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Checkpoint kinases Chk1, Chk2, Wee1 are playing a key role in DNA damage response and genomic integrity. Cancer-associated mutations identified in human Chk1, Chk2, and Wee1 were retrieved to understand the function associated with the mutation and also alterations in the folding pattern. Therefore, an attempt has been made to identify deleterious effect of variants using in silico and structure-based approach. Variants of uncertain significance for Chk1, Chk2, and Wee1 were retrieved from different databases and four prediction servers were employed to predict pathogenicity of mutations. Further, Interpro, I-Mutant 3.0, Consurf, TM-align, and have (y)our protein explained were used for comprehensive study of the deleterious effects of variants. The sequences of Chk1, Chk2, and Wee1 were analyzed using Clustal Omega, and the three-dimensional structures of the proteins were aligned using TM-align. The molecular dynamics simulations were performed to explore the differences in folding pattern between Chk1, Chk2, Wee1 wild-type, and mutant protein and also to evaluate the structural integrity. Thirty-six variants in Chk1, 250 Variants in Chk2, and 29 in Wee1 were categorized as pathogenic using in silico prediction tools. Furthermore, 25 mutations in Chk1, 189 in Chk2, and 14 in Wee1 were highly conserved, possessing deleterious effect and also influencing the protein structure and function. These identified mutations may provide underlying genetic intricacies to serve as potential targets for therapeutic inventions and clinical management.
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Neoplasias , Proteínas Quinases , Humanos , Proteínas Quinases/metabolismo , Quinase 1 do Ponto de Checagem/genética , Mutação , Quinase do Ponto de Checagem 2/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismoRESUMO
BACKGROUND: Mizoram, a northeastern state in India, shares international borders with Myanmar and Bangladesh and is considered to be one of the key routes through which drug-resistant parasites of Southeast Asia enter mainland India. Despite its strategic location and importance, malaria epidemiology and molecular status of chloroquine resistance had not been well documented, and since chloroquine (CQ), as the first-line treatment in Plasmodium falciparum infection was discontinued since 2008, it was expected that CQ-sensitive haplotype would be more abundant. METHODS: Malaria epidemiology data for the period 2010 to 2018 was collected from the office of State Vector Disease Control Programme. Plasmodium falciparum-positive blood samples were collected from government district hospitals, community health centres, primary health centres, sub-centres, and diagnostic centres from six malaria-prone districts. The samples were processed and analysed using genes-P. falciparum chloroquine-resistant transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) via sequencing of PCR amplicon from 2015 to 2017. RESULTS: Malaria occurred throughout the year and P. falciparum accounted for > 89% of total malaria cases. During 2010-2018, the highest number of malaria incidence was recorded in Lawngtlai (36% of total malaria cases; average API2010-2018 of 34.8) while Champhai remained consistently low (0.4%; average API2010-2018 of 0.04). Males of ≥ 15 years old contributed maximum (35.7%) among gender and age malarial distribution recorded during 2014-2018. Death due to malaria gradually decreased over the years. A higher abundance of mutated pfcrt (58.5% of the total sample analysed) and a lower prevalence of mutated pfmdr1 (48.7%) were observed. All mutations identified for pfcrt belong to the Southeast Asian CVIET haplotype. Only a single point mutation was observed at 86 (N â Y) position in pfmdr1 (48.7%). The key N86Y mutation in pfmdr1 that had been shown to modulate CQR was found in 67.1% of the samples positive for the CVIET haplotype. CONCLUSIONS: This is the first report that details malaria epidemiology and also the molecular status of CQ-resistance in P. falciparum population of the region. The efforts of the State Vector Borne Disease Control Programme have proved to be quite effective in controlling the malaria burden in the state. Despite the discontinuation of CQ for a decade, local P. falciparum is observed with decreased CQ-sensitive haplotype. It is believed that the present findings will form a basis for further studies on genetic diversity in P. falciparum, which could confer better understanding of the complexity of the disease in Southeast Asia.
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Antimaláricos/uso terapêutico , Cloroquina/uso terapêutico , Resistência a Medicamentos/genética , Malária Falciparum/epidemiologia , Plasmodium falciparum/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Haplótipos , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Malária Falciparum/parasitologia , Masculino , Proteínas de Membrana Transportadoras/análise , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/análise , Proteínas de Protozoários/análise , Adulto JovemRESUMO
Utonga-kupsu, Hentak and Ngari are traditional fermented fish products produced by the Manipuri people living in the North-Eastern part of India. The present study was designed with the aim to isolate, identify and characterize the microorganisms present in these fermented foods. Bacterial pure cultures were isolated using serially diluted samples and were further identified by conventional biochemical tests and Sanger sequencing of 16s rRNA gene. Results show that the number of bacterial count in Nutrient agar and Starch casein agar was 14-20 and 10-16 CFU/g, respectively. A total of 46 morphologically different bacterial strains were identified and assigned under the phylum Firmicutes. Identified bacterial strains belonged to the genus Bacillus and Staphylococcus and majority of the isolates were Bacillus subtilis and Staphylococcus nepalensis. Bacterial isolate HNS60 isolated from Hentak and identified as Bacillus subtilis was shown to possess high antimicrobial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Most of the identified bacteria were shown to possess DPPH radical scavenging as well as phosphatase, amylase, protease and cellulose activities. The isolate HNS60 contain high antimicrobial, enzymatic and probiotics activity which might responsible for the possible health benefits of the fermented foods. Utonga-kupsu, Hentak and Ngari thus can be further exploited as a potential source of probiotics and natural antioxidants.
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BACKGROUND: The aim of this study was to evaluate the risk of gastric cancer associated with individual or combined glutathione S-transferases (GSTs) polymorphism and their interaction with environmental factors. MATERIALS AND METHODS: Genotyping by PCR was carried out for 80 cases and controls each for GSTM1, GSTT1, and GSTP1 polymorphism and mapped for gene-environment association studies. The samples were subjected to pathogen detection and GSTP1 expression for analyzing their association with different genotypes. Logistic regression analyses were conducted to compute the influence of both genetic and environmental factors for gastric cancer. MDR analysis was performed to assess the risk of gastric cancer by studying the gene-gene and gene-environment effect on the basis of GST genotyping and GSTP1 gene expression. RESULTS: Infection with Helicobacter pylori and CagA+ strains was more frequent in patients with GSTM1/T1 null genotype. Intake of high fermented fat and smoked meat was found to be significantly associated with gastric cancer. The G/G, A/G (rs1695), and T/T (rs1138272) were found to be significantly associated with low expression of GSTP1 gene in cancer tissue. CONCLUSION: Presence of H. pylori with CagA genotype showed significant individual effect with GSTT1 polymorphism as well as strong synergistic effect in gastric cancer risk. Majority of the gastric cancer samples showed significant negative expression in G/G, A/G (rs1695), and T/T (rs1138272) genotypes. This study shows that GST gene polymorphism was significantly relevant for determining the individual susceptibility to gastric cancer.
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Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Infecções por Helicobacter/complicações , Neoplasias Gástricas/genética , Adulto , Idoso , Povo Asiático , Feminino , Técnicas de Genotipagem , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Genético , Medição de Risco , Neoplasias Gástricas/epidemiologiaRESUMO
Mitochondrial DNA (mtDNA) is known for its high frequencies of polymorphisms and mutations as it is prone to oxidative stress. The aim of the present study is to assess the novel mutations in mitochondrial genes from blood samples among the breast cancer patients from a less studied Northeast Indian population. D, B, L haplogroups were observed in the cancer samples and a total of 44 mtDNA D-loop sequence variations at 42 distinct nucleotide positions were found. All the sequence variations were transitional substitutions and 6 were heteroplasmic states, except for a cytosine copy number change (9C/8C) at np 303e309 in three samples examined. A total of 88 Cytochrome Oxidase C subunit I (COXI) sequence differences with respect to the Revised Cambridge Reference Sequence (rCRS) were identified including 20 missense variants with 100 % sample mutation frequency. All 20 missense mutations are highly conserved with a Cumulate Index of 100 %. Among 88 COXI mutations, 24 (13 were Non-Synonymous and 11 were Synonymous) were not previously reported (novel mutation) in the literature or the public mtDNA mutation databases. Analysis of three-dimensional structure of COXI open reading frame (ORF) predicted the effect of one single codon (96R > C, 217T > I, 224-225GG > EE and 227D > T) mutations located in the signal peptide binding position. Analysis of mitochondrial DNA mutations, as a viable alternative, has the advantage of being capable of detecting inherent risk factors for breast cancer development.
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Neoplasias da Mama/genética , DNA Mitocondrial/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Polimorfismo Genético , Adulto , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Análise por Conglomerados , Complexo IV da Cadeia de Transporte de Elétrons/química , Feminino , Frequência do Gene , Haplótipos , Humanos , Índia , Pessoa de Meia-Idade , Modelos Moleculares , Mutação , Filogenia , Estrutura Secundária de Proteína , Fatores de RiscoRESUMO
Growing evidence suggest that there is a connection between Parkinson's disease (PD) and insulin dysregulation in the brain, whilst the connection between PD and type 2 diabetes mellitus (T2DM) is still up for debate. Insulin is widely recognised to play a crucial role in neuronal survival and brain function; any changes in insulin metabolism and signalling in the central nervous system (CNS) can lead to the development of various brain disorders. There is accumulating evidence linking T2DM to PD and other neurodegenerative diseases. In fact, they have a lot in common patho-physiologically, including insulin dysregulation, oxidative stress resulting in mitochondrial dysfunction, microglial activation, and inflammation. As a result, initial research should focus on the role of insulin and its molecular mechanism in order to develop therapeutic outcomes. In this current review, we will look into the link between T2DM and PD, the function of insulin in the brain, and studies related to impact of insulin in causing T2DM and PD. Further, we have also highlighted the role of various insulin signalling pathway in both T2DM and PD. We have also suggested that T2DM-targeting pharmacological strategies as potential therapeutic approach for individuals with cognitive impairment, and we have demonstrated the effectiveness of T2DM-prescribed drugs through current PD treatment trials. In conclusion, this investigation would fill a research gap in T2DM-associated Parkinson's disease (PD) with a potential therapy option.
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Diabetes Mellitus Tipo 2 , Doença de Parkinson , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Doença de Parkinson/metabolismo , Insulina/uso terapêutico , Encéfalo/metabolismoRESUMO
The functional consequences of circular RNA (circRNA) expression on HIV-1 replication are largely unknown. Using a customized protocol involving direct RNA nanopore sequencing, here, we captured circRNAs from HIV-1-infected T cells and identified ciTRAN, a circRNA that modulates HIV-1 transcription. We found that HIV-1 infection induces ciTRAN expression in a Vpr-dependent manner and that ciTRAN interacts with SRSF1, a protein known to repress HIV-1 transcription. Our results suggest that HIV-1 hijacks ciTRAN to exclude serine/arginine-rich splicing factor 1 (SRSF1) from the viral transcriptional complex, thereby promoting efficient viral transcription. In addition, we demonstrate that an SRSF1-inspired mimic can inhibit viral transcription regardless of ciTRAN induction. The hijacking of a host circRNA thus represents a previously unknown facet of primate lentiviruses in overcoming transmission bottlenecks.
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HIV-1 , Nanoporos , Animais , Provírus/genética , HIV-1/genética , RNA Circular , Expressão GênicaRESUMO
A series of 4-hydroxy-3-methoxy benzaldehyde (vanillin) derivatives (3a-3r) was designed for the principle of Schiff base condensation with several individual sulfanilamide analogues. The inhibitory potencies of the designed compounds were evaluated through molecular docking simulation studies against the targets, breast cancer-topo isomerase-IIα and estrogen receptor-α; and the top scoring poses with higher binding energy were selected to assess the mode of binding and stability of each complex through molecular dynamics simulations. Compounds that remained stable in the active sites of the both target receptors through a number of strong H-bonds and hydrophobic contacts were selected. Based on the computational results, these selected compounds, 3b, 3e and 3f were synthesized and were followed up for structural elucidation attempts, by FT/ATR, 1H NMR and 13C NMR. From the experimental in vitro studies on 3b, 3e and 3f, the following remarkable activities against breast cancer cell line were done; IC50 values of 3b, 3e and 3f were noted, 6.7, 4.3 and 11 ng/mL, respectively. These newly synthesized compounds may be used as novel inhibitors of nuclear receptors with potential therapeutic applications in control of cancer.Communicated by Ramaswamy H. Sarma.
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Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Relação Estrutura-Atividade , Benzaldeídos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Proliferação de Células , Estrutura MolecularRESUMO
BACKGROUND: Various risk factors of tuberculosis have been studied across the globe, but these may be altered over time and can be specific to geographical regions and there is not much information available from Northeastern region of India. This study aims to investigate the various risk factors of tuberculosis and analyze the presence of any less-established risk factors. METHODS: A total of 400 TB cases and 840 healthy controls were interviewed from December 2017 - June 2020. Logistic regression model was used to analyze associated risk factors. Patients were categorized into pulmonary and extrapulmonary TB. RESULTS: Clinical presentation such as fever, cough, weight loss, chest pain and night sweats were more prominent among pulmonary TB patients. The most common mode of diagnosis among pulmonary and extrapulmonary TB were GeneXpert and X-ray, respectively. Tuberculosis was found to be strongly prevalent among patients from lower socio-economic status, less educated, unemployed and improper housing condition. Other risk factors associated were alcohol consumption, neighbours with TB, travel history, no BCG vaccine, mass gathering, and non-ideal weight. An interesting less-established risk factor that demands attention is the source of water supply (p-0.017, OR-2.313, CI: 1.160-4.613), which was significant in this study. CONCLUSION: Our data suggests that apart from all the well-established risk factors for TB, water supply might play a crucial role towards the transmission of TB, since proper hospital waste water treatment is yet to be adopted in Mizoram, Northeast India. From a public health standpoint, this highlights the need for further research in this area.
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Tuberculose Pulmonar , Tuberculose , Humanos , Fatores de Risco , Tuberculose/epidemiologia , Vacina BCG , Tuberculose Pulmonar/epidemiologia , TosseRESUMO
INTRODUCTION: Dengue is an emerging vector-borne public health threat and characterization at the molecular level is important for proper management of the disease. The aim of the study is to examine the diversity of the dengue viral serotypes from a hilly mountainous region of Northeast India. METHODOLOGY: Thirty-six blood samples that were positive for dengue virus IgM antibodies identified by the enzyme-linked immunosorbent assay (ELISA) method were collected and quantified for the IL6 gene expression by using reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: All the patients had dengue hemorrhagic fever (DHF); 12 samples had a monotypic infection and 14 samples had dual infection with various dengue virus (DENV) serotypes; one sample had triple infection with DENV-1, DENV-2, and DENV-3. CONCLUSIONS: This study identified DENV-1 as the major serotype in the state of Mizoram and it is the first report on the molecular typing of the dengue virus from the hilly mountainous state located in the Indo-Burma region bordering Myanmar and Bangladesh.
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Vírus da Dengue , Dengue , Humanos , Vírus da Dengue/genética , Dengue/epidemiologia , Sorogrupo , Ensaio de Imunoadsorção Enzimática , Tipagem Molecular , Índia/epidemiologia , Anticorpos AntiviraisRESUMO
The main aims in the development of a novel drug delivery vehicle is to efficiently carry therapeutic drugs in the body's circulatory system and successfully deliver them to the targeted site as needed to safely achieve the desired therapeutic effect. In the present study, a passive targeted functionalised nanocarrier was fabricated or wrapped the hollow mesoporous silica nanoparticles with 3-aminopropyl triethoxysilane (APTES) to prepare APTES-coated hollow mesoporous silica nanoparticles (HMSNAP). A nitrogen sorption analysis confirmed that the shape of hysteresis loops is altered, and subsequently the pore volume and pore diameters of GaC-HMSNAP was reduced by around 56 and 37%, respectively, when compared with HMSNAP. The physico-chemical characterisation studies of fabricated HMSNAP, Ga-HMSNAP and GaC-HMSNAP have confirmed their stability. The drug release capacity of the fabricated Ga-HMSNAP and GaC-HMSNAP for delivery of gallium and curcumin was evaluated in the phosphate buffered saline (pH 3.0, 6.0 and 7.4). In an in silico molecular docking study of the gallium-curcumin complex in PDI, calnexin, HSP60, PDK, caspase 9, Akt1 and PTEN were found to be strong binding. In vitro antitumor activity of both Ga-HMSNAP and GaC-HMSNAP treated MCF-7 cells was investigated in a dose and time-dependent manner. The IC50 values of GaC-HMSNAP (25 µM) were significantly reduced when compared with free gallium concentration (40 µM). The mechanism of gallium-mediated apoptosis was analyzed through western blotting and GaC-HMSNAP has increased caspases 9, 6, cleaved caspase 6, PARP, and GSK 3ß(S9) in MCF-7 cells. Similarly, GaC-HMSNAP is reduced mitochondrial proteins such as prohibitin1, HSP60, and SOD1. The phosphorylation of oncogenic proteins such as Akt (S473), c-Raf (S249) PDK1 (S241) and induced cell death in MCF-7 cells. Furthermore, the findings revealed that Ga-HMSNAP and GaC-HMSNAP provide a controlled release of loaded gallium, curcumin and their complex. Altogether, our results depicted that GaC-HMNSAP induced cell death through the mitochondrial intrinsic cell death pathway, which could lead to novel therapeutic strategies for breast adenocarcinoma therapy.
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The contribution of genes towards T2D development varies among different population groups across the world. It has been reported that a number of loci involved in T2D susceptibility are common across certain population groups, but ethnicity specific variants are also observed. The population of Mizoram has an independent ethnic identity and there are no scientific records about the history of the Mizo people; which makes this ethnic group unique and interesting to study. The aim of the study focuses on the identification of the gene variants which may contribute to T2D susceptibility in Mizo-Mongloid ethnic tribe of North east India through whole exome sequencing. The variants like 328G > C (KRT18), 997G > T (CYP4A11), 2368 T > C (SLC4A3), 508G > A (SLC26A5), 1659C > T (KCNS1), 650C > A (ABCD1) 821A > T (YTHDC2), 931G > T (PINX1), 3280C > A (TNRC6A), 48C > A(TACO1), 6035A > T(LAMA1), 805C > A(ACP7) and 806A > G(ACP7) variants were not reported for any disease in the database and were found to be pathogenic in different insilico analysis softwares. The changes in protein stability upon mutation has been predicted where 35.71% increases the stability of the protein, while 64.28% of the variants decrease the stability of the protein. These findings present the population specific variants which might involve in the susceptibility to T2D in Mizo population. Further, in this study some gene variants have contribution as a possible diagnostic or prognostic marker for other diseases as well, which suggests the need for performing association analysis for different disease manifestations in Mizo population in the near future.
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Diabetes Mellitus Tipo 2/genética , Etnicidade , Sequenciamento do Exoma , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/etnologia , Predisposição Genética para Doença , Humanos , Índia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , PrognósticoRESUMO
The rapid emergence of multidrug resistant microorganisms has become one of the most critical threats to public health. A decrease in the effectiveness of available antibiotics has led to the failure of infection control, resulting in a high risk of death. Among several alternatives, antimicrobial peptides (AMPs) serve as potential alternatives to antibiotics to resolve the emergence and spread of multidrug-resistant pathogens. These small proteins exhibit potent antimicrobial activity and are also an essential component of the immune system. Although several AMPs have been reported and characterized, studies associated with their potential medical applications are limited. This review highlights the novel sources of AMPs with high antimicrobial activities, including the entomopathogenic nematode/bacterium (EPN/EPB) symbiotic complex. Additionally, the AMPs derived from insects, nematodes, and marine organisms and the design of peptidomimetic antimicrobial agents that can complement the defects of therapeutic peptides have been used as a template.
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In the present study, we explored four different geothermal spots of the Deulajhari spring cluster at a proximity of 10-20 meters with temperatures of 43 to 65°C to unravel their genesis, bacterial diversity and CAZyme potential. However, minor variations in physicochemical properties; TOC, sodium, chloride, zinc and nitrate were observed, including the pH of the spring openings. Illumina based amplicon sequencing revealed Firmicutes, Proteobacteria and Chloroflexi as the major bacterial phylum with higher abundance in the DJ04 sample. The alpha diversity of all the springs was almost same, whereas beta diversity revealed variations in the degree of uniqueness of OTUs at different temperatures. Statistical analysis established a positive correlation between sulfur content with Heliobacterium, Thermodesulfovibrio, Thermodesulfobacterium and Herpetosipho as well as TOC and HCO3 with Thermoanaerobacter, Desulfovibrio, Candidatus solibacter and Dehalogenimona. The major hydrocarbon family genes and Carbohydrate Active Enzyme pathways were predicted to be highest in DJ04 with elevated concentrations of HCO3 and TOC. Higher homogeneity in geo-physicochemical and microbial features direct the possibility of the common origin of these springs through plumbing systems. However, the minor variations in diversity and functionality were due to variations in temperature in spring openings through the mixing of subsurface water contaminated with carbohydrates from leaf biomass litter. Functional characterization of the thermophilic bacteria of this spring provides essential scope for further industrial applications. The biogeochemical reasons hypothesized for the genesis of unique multiple openings in the cluster are also of interest to conservation scientists for taking measures toward necessary laws and regulations to protect and preserve these springs.
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Background The overwhelming majority of published articles have taken colon and rectal cancer as a single group, i.e., colorectal cancer, when normalizing gene expression data with housekeeping genes (HKG) in quantitative polymerase chain reaction (qPCR) experiments though there are published reports that suggest the differential expression pattern of genes between the colon and rectal cancer groups and hence the current experiment was attempted to find out the optimal set of housekeeping genes from the list of common HKG for rectal tumor gene expression analysis. Methods The expression of five potential housekeeping genes GAPDH, RPNI, PUM1, B2M, and PMM1 was analyzed through qPCR and Bestkeeper software (http://www.wzw.tum.de/gene-quantification/bestkeeper.html) in 20 stage II-IV rectal cancer samples to check for uniformity in their expression pattern. Cancer stem cell (CSC) marker ALDH1 and epithelial-mesenchymal transition marker (EMT) markers E cadherin, vimentin, Twist, and SNAI2 expression were evaluated in conjunction with the two optimal reference genes in 10 rectal cancers as part of validation. Results The standard deviation of the cycle threshold value of GAPDH was found the lowest at 0.65 followed by RPN1 at 0.88, PUM1 at 0.94, PMM1 at 0.94, and B2M at 1.21 when analyzed with BestKeeper software. Using GAPDH and PUM1 as the reference gene for the validation phase, rectal cancer patients with stage III/IV showed a 4.79-fold change (P=0.006) in ALDH1 expression, and an 11.76-fold change in Twist expression (P=0.003) with respect to stage II rectal tumor when normalized with GAPDH and PUM1. Conclusion GAPDH and PUM1 can be used as an optimal set of housekeeping genes for gene expression-related experiments in rectal tumors. ALDH1 and Twist were found significantly overexpressed in stage III/IV rectal tumors in comparison to stage II rectal cancer. Genes associated with cancer stem cells and EMT markers could be optimally analyzed by normalizing them with GAPDH and PUM1 as housekeeping genes.
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Tuberculosis caused by Mycobacterium tuberculosis is one of the main global health concerns. In this study, the entire mitochondrial genome from blood samples of tuberculosis patients was analyzed to understand the possible mtDNA variants. The potential impact of non-synonymous substitutions on protein functions were determined using prediction tools. 28 non- synonymous variants were found of which 2 variants (MT-ND2 g. Aâ¯>â¯G4824 p.T119A and MT-ND6 g. Tâ¯>â¯C14180 p.Y165C) were found to be deleterious among the cases only. Majority of the variants lie in the D-loop of the non-protein coding region of the mitochondrial DNA. We propose that mutations in the mitochondrial genome need to be validated further to understand their association with tuberculosis.
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Mitocôndrias/genética , NADH Desidrogenase/genética , Polimorfismo de Nucleotídeo Único , Tuberculose/genética , Predisposição Genética para Doença , Genoma Mitocondrial , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Índia , NADH Desidrogenase/química , Domínios Proteicos , Análise de Sequência de DNA , População Branca/genéticaRESUMO
Leukemia is the most common childhood malignancy and studies had been carried out with promising revelations in its diagnosis and prognosis. However, majority of the studies are focused on nuclear alterations, while mitochondrial mutations are not well studied. Although there are studies of mitochondrial mutations in the adult leukemias, it does not represent the same for childhood malignancy. This is the first scientific report on the mtDNA mutational pattern of pediatric leukemic cases from a endogamous tribal population in Northeast India. ATP6 involved in the Complex V was found to be more altered with respect to the Non-synonymous variants. mtDNA variations in the non-coding region (D-Loop - g.152 T>C) and in the coding region (MT-ND2, g.4824 A>G, p.T119A) showed a maternal inheritance which could reveal a genetic predisposition with lower penetrance. D-Loop variant (g.152 T>C) could be a diagnostic marker in accordance with previous report but is in contrast to pertaining only in AML - M3 subtype rather was found across in myeloid malignancies.
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Leucemia/genética , Mitocôndrias/genética , ATPases Mitocondriais Próton-Translocadoras/genética , NADH Desidrogenase/genética , Adolescente , Criança , Pré-Escolar , Feminino , Genes Mitocondriais , Predisposição Genética para Doença , Humanos , Índia/etnologia , Leucemia/etnologia , Masculino , Herança Materna , ATPases Mitocondriais Próton-Translocadoras/química , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Seleção Genética , Sequenciamento Completo do GenomaRESUMO
The novel Coronavirus disease 2019 (COVID-19) is an illness caused due to Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The World Health Organization (WHO) has declared this outbreak a global health emergency and as on April 24, 2020, it has spread to 213 countries, with 25,91,015 confirmed cases and 742,855 cases have been recovered from COVID-19. In this dreadful situation our team has already published an article in the Science of the Total Environment, which elaborates the various aspects of the SARS-CoV-2 infection. In this situation, it is imperative to understand the possible outcome of COVID-19 recovered patients and determine if they have any other detrimental illnesses by longitudinal analysis to safeguard their life in future. It is necessary to follow-up these recovered patients and performs comprehensive assessments for detection and appropriate management towards their psychological, physical, and social realm. This urges us to suggest that it is highly important to provide counselling, moral support as well as a few recommended guidelines to the recovered patients and society to restore to normalcy. Epidemiological, clinical and immunological studies from COVID-19 recovered patients are particularly important to understand the disease and to prepare better for potential outbreaks in the future. Longitudinal studies on a larger cohort would help us to understand the in-depth prognosis as well as the pathogenesis of COVID-19. Also, follow-up studies will help us provide more information for the development of vaccines and drugs for these kinds of pandemics in the future. Hence, we recommend more studies are required to unravel the possible mechanism of COVID-19 infection and the after-effects of it to understand the characteristics of the virus and to develop the necessary precautionary measures to prevent it.
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Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , COVID-19 , Seguimentos , Humanos , SARS-CoV-2RESUMO
Pierisin-5 protein (pie-5) belongs to a family of proteins possessing DNA-dependent ADP-ribosyltransferase activity, which can induce apoptotic cell death. The baculovirus-mediated expression vector system (BEVS) has been commonly used for in vitro expression of heterologous protein subunits for basic scientific research, in addition to the development and production of diagnostics and vaccines. In this study, a new method for the in vitro expression of the cytotoxic protein was established using the baculovirus expression system. The antiproliferative and apoptotic effect of the novel recombinant pierisin-5 protein (rpie-5) was investigated in different human cancer cell lines, such as HeLa, HepG2, and AGS. Cloning, in vitro overexpression, and purification of the rpie-5 protein were performed by using BEVS in Sf21 (Spodoptera frugiperda) insect cell line. The rpie-5 protein exhibits cytotoxicity in all the cell lines, but HeLa (IC50 0.6 µg/mL) was more sensitive when compared with HepG2 (IC50 1.9 µg/mL) and AGS (IC50 3.7 µg/mL) cell lines. The cytotoxic effects of rpie-5 lead to apoptotic cell death in cancer cells and resulted in nuclear fragmentation, enlargement of the nucleus, loss of mitochondrial membrane potential, and finally release of lactose dehydrogenase (LDH) enzyme from the cell membrane. This study reports the molecular mechanism of apoptotic cell death through the upregulation of Bax (Bcl-2 family activating protein-X), Bad, APAF-1 (apoptotic protease activating factor-1), Cyt-c, and caspase-3/9 and the downregulation of Bcl-2 (B-cell lymphoma 2) in rpie-5-treated cancer cells. The study concludes that rpie-5 has p53-independent apoptosis in HepG2 cells and p53-dependent apoptosis in HeLa and AGS cell lines. In the future, this study helps to understand the molecular mechanism of rpie-5 to induction of apoptosis and cell death.
Assuntos
ADP Ribose Transferases/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Insetos/farmacologia , Proteínas Recombinantes/farmacologia , ADP Ribose Transferases/genética , Animais , Apoptose/fisiologia , Baculoviridae/genética , Linhagem Celular Tumoral , Clonagem Molecular , Humanos , Proteínas de Insetos/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Engenharia de Proteínas/métodos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Recombinantes/genética , Células Sf9 , Proteína Supressora de Tumor p53/genética , Proteína X Associada a bcl-2/genéticaRESUMO
Worldwide and in India, malaria elimination efforts are being ramped up to eradicate the disease by 2030. Malaria elimination efforts in North-East (NE) India will have a great bearing on the overall efforts to eradicate malaria in the rest of India. The first cases of chloroquine and sulfadoxine-pyrimethamine resistance were reported in NE India, and the source of these drug resistant parasites are most likely from South East Asia (SEA). NE India is the only land route through which the parasites from SEA can enter the Indian mainland. India's malaria drug policy had to be constantly updated due to the emergence of drug resistant parasites in NE India. Malaria is highly endemic in many parts of NE India, and Plasmodium falciparum is responsible for the majority of the cases. Highly efficient primary vectors and emerging secondary vectors complicate malaria elimination efforts in NE India. Many of the high transmission zones in NE India are tribal belts, and are difficult to access. The review details the malaria epidemiology in seven NE Indian states from 2008 to 2018. In addition, the origin and evolution of resistance to major anti-malarials are discussed. Furthermore, the bionomics of primary vectors and emergence of secondary malaria vectors, and possible strategies to prevent and control malaria in NE are outlined.