish their pathogenicity. In the absence of such methods, we have devised an indirect approach named heterologous inferential analysis (HIA ) that can be used to make predictions concerning the disruptive potential of a large subset of mt-rRNA variants. We have used HIA to explore the mutational landscape of 12S and 16S mt-rRNA genes. Our HIA studies include a thorough classification of all rare variants reported in the literature as well as others obtained fromstudies performed in collaboration with physicians. HIA has also been used with non-mammalian mt-rRNA genes to elucidate how mitotypes influence the interaction of the individual and the environment. Regarding mt-tRNA variations, rapidly growing evidence shows that the spectrum of mutations causing mitochondrial disease might differ between the different mitochondrial haplogroups seen in human populations.

In pursuit of the unicorn.

This short review was prompted by The Physiological Society's recent online symposium on variability. It does not deal with a specific methodology, but rather with the myth that certain environmentally-induced clinical conditions can be identified, quantified, simplified and monitored with a single methodology. Although this might be possible with some clinical conditions, others resist the prevailing reductionist approach of minimizing rather than exploring variation in pathogenesis and pathology, and will not be understood fully until the variation in cause and effect are embraced. This is likely to require comprehensive methodologies and collaboration.

Circadian variations in pathogenesis of ST-segment elevation myocardial infarction

Abstract Background Previous studies have reported a circadian variation in the onset of ST-segment elevation myocardial infarction (STEMI). However, underlying mechanisms for the circadian variation have not been fully elucidated. Purpose We investigated the relationship between onset of STEMI and the underlying pathology using optical coherence tomography (OCT). Methods Patients presenting with STEMI were selected from an international, multi-center, longitudinal registry study, which included patients who underwent OCT imaging of the culprit lesion at 11 institutions in 6 countries. Onset of MI was estimated using the time of OCT imaging. Patients were divided into 4 groups based on the estimated time of onset (00:00–05:59, 06:00–11:59, 12:00–17:59, or 18:00–23:59). Underlying pathologies of MI (plaque rupture, plaque erosion, and calcified plaque) were compared among the 4 groups. Results Among 648 patients, plaque rupture was diagnosed in 386 patients (59.6%), plaque erosion in 197 patients (30.4%), and calcified plaque in 65 patients (10.0%). A marked circadian variation was detected in the incidence of plaque rupture with a peak at 9:00, whereas it was not evident in plaque erosion or calcified plaque. The probability of plaque rupture increased in the periods of 06:00–11:59 (odds ratio: 2.13, 95% confidence interval: 1.30 to 3.49, p=0.002) and 12:00–17:59 (odds ratio: 2.10, 95% confidence interval: 1.23 to 3.58, p=0.005), compared to the period of 00:00–05:59. This circadian pattern was observed only during weekdays (p=0.013) and it was not evident during the weekend (p=0.742). Conclusions Plaque rupture occurred most frequently in the morning and the circadian variation was evident only during the weekdays. Acute MI caused by plaque rupture may be related to catecholamine surge. Funding Acknowledgement Type of funding source: None

Integration analysis of methylation quantitative trait loci and GWAS identify three schizophrenia risk variants.

Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with schizophrenia (SCZ). However, prioritizing risk variants and regulatory elements for follow-up functional studies remains a major challenge. Therefore, we performed an integrated analysis to identify variants who affect methylation levels of nearby genes and contribute to the risk of SCZ, and to explore the potential role of these variants in SCZ pathogenesis. First, we used the Summary data-based Mendelian Randomization (SMR) method to integrate GWAS and methylation quantitative trait loci data. Then, the SNP-methylation combinations as associated with SCZ were replicated across multiple samples. Totally, we identified and replicated 14 and one SNP-methylation combinations in blood and brain tissues, respectively, that significantly associated with SCZ. Furthermore, our expression quantitative trait loci analysis, differential methylation analysis, neuroimaging genetics, and cognitive genetics analysis consistently supported the potential roles of these 15 SNPs in the pathogenesis of SCZ. Finally, using the convergent functional genomics method, we prioritized three risk SNPs, including rs3765971 (RERE, PSMR = 3.87 × 10-8), rs55742290 (ARL6IP4, PSMR = 1.50 × 10-7), and rs7293091 (CENPM, PSMR = 5.09 × 10-7), may represent promising risk variants in SCZ. These convergent lines of evidence suggest that three risk variants may be involved in the pathogenesis of SCZ. Further investigation of the roles of these variants in the pathogenesis of SCZ is warranted.

A Perspective of Dietary Therapy for Type 2 Diabetes Based on Diversity in Pathogenesis and Aging

A Perspective of Dietary Therapy for Type 2 Diabetes Based on Diversity in Pathogenesis and Aging

Genotypic-Phenotypic Screening of Galectin-3 in Relation to Risk Towards Rheumatoid Arthritis

Galectin-3, a 35kDa protein, is the only known member of chimera type galectin family. A growing body of evidences demonstrated the pro-inflammatory role of galectin-3 in the pathogenesis of Rheumatoid arthritis (RA). Keeping in view the pivotal role of galectin-3 in pathogenesis of RA, the present case-control study was designed for genotypic and phenotypic screening of galectin-3 in RA. A case-control association study recruited 200 RA patients and 200 age- as well as gender- matched (p>0.05) controls, after written informed consent. A total of eight SNPs were selected on the basis of in silico analysis, which were subjected to genetic analysis using different techniques. LD was calculated and different haplotypes were constructed. Significant association of three SNPs i.e. rs1009977, rs4644, and rs74050921 along with elevated galectin-3 levels were observed with susceptibility towards RA. Further, high prevalence of TACGTAGC haplotype were observed in RA patients. In addition to the studied SNPs, eight novel variants were also identified in the CRD region of LGALS3. Genotype phenotype correlation indicated significant elevated galectin-3 levels among different genotypes in rs1009977 and rs74050921. The findings of the present study may indicate the role of galectin-3 and its variants in pathogenesis of RA.

Role of mtDNA3010 A/G genotype variation in pathogenesis of high-altitude pulmonary edema

Role of mtDNA3010 A/G genotype variation in pathogenesis of high-altitude pulmonary edema

Investigating Association of rs5918 Human Platelets Antigen 1 and rs1800790 Fibrinogen β Chain as Critical Players with Recurrent Pregnancy Loss.

Thrombophilia gene variants have been shown to be associated with higher risk of recurrent pregnancy loss (RPL). Due to the role of human platelets antigen 1 (HPA-1) and fibrinogen β chain (FGB) as critical players in the coagulation process, their most important variants including rs5918 T > C and rs1800790 G > A were selected to be studied in women affected by RPL. Three milliliters of peripheral blood were drawn from 110 women with history of at least two consecutive spontaneous abortion and 110 healthy women controls. rs5918 T > C and rs1800790 G > A of HPA-1 and FGB genes, respectively, were selected to be analyzed through polymerase chain reaction-restriction fragment length polymorphism (PCR_RFLP) following DNA isolation using QIAamp DNA Blood Mini Kit. Heterozygote genotype (TC) of HPA-1 gene rs5918 polymorphism was significantly associated with risk of RPL (p-value = 0.02). Although, rs1800790 G > A of FGB gene was not associated with RPL, its combination with rs5918 polymorphism was associated with increased risk of RPL. Owing to the critical roles of FGB and HPA-1 genes in coagulation, and thrombosis and several confinements on the meaningful association between the combination of those polymorphism with risk of RPL, including them in the thrombophilia panel may increase detection rate of hereditary thrombophilia patients. However, further studies with larger sample sizes are required to shed light on the exact role of the studied gene polymorphism, especially rs1800790 G > A of FGB gene variant in pathogenesis of RPL.

KANSL1 variation is not a major contributing factor in self-limited focal epilepsy syndromes of childhood.

BackgroundKANSL1 haploinsufficiency causes Koolen-de Vries syndrome (KdVS), characterized by dysmorphic features and intellectual disability; amiable personality, congenital malformations and seizures also commonly occur. The epilepsy phenotypic spectrum in KdVS is broad, but most individuals have focal seizures with some having a phenotype resembling the self-limited focal epilepsies of childhood (SFEC). We hypothesized that variants in KANSL1 contribute to pathogenesis of SFEC.Materials and methodsWe screened KANSL1 for single nucleotide variants in 90 patients with SFEC. We then screened a cohort of 208 patients with two specific SFEC syndromes, childhood epilepsy with centrotemporal spikes (CECTS) and atypical childhood epilepsy with centrotemporal spikes (ACECTS) for KANSL1 variants. The second cohort was also used to evaluate minor allelic variants that appeared overrepresented in the initial cohort.ResultsOne variant, p.Lys104Thr, was predicted damaging and appeared overrepresented in our 90-patient cohort compared to Genome Aggregation Database (gnomAD) allele frequency (0.217 to 0.116, with no homozygotes in gnomAD). However, there was no difference in p.Lys104Thr allele frequency in the follow-up CECTS/ACECTS cohort and controls. Four rare KANSL1 variants of uncertain significance were identified in the CECTS/ACECTS cohort.DiscussionOur data do not support a major role for KANSL1 variants in pathogenesis of SFEC.