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Introduction: Oral cancer (OC) is a multifactorial disease caused due to various genomic changes. Alternative splicing (AS) is a regulatory genetic process through which messenger RNA forms diverse protein variants. This study aims to study the variation in the AS events at tongue and gingiva locations of OC. Materials and Methods: Forty-five paired end OC RNA-seq data were downloaded from Sequence Read Archive (SRA) data repository. Twenty four paired end OC (tongue 13, gingival 11) RNA sequences passed the stringent inclusion/ exclusion criteria which were analyzed following Tuxedo pipeline. The ClueGO (v2.5.8) tool in Cytoscape app manager (v3.7.1) was used for gene set enrichment analysis keeping false discovery rate (FDR

Aim: Laparoscopic CBD exploration (LCBDE) for Common bile duct (CBD) stones with laparoscopic cholecystectomy (LC) is an alternative to open CBD exploration, in patients with failed endoscopic retrograde cholangio-pancreatography (ERCP). It is being performed at few centres with adequate surgical expertise. Herein, we present our experience of LCBDE with LC over a period of 10 years. Patients and Methods: A retrospective analysis of prospectively recorded data of 121 consecutive patients was performed from February 2010 to November 2019, who underwent LC and LCBDE by choledochotomy in a single surgical unit. These included all patients with failed pre-operative ERCP. Results: Out of 121 patients, LCBDE successfully cleared the CBD in 118, and three patients were converted to open surgery. All these patients underwent choledochotomy for adequate exploration of CBD. T-tube closure of CBD was performed in 103 patients and removed after a mean of 14.6 ± 2.4 days. Primary closure was performed in 15 patients. The mean hospital stay post-procedure was 3.4 ± 0.7 days. Complete ductal clearance was achieved in 115 patients, and residual stone fragments reported in three patients were removed by ERCP. None of the patients experienced biliary peritonitis, biliary fistula, pancreatitis or cholangitis. There was no 30-day mortality and no recurrent stones reported with a mean follow-up of 12.4 ± 3.9 months. Conclusion: With adequate surgical expertise, LCBDE is a feasible alternative to open surgery for CBD stones after failed ERCP with early recovery and low morbidity.

Naive CD4+ T cells differentiate into effector (Th1, Th2, Th17) cells and immunosuppressive (Treg) cells upon antigenic stimulation in the presence of a specific cytokine milieu. The T cell in vitro culture system provides a very efficient model to study compounds’ therapeutic activity and mechanism of action. Tinospora cordifolia (Willd.) Hook.f. & Thomson (Family. Menispermaceae) is one of the widely used drugs in Ayurveda (ancient Indian system of medicine) for various ailments such as inflammatory conditions, autoimmune disorders, and cancer as well as for promoting general health. In vitro and in vivo studies on immune cells comprising dendritic cells, macrophages, and B cells suggest its immune-modulating abilities. However, to date, the effect of T. cordifolia on individual purified and polarized T cell subsets has not been studied. Studying drug effects on T cell subsets is needed to understand their immunomodulatory mechanism and to develop treatments for diseases linked with T cell abnormalities. In this study, we examined the immunomodulatory activity of T. cordifolia on primary CD4+ T cells, i.e., Th1, Th17, and iTreg cells. An aqueous extract of T. cordifolia was non-cytotoxic at concentrations below 1500 µg/ml and moderately inhibited the proliferation of naive CD4+ T cells stimulated with anti-CD3ε and anti-CD28 for 96 h. T. cordifolia treatment of naive CD4+ T cells differentiated under Th17-polarizing conditions exhibited reduced frequency of IL-17 producing cells with inhibition of differentiation and proliferation. For the first time, in-depth genome-wide expression profiling of T. cordifolia treated naive CD4+ T cells, polarized to Th17 cells, suggests the broad-spectrum activity of T. cordifolia. It shows inhibition of the cytokine-receptor signaling pathway, majorly via the JAK-STAT signaling pathway, subsequently causing inhibition of Th17 cell differentiation, proliferation, and effector function. Additionally, the molecular docking studies of the 69 metabolites of T. cordifolia further substantiate the inhibitory activity of T. cordifolia via the cytokine-receptor signaling pathway. Furthermore, in vitro polarized Th1 and iTreg cells treated with T. cordifolia extract also showed reduced IFN-γ production and FoxP3 expression, respectively. This study provides insight into the plausible mechanism/s of anti-inflammatory activity of T. cordifolia involving T cells, mainly effective in Th17-associated autoimmune and inflammatory diseases.

Abstract Background Alternative splicing (AS) is a regulatory mechanism used to create many forms of mature messengers RNAs (mRNAs) from the same gene. Sequencing of RNA (RNA-Seq) is an advanced technology, which has been utilized by different studies to find AS mechanisms in head and neck cancer (HNC). Hitherto, there is no available review that could inform us of the major findings from these studies. Hence, we aim to perform a systematic literature search following PRISMA guidelines to study AS events in HNC identified through RNA-Seq studies. Results A total of five records were identified that utilized RNA-Seq data for identifying AS events in HNC. Five software was used in these records to identify AS events. Two genes influenced by AS i.e. MLL3 and RPS9 were found to be common in 4 out of 5 records. Likewise, 38 genes were identified to be similar in at least 3 records. Conclusions Alternative splicing in HNC is a multifaceted regulatory mechanism of gene expression. It can be studied via RNA-Seq using different bioinformatics tools. Genes MLL3, as well as RPS9, were repeatedly found to be associated with HNC, however needs further functional validation.

PURPOSE: Cervical cancer (CC) is the most common cancer affecting women worldwide. Human papillomavirus (HPV) infection is a major contributing factor for the development of CC. The development of CC occurs progressively from precancer stages to cancerous stages (ie, invasive squamous cell carcinoma [ISCC] and adenocarcinoma [ADC]). ADC is a rare form of CC that develops from the mucinous endocervical epithelium. It is believed that the downstream targets of Notch signaling contribute to the etiology of CC. One such target is HES1, whose role in the modulation of ADC is unknown. The purpose of this study is to determine the role of HES1 protein in HPV-associated ADC subtype of CC and also to compare its expression in histologic subtypes of precancer and ISCC. PATIENTS AND METHODS: A total of 148 patients (30 with precancers, 98 with ISCC, and 20 with ADC) and 40 normal control participants were analyzed for the expression of HES1 via immunohistochemistry, with results validated by immunoblotting. RESULTS: The comparison between HPV-16 and HES1 expression was significant in precancer (cervical intraepithelial neoplasia grades 1 to 3; P = .013), ISCC (International Federation of Gynecology and Obstetrics stages I to IV; P = .001), and ADC (P = .007). An overall significant mean difference was observed between HES1, JAG1, and Notch-3 proteins in precancer (P = .001), ISCC (P = .001), and ADC (P = .001). Pairwise comparisons between HES1 and JAG1 and HES1 and Notch-3 were also found to be significant. CONCLUSION: This study showed that among all HPV-16–positive precancers, the major HES1 positivity signal arises from cervical intraepithelial neoplasia grades 2 and 3 that develops into ISCC. Moreover, HPV-16–positive ADC also showed an association with HES1. The HES1, JAG1, and Notch-3 proteins showed their synergistic role in modulating HPV associated ADC along with histologic subtypes of precancer and ISCC of CC.

Introduction Dohra is a locally produced areca nut preparations used with or without tobacco in Allahabad, Jaunpur and Pratapgarh districts of Uttar Pradesh (UP), India. Different varieties of Dohra exist such as Sukha Dohra, Geela Dohra, etc. Evidence suggests that it causes Oral Potentially Malignant Disorders and Oral Cancer. It contains arecoline which is a well-known carcinogen. In order to understand the potential role of Dohra in causing cancer biochemical profiling of different varieties of Dohra is needed. Aim To describe the biochemical profile of different varieties of Dohra. Methods Different varieties of Dohra were collected from Allahabad, Jaunpur and Pratapgarh districts of UP. All the varieties of Dohra were analyzed for biochemical profiling through Continuous Flow Autoanalyzer (CFA) using Flow View Solution 3700 Analyzer (version 1.2.2) software. Results The biochemical changes at arecoline levels were observed in different varieties of Dohra. The detailed chemical profiling will be furnished in the meeting. Conclusions Different varieties of Dohra preparations are produced and each of them have a different biochemical profile. The Dohra is rich is arecoline and hence its use should be banned/avoided.

Introduction Kiwam (Qiwam) is a partially fermented tobacco product consumed with Betal Quid (Paan). The major constituents of this product are tobacco, saffron (Zaffrani) and some additives. It contains Tobacco-Specific Nitrosamines (TSNA) which is considered as a cancer-causing agent. To elucidate the carcinogenic property of Kiwam, biochemical profiling of its constituents at different stages of processing is needed. The major processing steps involved in the formation of Kiwam and biochemical profiling/changes at each processing step is still unknown. Aim To describe the major processing steps and biochemical changes that occurs at each processing step during the preparation of Kiwam. Method Tobacco leaves and stems were boiled in water followed by filtering of the constituents to remove the leaves and stem residues. The filtrate is again boiled to form a thick paste residue. The resultant paste was partially fermented through sun curing, and lastly saffron along with some additives were added. The samples from each step were analyzed for biochemical profiling through Continuous Flow Autoanalyzer (CFA) using Flow View Solution 3700 Analyzer (version 1.2.2) software. Results The biochemical changes at TSNA levels were observed at each processing steps. The detailed chemical profiling will be presented during the meeting. Conclusions Processing of Kiwam involves four major steps i.e. (i) boiling of tobacco leaves and stem (ii) filtration of product (iii) re-boiling of the filtrate till the paste is formed (iv) partial fermentation through sun curing. Kiwam is rich in TSNA and hence its use should be avoided.

Purpose: The purpose of this study is to evaluate the clinical and radiologic outcomes after revision total hip arthroplasty (THA) using fourth-generation ceramic-on-ceramic (CoC) bearing surfaces. Methods: A total of 52 revision THAs (28 men and 19 women) using the fourth-generation CoC bearing surfaces were retrospectively evaluated. Both acetabular cup and femoral stem were revised in all cases. The mean follow-up period was 7.3 years (range, 4.0–9.9 years). The clinical results with Harris hip score (HHS), Western Ontario McMaster Osteoarthritis Index (WOMAC), and radiologic outcomes were evaluated. Results: At the final follow-up examination, the average HHS was 90.4 (range, 67–100). The average WOMAC pain and physical function score were 2.8 (range, 0–12) and 16.4 (range, 0–42), respectively. Complications were observed in 10 hips (19.2%). However, there were no bearing surface-related complications, and no cases of dislocation and squeaking. Retroacetabular pelvic osteolysis without cup loosening was observed in one hip at the final follow-up. However, no hip showed radiographic signs of cup loosening, vertical or horizontal acetabular cup migrations, and changes of inclinations during the follow-up period. Conclusion: Our data showed that clinical and radiologic outcomes after revision THA using fourth-generation CoC bearing were favorable. Hence, revision THA with the use of CoC bearing surfaces can be preferentially considered. Further studies with long-term follow-up data are warranted.

Oral cancer etiology is complex and controlled by multi-factorial events including genetic events. Candidate gene studies, genome-wide association studies, and next-generation sequencing identified various chromosomal loci to be associated with oral cancer. There is no available review that could give us the comprehensive picture of genetic loci identified to be associated with oral cancer by candidate gene studies–based, genome-wide association studies–based, and next-generation sequencing–based approaches. A systematic literature search was performed in the PubMed database to identify the loci associated with oral cancer by exclusive candidate gene studies–based, genome-wide association studies–based, and next-generation sequencing–based study approaches. The information of loci associated with oral cancer is made online through the resource “ORNATE.” Next, screening of the loci validated by candidate gene studies and next-generation sequencing approach or by two independent studies within candidate gene studies or next-generation sequencing approaches were performed. A total of 264 loci were identified to be associated with oral cancer by candidate gene studies, genome-wide association studies, and next-generation sequencing approaches. In total, 28 loci, that is, 14q32.33 (AKT1) , 5q22.2 (APC) , 11q22.3 (ATM) , 2q33.1 (CASP8) , 11q13.3 (CCND1) , 16q22.1 (CDH1) , 9p21.3 (CDKN2A) , 1q31.1 (COX-2) , 7p11.2 (EGFR) , 22q13.2 (EP300) , 4q35.2 (FAT1) , 4q31.3 (FBXW7) , 4p16.3 (FGFR3) , 1p13.3 (GSTM1-GSTT1) , 11q13.2 (GSTP1) , 11p15.5 (H-RAS) , 3p25.3 (hOGG1) , 1q32.1 (IL-10) , 4q13.3 (IL-8) , 12p12.1 (KRAS) , 12q15 (MDM2) , 12q13.12 (MLL2) , 9q34.3 (NOTCH1) , 17p13.1 (p53) , 3q26.32 (PIK3CA) , 10q23.31 (PTEN) , 13q14.2 (RB1) , and 5q14.2 (XRCC4) , were validated to be associated with oral cancer. “ORNATE” gives a snapshot of genetic loci associated with oral cancer. All 28 loci were validated to be linked to oral cancer for which further fine-mapping followed by gene-by-gene and gene–environment interaction studies is needed to confirm their involvement in modifying oral cancer.

The population of India harbors one of the world's most highly diverse gene pools, owing to the influx of successive waves of immigrants over regular periods in time. Several phylogenetic studies involving mitochondrial DNA and Y chromosomal variation have demonstrated Europeans to have been the first settlers in India. Nevertheless, certain controversy exists, due to the support given to the thesis that colonization was by the Austro-Asiatic group, prior to the Europeans. Thus, the aim was to investigate pre-historic colonization of India by anatomically modern humans, using conserved stretches of five amino acid (EPIYA) sequences in the cagA gene of Helicobacter pylori. Simultaneously, the existence of a pathogenic relationship of tyrosine phosphorylation motifs (TPMs), in 32 H. pylori strains isolated from subjects with several forms of gastric diseases, was also explored. High resolution sequence analysis of the above described genes was performed. The nucleotide sequences obtained were translated into amino acids using MEGA (version 4.0) software for EPIYA. An MJ-Network was constructed for obtaining TPM haplotypes by using NETWORK (version 4.5) software. The findings of the study suggest that Indian H. pylori strains share a common ancestry with Europeans. No specific association of haplotypes with the outcome of disease was revealed through additional network analysis of TPMs.

BACKGROUND and AIM: Helicobacter pylori has been proven to be responsible for causing various gastrointestinal disorders including gastric adenocarcinoma. Several genes of pathogen (the genes of the cag-PAI, vacA, iceA, and babA) either in combination or independently have been reported to significantly increase the risk of ulceration/gastric carcinoma, with the cagA gene having the strongest predictive value. Pursuit to identify new genes which could serve as a marker of overt disease progression, lead to the discovery of hrgA gene. METHODS: Fifty-six indigenous strains of H. pylori from subjects with various gastric disorder were screened to assess the status of hrgA gene along with the cagA gene using simple polymerase chain reaction using specific oligonucleotide primers. Post-amplification, amplicons were subjected for sequencing to identify any strain specific variations in sequences from the H. pylori isolated from different disease manifestations. Histopathological analysis was done to ascertain any significant change in the histological scores of subjects infected with cagA+/hrgA+ and cagA-/hrg+ strains. RESULTS: All the 56 (100%) subjects amplified with the oligonucleotide primers specific to hrgA gene, whereas 81.71% subjects showed the presence of cagA gene. Sequencing of the amplimers showed 99% homology. Histology of the cagA+/hrgA+ and cagA-/hrg+ subjects did not show any significant difference. CONCLUSION: hrgA gene of Helicobacter pylori is not a ideal surrogate marker for identifying individuals with higher risk of developing overt gastro-duodenal diseases such as neoplasia of the stomach.RACIONAL e OBJETIVOS: O Helicobacter pylori tem sido incriminado como causador de vários distúrbios digestivos, incluindo o adenocarcinoma gástrico. Diversos genes patogênicos (os genes do cag-PAI, vacA, iceA e babA), em combinação ou independentes, têm sido reportados como fatores de aumento de risco para ulceração/carcinoma gástrico, tendo o gene cagA forte valor preditivo. A procura da identificação de novos genes que possam vir a ser marcadores da progressão da doença levaram à descoberta do gene hrgA. MÉTODOS: Cinqüenta e seis amostras de H. pylori provenientes de pacientes com diversas afecções gástricas foram examinadas para caracterizar a presença do hrgA juntamente ao cagA, usando iniciadores específicos da reação de cadeia da polimerase. Após amplificação, os produtos amplificados pela PCR foram seqüenciados para a identificação de variações específicas nas seqüências do H. pylori isolado de diferentes doenças gastroduodenais. A análise histopatológica foi feita para assegurar qualquer mudança significativa nos escores dos indivíduos infectados com cagA+hrgA+ e cagA-/hrgA+. RESULTADOS: Todas as 56 amostras (100%) foram amplificadas com iniciadores específicos para o hrgA, enquanto que 81,71% mostraram a presença do cagA. O seqüenciamento do produto amplificado pela PCR mostrou 99% de homologia. A histologia entre os grupos cagA+/hrgA+ e cagA-/hrgA+ não mostrou nenhuma diferença significante. CONCLUSÃO: O gene hrgA do H. pylori não é o marcador ideal para identificar indivíduos com alto risco de desenvolvimento de doenças gastrointestinais como a neoplasia de estômago.

BackgroundThe phylogeny of the indigenous Indian-specific mitochondrial DNA (mtDNA) haplogroups have been determined and refined in previous reports. Similar to mtDNA superhaplogroups M and N, a profusion of reports are also available for superhaplogroup R. However, there is a dearth of information on South Asian subhaplogroups in particular, including R8. Therefore, we ought to access the genealogy and pre-historic expansion of haplogroup R8 which is considered one of the autochthonous lineages of South Asia.Methodology/principal findingsUpon screening the mtDNA of 5,836 individuals belonging to 104 distinct ethnic populations of the Indian subcontinent, we found 54 individuals with the HVS-I motif that defines the R8 haplogroup. Complete mtDNA sequencing of these 54 individuals revealed two deep-rooted subclades: R8a and R8b. Furthermore, these subclades split into several fine subclades. An isofrequency contour map detected the highest frequency of R8 in the state of Orissa. Spearman's rank correlation analysis suggests significant correlation of R8 occurrence with geography.Conclusions/significanceThe coalescent age of newly-characterized subclades of R8, R8a (15.4+/-7.2 Kya) and R8b (25.7+/-10.2 Kya) indicates that the initial maternal colonization of this haplogroup occurred during the middle and upper Paleolithic period, roughly around 40 to 45 Kya. These results signify that the southern part of Orissa currently inhabited by Munda speakers is likely the origin of these autochthonous maternal deep-rooted haplogroups. Our high-resolution study on the genesis of R8 haplogroup provides ample evidence of its deep-rooted ancestry among the Orissa (Austro-Asiatic) tribes.

Aim: Laparoscopic CBD exploration (LCBDE) for Common bile duct (CBD) stones with laparoscopic cholecystectomy (LC) is an alternative to open CBD exploration, in patients with failed endoscopic retrograde cholangio-pancreatography (ERCP). It is being performed at few centres with adequate surgical expertise. Herein, we present our experience of LCBDE with LC over a period of 10 years. Patients and Methods: A retrospective analysis of prospectively recorded data of 121 consecutive patients was performed from February 2010 to November 2019, who underwent LC and LCBDE by choledochotomy in a single surgical unit. These included all patients with failed pre-operative ERCP. Results: Out of 121 patients, LCBDE successfully cleared the CBD in 118, and three patients were converted to open surgery. All these patients underwent choledochotomy for adequate exploration of CBD. T-tube closure of CBD was performed in 103 patients and removed after a mean of 14.6 ± 2.4 days. Primary closure was performed in 15 patients. The mean hospital stay post-procedure was 3.4 ± 0.7 days. Complete ductal clearance was achieved in 115 patients, and residual stone fragments reported in three patients were removed by ERCP. None of the patients experienced biliary peritonitis, biliary fistula, pancreatitis or cholangitis. There was no 30-day mortality and no recurrent stones reported with a mean follow-up of 12.4 ± 3.9 months. Conclusion: With adequate surgical expertise, LCBDE is a feasible alternative to open surgery for CBD stones after failed ERCP with early recovery and low morbidity. [ABSTRACT FROM AUTHOR]

Intrusion detection systems (("IDSs ") are generating volumes of alert messages around the clock leaving alert response teams with a daunting task: determining which alerts are worth investigation and which alerts are not. IDS analysts must quickly identify false positives in order to maximize the response time dedicated to concrete threats. We explore the using open dataset bootstrapping for IDS alerts. Our method requires using generically trained machine learning ("ML") models derived from modern trafficjlow data as aguide in initial IDS configuration and deployment followed by suggested periodic private retraining of these models. Our technique also suggests adoption of a baseline metric for analysts: helping rank trafficflow data by likeliness of a threat. We surveyed several datasets including the CSE-CIC-IDS2018 dataset: used, for collecting baseline threat detection accuracy measurements. Some models tested including decision trees and randomforests, yielded less than 2% Type 1 and Type 2 combined error. We have also published selected online samples from our tests as illustrative supplements. Our method strives is simple to implement and uses publicly available IDS and ML tools including various Python frameworks. We intend to give analysts hoping to augment their security workflows with ML, a proven and accessible workflow, and establish a standard for comparison. [ABSTRACT FROM AUTHOR]

In this technology-based era, network-based systems are facing new cyber-attacks on daily bases. Traditional cybersecurity approaches are based on old threat-knowledge databases and need to be updated on a daily basis to stand against new generation of cyber-threats and protect underlying network-based systems. Along with updating threat-knowledge databases, there is a need for proper management and processing of data generated by sensitive real-time applications. In recent years, various computing platforms based on representation learning algorithms have emerged as a useful resource to manage and exploit the generated data to extract meaningful information. If these platforms are properly utilized, then strong cybersecurity systems can be developed to protect the underlying network-based systems and support sensitive real-time applications. In this survey, we highlight various cyber-threats, real-life examples, and initiatives taken by various international organizations. We discuss various computing platforms based on representation learning algorithms to process and analyze the generated data. We highlight various popular datasets introduced by well-known global organizations that can be used to train the representation learning algorithms to predict and detect threats. We also provide an in-depth analysis of research efforts based on representation learning algorithms made in recent years to protect the underlying network-based systems against current cyberthreats. Finally, we highlight various limitations and challenges in these efforts and available datasets that need to be considered when using them to build cybersecurity system [ABSTRACT FROM AUTHOR]

Alternative splicing (AS) is an important mechanism that is responsible for the production of protein diversity. An increasing body of evidence has suggested that out-of-control AS is closely related to the genesis and development of cancer. Systematic analysis of genome-wide AS in head and neck squamous cell carcinoma (HNSCC) has not yet been carried out, and consideration of this topic remains at the preliminary stage and requires further investigation. In this study, systemic bioinformatic analysis was carried out on the genome-wide AS events of 555 clinical HNSCC samples from the TCGA database. Firstly, we statistically analyzed the distributions of seven AS event types in HNSCC samples. Then, through univariate survival analysis, we observed the relationship between AS and the prognosis of the disease and found that 437 intersections of AS events were significantly related to overall survival. Among them, 335 cross-genes showed a high degree of consistency in the genes associated with overall survival and recurrence. The overall survival was significantly related to AS events. Besides, the frequency of overall survival-related ES events was evidently reduced, while the AP and the AT events were increased. In addition, AT events accounted for the largest proportion. Further, multiple regression model analysis proved that AS could become a new classification method for HNSCC, and KEGG enrichment analysis proved that most genes and proteins interacting with AS events had different biological functions and were associated with a variety of diseases. Finally, through the selection of characteristic HNSCC genes and the construction of a prognostic model, seven cross-genes related to survival and recurrence were screened out, and these characteristic genes were verified by multivariate survival model analysis so as to classify the prognosis at different splicing times and gene expression levels. These results have laid a solid foundation for our further research and play a decisive role in showing the correlation of AS with the prognosis of HNSCC. [ABSTRACT FROM AUTHOR]

The rugged topography of the Himalayan region has hindered large-scale human migrations, population admixture and assimilation. Such complexity in geographical structure might have facilitated the existence of several small isolated communities in this region. We have genotyped about 850,000 autosomal markers among 35 individuals belonging to the four major populations inhabiting the Himalaya and adjoining regions. In addition, we have genotyped 794 individuals belonging to 16 ethnic groups from the same region, for uniparental (mitochondrial and Y chromosomal DNA) markers. Our results in the light of various statistical analyses suggest a closer link of the Himalayan and adjoining populations to East Asia than their immediate geographical neighbours in South Asia. Allele frequency-based analyses likely support the existence of a specific ancestry component in the Himalayan and adjoining populations. The admixture time estimate suggests a recent westward migration of populations living to the East of the Himalaya. Furthermore, the uniparental marker analysis among the Himalayan and adjoining populations reveal the presence of East, Southeast and South Asian genetic signatures. Interestingly, we observed an antagonistic association of Y chromosomal haplogroups O3 and D clines with the longitudinal distance. Thus, we summarise that studying the Himalayan and adjoining populations is essential for a comprehensive reconstruction of the human evolutionary and ethnolinguistic history of eastern Eurasia. [ABSTRACT FROM AUTHOR]

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Background Genomewide association and epigenetic studies found a region within the RAD50 gene on chromosome 5q31 to be associated with total serum IgE levels and asthma. In mice, this region harbors a locus control region for nearby TH2 cytokines, which is characterized by four Rad50 DNase I hypersensitive sites ( RHS4-7). Among these, RHS7 seems to have the strongest impact on TH2 differentiation. We investigated whether within the human homolog of RHS7, functional polymorphisms exist, which could affect DNA methylation or gene expression in the 5q31 locus and might have an influence on asthma status or IgE regulation. Methods The human RHS7 region was fine mapped using 1000 genomes database information. In silico analysis and electrophoretic mobility shift assays were used to assess SNP function. Allele-specific effects on DNA methylation were evaluated in cord blood ( n = 73) and at age of 4.5 years ( n = 61) by pyrosequencing. Allele-specific effects on RAD50, IL4, and IL13 expression were analyzed in 100 subjects. Associations with asthma and IgE levels were investigated in the MAGICS/ ISAAC II population ( n = 1145). Results Polymorphism rs2240032 in the RHS7 region is suggestive of allele-specific transcription factor binding, affects methylation of the IL13 promoter region and influences RAD50 and IL4 expression (lowest P = 0.0027). It is also associated with total serum IgE levels ( P = 0.0227). Conclusion A functional relevant polymorphism in the TH2 locus control region, equivalent to RHS7 in mice, affects DNA methylation and gene expression within 5q31 and influences total serum IgE on the population level. [ABSTRACT FROM AUTHOR]

Background Genome-wide association studies ( GWAS) repeatedly identified 1q23 ( FCER1A), 5q31 ( RAD50- IL13 and IL4), and 12q13 ( STAT6) as major susceptibility loci influencing the regulation of total serum IgE levels. As GWAS may be insufficient to capture causal variants, we performed fine-mapping and re-genotyping of the three loci using 1000 Genomes Project datasets. Methods Linkage disequilibrium tagging polymorphisms and polymorphisms of putative functional relevance were genotyped by chip technology (24 polymorphisms) or MALDI- TOF- MS (40 polymorphisms) in at least 1303 German children (651 asthmatics). The effect of polymorphisms on total serum IgE, IgE percentiles, and atopic diseases was assessed, and a risk score model was applied for gene-by-gene interaction analyses. Functional effects of putative causal variants from these three loci were studied in silico. Results Associations from GWAS were confirmed and extended. For 1q23 and 5q31, the majority of associations were found with mild to moderately elevated IgE levels, while in the 12q13 locus, single-nucleotide polymorphisms ( SNPs) were associated with strongly elevated IgE levels. Gene-by-gene interaction analyses suggested that the presence of mutations in all three loci increases the risk for elevated IgE up to fourfold. Conclusion This fine-mapping study confirmed previous associations and identified novel associations of SNPs in 1q23, 5q31, and 12q13 with different levels of serum IgE and their concomitant contribution to IgE regulation. [ABSTRACT FROM AUTHOR]

Background Both FCER2 and FCER1A encode subunits of IgE receptors. Variants in FCER1A were previously identified as major determinants of IgE levels in genome-wide association studies. Methods Here we investigated in detail whether FCER2 polymorphisms affect IgE levels alone and/or by interaction with FCER1A polymorphisms. To cover the genetic information of FCER2, 21 single-nucleotide polymorphisms ( SNPs) were genotyped by Illumina HumanHap300 BeadChip (5 SNPs) and the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry ( MALDI- TOF MS; 14 SNPs) in at least 1303 Caucasian children (651 asthmatics) ( ISAAC II/ MAGICS population); genotypes of two SNPs were imputed. Results SNP rs3760687 showed the most consistent effect on total serum IgE levels (b [ SE] = −0.38 [0.16]; P = 0.016), while FCER2 polymorphisms in general were predominantly associated with mildly-to-moderately increased IgE levels (50th and 66th percentiles). Gene-by-gene interaction analysis suggests that FCER2 polymorphism rs3760687 influences IgE levels mainly in individuals not homozygous for the risk allele of FCER1A polymorphism rs2427837, which belongs to the major IgE-determining tagging bin in the population. Conclusion FCER2 polymorphism rs3760687 affects moderately elevated total serum IgE levels, especially in the absence of homozygosity for the risk allele of FCER1A SNP rs2427837. [ABSTRACT FROM AUTHOR]

Background Recently, three genome-wide association studies ( GWAS) demonstrated FCER1 A, the gene encoding a ligand-binding subunit of the high-affinity Ig E receptor, to be a major susceptibility locus for serum Ig E levels. The top association signal differed between the two studies from the general population and the one based on an asthma case-control design. In this study, we investigated whether different FCER1 A polymorphisms are associated with total serum Ig E in the general population and asthmatics specifically. Methods Nineteen polymorphisms were studied in FCER1 A based on a detailed literature search and a tagging approach. Polymorphisms were genotyped by the Illumina Human Hap300 Chip (6 polymorphisms) or MALDI- TOF MS (13 polymorphisms) in at least 1303 children (651 asthmatics) derived from the German International Study of Asthma and Allergies in Childhood II and Multicentre Asthma Genetics in Childhood Study. Results Similar to two population-based GWAS, the peak association with total serum Ig E was observed for SNPs rs2511211, rs2427837, and rs2251746 (mean r 2 > 0.8), with the lowest p-value of 4.37 × 10−6. The same 3 polymorphisms showed the strongest association in non-asthmatics (lowest p = 0.0003). While these polymorphisms were also associated with total serum Ig E in asthmatics (lowest p = 0.003), additional polymorphisms (rs3845625, rs7522607, and rs2427829) demonstrated associations with total serum Ig E in asthmatics only (lowest p = 0.01). Conclusions These data suggest that FCER1 A polymorphisms not only drive Ig E levels in the general population but that specific polymorphisms may also influence Ig E in association with asthma, suggesting that disease-specific mechanisms in Ig E regulation exist. [ABSTRACT FROM AUTHOR]

Immunoglobulin E (IgE) mediated immune responses seem to be directed against parasites and neoplasms, but are best known for their involvement in allergies. The IgE network is tightly controlled at different levels as outlined in this review. Genetic determinants were suspected to influence IgE regulation and IgE levels considerably for many years. Linkage and candidate gene studies suggested a number of loci and genes to correlate with total serum IgE levels, and recently genome-wide association studies (GWAS) provided the power to identify genetic determinants for total serum IgE levels: 1q23 (FCER1A), 5q31 (RAD50, IL13, IL4), 12q13 (STAT6), 6p21.3 (HLA-DRB1) and 16p12 (IL4R, IL21R). In this review, we analyse the potential role of these GWAS hits in the IgE network and suggest mechanisms of how genes and genetic variants in these loci may influence IgE regulation. [ABSTRACT FROM AUTHOR]

Persistent infection with Helicobacter pylori confers an increased risk of peptic ulceration and gastric adenocarcinoma. Reactive oxygen and nitrogen species play a crucial role in the progression from normal gastric mucosa to cancer. The aim of the present study was to investigate the plasma malondialdehyde and nitric oxide levels in H. pylori related gastroduodenal diseases and associate their levels with gastric pathology and genotypes of H. pylori. Malondialdehyde and nitric oxide levels in plasma samples of 250 subjects were spectrophotometrically determined. Subsequently, genotypic and histopathological assessment was performed in gastric biopsies obtained during endoscopy. The levels of MDA and NO exceeded in subjects infected with genotype-1 of Hp than thosewith other genotypes suggesting more precise interaction of highly virulent strains of Hp in eliciting severe tissue damage. In conclusion, the study demonstrates close relationship between the plasma malondialdehyde and nitric oxide levels, gastric histopathology and genotypes of H. pylori. [ABSTRACT FROM AUTHOR]

The dopamine transporter (DAT1) is a membrane spanning protein that binds the neurotransmitter dopamine and performs re-uptake of dopamine from the synapse into a neuron. The gene encoding DAT1 consists of 15 exons spanning 60 kb on chromosome 5p15.32. Several studies have investigated the possible associations between variants in DAT1 gene and psychiatric disorders. The present study aimed to determine the distribution of the variable number of tandem repeat (VNTR) polymorphism in the 3′ untranslated region of DAT1 in 12 Indian populations. A total of 471 healthy unrelated individuals in 12 Indian populations from 3 linguistic groups were included in the present study. The analysis was carried out using PCR and electrophoresis. Overall, 4 alleles of the DAT1 40-bp VNTR, ranging from 7 to 11 repeats were detected. Heterozygosity indices were low and varied from 0.114 to 0.406. The results demonstrate the variability of the DAT1 40-bp VNTR polymorphism in Indian populations and revealed a high similarity with East Asian populations. [ABSTRACT FROM AUTHOR]

Oral cancer etiology is complex and controlled by multi-factorial events including genetic events. Candidate gene studies, genome-wide association studies, and next-generation sequencing identified various chromosomal loci to be associated with oral cancer. There is no available review that could give us the comprehensive picture of genetic loci identified to be associated with oral cancer by candidate gene studies–based, genome-wide association studies–based, and next-generation sequencing–based approaches. A systematic literature search was performed in the PubMed database to identify the loci associated with oral cancer by exclusive candidate gene studies–based, genome-wide association studies–based, and next-generation sequencing–based study approaches. The information of loci associated with oral cancer is made online through the resource “ORNATE.” Next, screening of the loci validated by candidate gene studies and next-generation sequencing approach or by two independent studies within candidate gene studies or next-generation sequencing approaches were performed. A total of 264 loci were identified to be associated with oral cancer by candidate gene studies, genome-wide association studies, and next-generation sequencing approaches. In total, 28 loci, that is, 14q32.33 (AKT1), 5q22.2 (APC), 11q22.3 (ATM), 2q33.1 (CASP8), 11q13.3 (CCND1), 16q22.1 (CDH1), 9p21.3 (CDKN2A), 1q31.1 (COX-2), 7p11.2 (EGFR), 22q13.2 (EP300), 4q35.2 (FAT1), 4q31.3 (FBXW7), 4p16.3 (FGFR3), 1p13.3 (GSTM1-GSTT1), 11q13.2 (GSTP1), 11p15.5 (H-RAS), 3p25.3 (hOGG1), 1q32.1 (IL-10), 4q13.3 (IL-8), 12p12.1 (KRAS), 12q15 (MDM2), 12q13.12 (MLL2), 9q34.3 (NOTCH1), 17p13.1 (p53), 3q26.32 (PIK3CA), 10q23.31 (PTEN), 13q14.2 (RB1), and 5q14.2 (XRCC4), were validated to be associated with oral cancer. “ORNATE” gives a snapshot of genetic loci associated with oral cancer. All 28 loci were validated to be linked to oral cancer for which further fine-mapping followed by gene-by-gene and gene–environment interaction studies is needed to confirm their involvement in modifying oral cancer. [ABSTRACT FROM AUTHOR]