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1.
Arab J Gastroenterol ; 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35477852

RESUMO

BACKGROUND AND STUDY AIMS: Dubin-Johnson syndrome (DJS) is a benevolent genetic disorder of the liver with autosomal inheritance. It is a rare disorder characterized by an increase in conjugated bilirubin and anomaly in coproporphyrin clearance. DJS is caused by deleterious mutations in the ABCC2 gene. A polymorphism in the ABCC2 gene causes malfunctions in its ability to regulate the efflux of different organic anions, such as bilirubin, from hepatocytes to the canaliculi. Multidrug resistance protein 2 (MRP2) encoded by the ABCC2 gene is one of the main regulators of the export of bilirubin to respective sites. ABCC2 gene mutations have widely drawn attention in the pathology of DJS in various populations. PATIENTS AND METHODS: The ABCC2 gene was subjected to the National Center for Biotechnology Information (NCBI) database in 2020, and non-synonymous single-nucleotide polymorphisms (nsSNPs) and variants in untranslated regions were studied using different computational servers. SIFT, Protein variation effect analyzer, and PolyPhen-2 were used to retrieve the damaging Single-nucleotide polymorphisms (SNPs); PhD-SNP, SNPs&GO, and Protein Analysis Through Evolutionary Relationships were used to predict the association of nsSNPs with DJS; Mutation3D illustrated the location of variants in the protein; SNAP2, MutPred2, ELASPIC, and HOPE were used to predict the structural and functional effects of these mutations on MRP2; and I-mutant 3.0 and MuPro were used to determine the effects of polymorphism on the function of MRP2. RESULTS: In this study, 18,947 SNPs were screened from the NCBI database, followed by a series of refinement of variants using online available servers. We concluded that 41 ABCC2 gene variants are vital etiological candidates for DJS in humans. These 41 variants had highly damaging effects on the MRP2 protein, which may lead to deficient transportation capacity, thereby affecting the efflux of bilirubin across the canalicular membrane. CONCLUSION: In silico tools are an alternative approach for predicting the target SNPs. Hence, previously unreported variants can be considered strong etiological candidates for diseases related to MRP2.

2.
Bioengineering (Basel) ; 9(4)2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35447736

RESUMO

Food security and crop production are challenged worldwide due to overpopulation, changing environmental conditions, crop establishment failure, and various kinds of post-harvest losses. The demand for high-quality foods with improved nutritional quality is also growing day by day. Therefore, production of high-quality produce and reducing post-harvest losses of produce, particularly of perishable fruits and vegetables, are vital. For many decades, attempts have been made to improve the post-harvest quality traits of horticultural crops. Recently, modern genetic tools such as genome editing emerged as a new approach to manage and overcome post-harvest effectively and efficiently. The different genome editing tools including ZFNs, TALENs, and CRISPR/Cas9 system effectively introduce mutations (In Dels) in many horticultural crops to address and resolve the issues associated with post-harvest storage quality. Henceforth, we provide a broad review of genome editing applications in horticulture crops to improve post-harvest stability traits such as shelf life, texture, and resistance to pathogens without compromising nutritional value. Moreover, major roadblocks, challenges, and their possible solutions for employing genome editing tools are also discussed.

3.
Xenobiotica ; : 1-10, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35445643

RESUMO

Genetic polymorphism of drug-metabolising enzymes such as NQO1, SULT1A1, EPHX1, and NAT2 alters its activity which hampers the detoxification and disposal of chemotherapeutic compounds. Thus, in the present study, we have comprehensively investigated the associations between SNPs of the Phase II detoxifying genes and its relationship towards platinum-induced toxicity of lung cancer patients.NQO1 (609 C > T), SULT1A1 (Arg213 His), EPHX1 (Tyr113His, His139Arg), and NAT2 (481 C > T, 803 A > G, 590 G > A, 857 G > A) were evaluated in our study for their associated adverse events caused due to the administration of platinum-based chemotherapy to the lung cancer patients.For NQO1 609 C > T polymorphism, the TT genotype showed reduced risk of constipation (OR = 0.10, p = 0.04) and anorexia (OR = 0.15, p = 0.03). For SULT1A1 Arg213His, heterozygous genotype (Arg/His) (AOR = 0.38, p = 0.006) and combined genotype (Arg/His + His/His) were not associated with increased risk of nephrotoxicity (AOR = 0.38, p = 0.004). For NAT2, heterozygous (NAT2*4/*6) and combined genotypes (NAT2*4/*4+*4/*6) for NAT2*6 polymorphism exhibit 2.4 folds (p = 0.005), and two-folds (p = 0.01) increased risk of hematological toxicity. The heterozygous (AOR = 0.45, p = 0.004) and variant genotype (AOR = 0.39, p = 0.02) for NAT2*5C had decreased risk for hematological toxicity. The heterozygous genotype for NAT2*7 polymorphism showed two-fold increased risk for developing thrombocytopenia.This study provides association of NAT2 polymorphic variants in predicting haematological toxicity.

4.
Med J Armed Forces India ; 78(2): 157-163, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35463538

RESUMO

Background: Mechanical debridement of periodontal pockets remains the mainstay of therapy in all forms of periodontitis. There is 47% greater reduction in plaque amount when sodium hypochlorite (NaOCl) is used as an adjunct when compared with water rinsing. The aim of this study was to evaluate the effects of 0.05% NaOCl and 0.12% chlorhexidine gluconate twice daily rinse on periodontal parameters and gingival crevicular fluid (GCF) HSV1 and CMV levels in chronic periodontitis. Methods: Patients assigned to group A were prescribed 0.05% NaOCl mouthwash for twice daily rinse. Patients in group B were prescribed 0.12% chlorhexidine gluconate mouthwash to be used twice daily. Evaluation of periodontal parameters was done at baseline and after six months following therapy. GCF HSV1 and CMV levels were evaluated using a polymerase chain reaction. Results: A statistically significant difference was noted in the improvement in periodontal parameters between both groups, when evaluated six months following therapy with greater reduction in group A vis-a-vis group B. Conclusion: NaOCl when prescribed as a twice daily mouthwash can be recommended as a part of the home care regime in patients with chronic periodontitis. It is more cost-effective, easily available and can be beneficial to the troops in difficult terrains and extremes of climates, where oral healthcare facilities are not easily accessible.

6.
Antioxidants (Basel) ; 11(3)2022 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-35326108

RESUMO

The present study investigates the potential ameliorative role of seven secondary metabolites, viz., ascorbate (AsA), reduced glutathione (GSH), jasmonic acid (JA), salicylic acid (SA), serotonin (5-HT), indole-3-acetic acid (IAA) and gibberellic acid (GA3), for mitigation of aluminium (Al3+) and manganese (Mn2+) stress associated with acidic soils in rice, maize and wheat. The dehydroascorbate reductase (DHAR) and mono-dehydroascorbate reductase (MDHAR) of the cereals were used as model targets, and the analysis was performed using computational tools. Molecular docking approach was employed to evaluate the interaction of these ions (Al3+ and Mn2+) and the metabolites at the active sites of the two target enzymes. The results indicate that the ions potentially interact with the active sites of these enzymes and conceivably influence the AsA-GSH cycle. The metabolites showed strong interactions at the active sites of the enzymes. When the electrostatic surfaces of the metabolites and the ions were generated, it revealed that the surfaces overlap in the case of DHAR of rice and wheat, and MDHAR of rice. Thus, it was hypothesized that the metabolites may prevent the interaction of ions with the enzymes. This is an interesting approach to decipher the mechanism of action of secondary metabolites against the metal or metalloid - induced stress responses in cereals by aiming at specific targets. The findings of the present study are reasonably significant and may be the beginning of an interesting and useful approach towards comprehending the role of secondary metabolites for stress amelioration and mitigation in cereals grown under acidic soil conditions.

7.
Curr Treat Options Oncol ; 23(2): 268-294, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35226309

RESUMO

OPINION STATEMENT: Despite advancements in clinical research, both prognosis and treatment for SCLC patients are still in the nascent stage. SCLC is a fatal disease with high tumor mutational burden and is strongly associated with exposure to tobacco. This leads to the development of potential neo-antigens, inhibition of immune responses, and development of paraneoplastic disorders. Surgery, radiation, and chemotherapy are widely accepted treatments for cancer globally, and most recently, immunotherapy has now become the "fourth pillar" of SCLC treatment. Various immune checkpoint pathways regulate the activation of T cells at multiple stages during an immune response. T cell checkpoint inhibitors such as anti-PD1 (pembrolizumab, nivolumab), anti-PDL1, and anti-CTLA-4 (tremelimumab, ipilimumab) have potential to show anti-cancer activity along with the promise to prolong survival in patients with SCLC. Treatment with the CTLA-4-specific antibodies can restore the immune response by increasing the accumulation and survival of T-cells whereas monoclonal antibodies block either PD-1 or its ligands that prevent downregulation of effector T-cell, which enables the T-cells to mediate the death of tumor cells. Furthermore, monoclonal antibody in combination with chemotherapy has attained quite a focus to enhance the survival of SCLC patients. Apart from this, various immunotherapeutic approaches have been evaluated in the clinical trials for SCLC patients such as TLR9 agonist, anti-CD47, anti-ganglioside therapy, and anti-Notch signaling. The current review focuses on the rationale as well as on the clinical studies of immunotherapy in SCLC along with the clinical end results of certain immunotherapeutic agents and novel therapeutic combinations in SCLC patients.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4 , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Nivolumabe/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/terapia
8.
Oncology ; 2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35086099

RESUMO

BACKGROUND: With an estimated 1.8 million deaths, lung cancer is one of the widely reported malignancies, with substantial morbidity and mortality rates. Thymidylate synthase (TS) is an important drug target for platinum-based doublet chemotherapy as it is the only de novo source of thymidylate production in the cell. TS polymorphisms in the 5'UTR of Thymidylate synthase enhancer region (TSER) 2R/3R and 3'- UTR 1494del6 are investigated in this study. METHODS: A total of 700 lung cancer patients with platinum-based doublet chemotherapy were recruited in this study. TSER (2R/3R) and TS 1494del6 polymorphisms in North Indian lung cancer patients were examined, and statistical analysis was performed. RESULTS: According to our findings, patients with the wild genotype (2R/2R) for the TSER polymorphism had a longer median survival time as compared to patients harboring the mutant type genotype (3R/3R) [MST=9.77 vs. 7.57 months; p=0.04]. On the contrary, patients with the mutant 14946del6 polymorphism (-6/-6) had a longer survival time than patients with the wild-type genotype (+6/+6) [MST=7.23 vs. 9 months]. Further, our findings elucidated that the patients with heterozygous genotype (2R3R) for TSER polymorphism had a 2.30-fold increased risk of developing leukopenia (AOR=2.30, 95% CI=0.96-5.52; p=0.05). A substantial risk of 5.14-fold constipation was found in heterozygous genotype (2R3R) when intermediate grade 2 toxicity was compared with low toxicity (grade 1) (p=0.007).An increased risk of nausea/vomiting was observed in patients with mutant genotype (-6/-6bp) for 1494 ins/del6 polymorphism compared to patients with wild-type genotype (+6/+6bp) (AOR= 2.77; 95%CI=1.10-6.96, p=0.03). CONCLUSION: According to our findings, TSER and the 1494del6 polymorphism may operate as a prognostic marker in lung cancer patients receiving platinum-based chemotherapy. Furthermore, TS polymorphisms may influence the onset of platinum-related toxicity, such as hematological and gastrointestinal toxicity. These findings might facilitate therapeutic decisions for individualized therapy in lung cancer patients.

9.
ISME J ; 16(3): 890-897, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34689184

RESUMO

Earth's radiation budget and frequency and intensity of precipitation are influenced by aerosols with ice nucleation activity (INA), i.e., particles that catalyze the formation of ice. Some bacteria, fungi, and pollen are among the most efficient ice nucleators but the molecular basis of INA is poorly understood in most of them. Lysinibacillus parviboronicapiens (Lp) was previously identified as the first Gram-positive bacterium with INA. INA of Lp is associated with a secreted, nanometer-sized, non-proteinaceous macromolecule or particle. Here a combination of comparative genomics, transcriptomics, and a mutant screen showed that INA in Lp depends on a type I iterative polyketide synthase and a non-ribosomal peptide synthetase (PKS-NRPS). Differential filtration in combination with gradient ultracentrifugation revealed that the product of the PKS-NRPS is associated with secreted particles of a density typical of extracellular vesicles and electron microscopy showed that these particles consist in "pearl chain"-like structures not resembling any other known bacterial structures. These findings expand our knowledge of biological INA, may be a model for INA in other organisms for which the molecular basis of INA is unknown, and present another step towards unraveling the role of microbes in atmospheric processes.


Assuntos
Gelo , Policetídeo Sintases , Fungos , Peptídeo Sintases/genética , Policetídeo Sintases/genética
11.
Int J Appl Basic Med Res ; 11(4): 214-220, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912683

RESUMO

CONTEXT: Bisphenol A (BPA), a known endocrine disrupting chemical, is of widespread use in manufacturing of plastic products. Documenting ill health effects of BPA has led the plastic industrialists to replace BPA by its alleged safer alternative, bisphenol S (BPS). BPS belongs to the same chemical family and shares endocrine disrupting properties with BPA. AIMS: We compared the effects of 28-day exposure of BPA and BPS on body weight changes, organ histology, and relative organ weight in rats. In addition, we detected BPA and BPS in the rat's blood serum. SETTINGS AND DESIGN: Adult male albino rats were administered BPA (50 mg/kg/day) or BPS (50 mg/kg/day) or equivolume vehicle in different groups by oral gavage for 28 days. SUBJECTS AND METHODS: The weight of each rat was noted at the commencement of the study and weekly afterward. On 29th day, the animals were sampled for whole blood and then sacrificed. The dissected out wet viscera were weighed and subjected to the standard protocol for histological examination. Serum samples were prepared and analyzed for the detection of BPA and BPS by high-pressure liquid chromatography. STATISTICAL ANALYSIS USED: Paired and unpaired Student's t-test, one-way ANOVA test, and Bonferroni test for multiple comparisons were used, as required for statistical analysis, and P < 0.05 was considered statistically significant. RESULTS: Both BPA and BPS produced similar detrimental changes in body weight, histology of stomach, small intestine, lung, and kidney, and relative organ weight of lung and kidney. BPA and BPS detected in the serum of rats were nearly 45 times of the control. CONCLUSIONS: Present data suggest caution about the application of BPS as a substitute of BPA.

12.
Pharmacogenomics ; 22(18): 1211-1235, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34783261

RESUMO

The expression of ATP-binding cassette transporter (ABC transporters) has been reported in various tissues such as the lung, liver, kidney, brain and intestine. These proteins account for the efflux of different compounds and metabolites across the membrane, thus decreasing the concentration of the toxic compounds. ABC transporter genes play a vital role in the development of multidrug resistance, which is the main obstacle that hinders the success of chemotherapy. Preclinical and clinical trials have investigated the probability of overcoming drug-associated resistance and substantial toxicities. The focus has been put on several strategies to overcome multidrug resistance. These strategies include the development of modulators that can modulate ABC transporters. This knowledge can be translated for clinical oncology treatment in the future.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Neoplasias/metabolismo , Animais , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Neoplasias/tratamento farmacológico
13.
J Robot Surg ; 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34709536

RESUMO

To compare the disease-free survival (DFS) and overall survival (OS) at 3 years and 5 years in patients undergoing treatment for early-stage cervical cancer with either robotic (RRH) or open radical hysterectomy (ORH). This retrospective study compared all patients with stage IA1 (lymphovascular invasion), IA2, IB1, IB2 and II A cervical cancer in accordance with International Federation of Gynaecology and Obstetrics staging (FIGO 2009) of cancer of the cervix uteri. Patients who underwent Radical Hysterectomy at our centre from January 2011 till January 2018 were included in the study. One hundred and eighty-nine patients ( ORH = 67, RRH = 122) were included. The median follow-up time was 46.3 months in RRH group and 70.0 months in the ORH group. The 3-year DFS was comparable in both the arms, 91.5% in RRH and 91.6% in ORH. The 5-year DFS was 88.9% and 85.9% in robotic and open approaches, respectively (P = 0.258), hazard ratio (HR) 0.616 (CI = 0.266-1.427). The 3-year overall survival for robotic approach was 93.4% and for open was 95%, whereas 5-year overall survival was 84.7% and 87.4% in robotic and open approaches, respectively (P = 0.813). The median estimated blood loss for robotics was lower (100 ml vs 300 ml, P < 0.001) and median operative time was less (162.5 min vs. 180 min, P = 0.005) in robotics. The patients in RRH cohort had shorter median hospital stay (3.9 days vs. 6.3 days, P < 0.001). Robotic radical hysterectomy had comparable survival outcomes to open radical hysterectomy in cancer cervix. RRH is associated with improved peri-operative surgical outcomes and better resource utilisation.

14.
Nat Commun ; 12(1): 5469, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552091

RESUMO

SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.


Assuntos
Anticorpos Neutralizantes/farmacologia , COVID-19/tratamento farmacológico , Anticorpos de Domínio Único/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Administração Intranasal , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Microscopia Crioeletrônica , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Epitopos/química , Epitopos/metabolismo , Feminino , Masculino , Mesocricetus , Testes de Neutralização , SARS-CoV-2/efeitos dos fármacos , Anticorpos de Domínio Único/administração & dosagem , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/metabolismo , Glicoproteína da Espícula de Coronavírus/química
15.
Strategies Trauma Limb Reconstr ; 16(1): 20-26, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326898

RESUMO

AIM AND OBJECTIVE: To assess the use of arm length (AL) for the estimation of tibial nail length preoperatively and compare its accuracy to various established upper and lower limb anthropometric parameters. MATERIAL AND METHODS: This prospective study of 54 patients assessed upper limb parameters as a possible alternative for intraoperatively measured tibial nail length. The anthropometric parameters measured independently by two observers were AL, olecranon to fifth metacarpal head (OMD), tibial tuberosity to medial malleolus (TT-MM), tibial tuberosity to medial malleolus minus 20 mm (TT-MM-20 mm) and knee joint line to medial malleolus minus 40 mm (KJL-MM-40) and compared to final nail size used intraoperatively. Two observers were used. Bland-Altman plots were constructed to assess the limits of agreement to intraoperative estimates of optimum nail length. A repeatability assessment was also assessed by both observers. RESULTS: None of the anthropometric parameters showed limits of agreement within ±10 mm of nail length. AL showed the least average difference and best limits of agreement among all the anthropometric parameters. Among the lower limb parameters, the KJL-MM showed the least average difference but poorer limits of agreement to nail length. The OMD measurement showed a greater average difference than the AL indicating it is a poorer upper limb parameter for predicting nail length. CONCLUSION: AL as measured between the angle of the acromion to the lateral epicondyle can be used as a preoperative upper limb anthropometric estimate of nail length to one nail size of the optimum length. Further studies with a larger sample size may reduce the confidence intervals and help justify its wider use. HOW TO CITE THIS ARTICLE: Sharma A, Sinha S, Gupta S, et al. Evaluation of Arm Length as a New Upper Limb Anthropometric Method for Preoperative Estimation of Tibial Intramedullary Nail Length. Strategies Trauma Limb Reconstr 2021;16(1):20-26.

16.
FEBS Lett ; 595(18): 2323-2340, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34331769

RESUMO

The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has triggered a worldwide health emergency. Here, we show that ferritin-like Dps from hyperthermophilic Sulfolobus islandicus, covalently coupled with SARS-CoV-2 antigens via the SpyCatcher system, forms stable multivalent dodecameric vaccine nanoparticles that remain intact even after lyophilisation. Immunisation experiments in mice demonstrated that the SARS-CoV-2 receptor binding domain (RBD) coupled to Dps (RBD-S-Dps) elicited a higher antibody titre and an enhanced neutralising antibody response compared to monomeric RBD. A single immunisation with RBD-S-Dps completely protected hACE2-expressing mice from serious illness and led to viral clearance from the lungs upon SARS-CoV-2 infection. Our data highlight that multimerised SARS-CoV-2 subunit vaccines are a highly efficacious modality, particularly when combined with an ultra-stable scaffold.


Assuntos
Enzima de Conversão de Angiotensina 2/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Receptores Virais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Proteínas de Bactérias/química , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/química , Proteínas de Ligação a DNA/química , Ferritinas/química , Humanos , Imunização , Camundongos , Nanopartículas , Domínios Proteicos , Multimerização Proteica , Glicoproteína da Espícula de Coronavírus/química , Sulfolobus
17.
Front Genet ; 12: 631340, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054914

RESUMO

Rare monogenic autoinflammatory diseases are a group of recurrent inflammatory genetic disorders caused due to genetic variants in over 37 genes. While a number of these disorders have been identified and reported in Middle Eastern populations, the carrier frequency of these genetic variants in the Middle Eastern population is not known. The availability of whole-genome and exome datasets of over 1,000 individuals from Qatar persuaded us to explore the genetic epidemiology of rare autoinflammatory genetic variants. We have systematically analyzed genetic variants in genome-scale datasets from Qatar with a compendium of variants associated with autoinflammatory diseases. The variants were systematically reclassified according to the American College of Medical Genetics and Genomics guidelines for interpretation of variant pathogenicity. Our analysis identified seven pathogenic and likely pathogenic variants with significant differences in their allele frequencies compared to the global population. The cumulative carrier frequency of these variants was found to be 2.58%. Furthermore, our analysis revealed that five genes, implicated in rare autoinflammatory diseases, were under natural selection. To the best of our knowledge, this is the first and most comprehensive study on the population-scale analysis and genetic epidemiology of genetic variants that cause rare autoinflammatory disease in Middle Eastern populations.

18.
Adv Med Educ Pract ; 12: 237-243, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692645

RESUMO

INTRODUCTION: During the COVID-19 pandemic, most educational institutions have opted for online education rather than traditional modes of education to protect their employees and students. Online education has been gaining momentum in almost all countries around the world. This coincides with the recently introduced competency-based medical education in India which has embraced online education. This poses a new challenge for the institutions involved, the instructors or teachers, and the students since they must adapt quickly to the new mode of learning. Online education requires teachers to improve their competency in three major areas; pedagogy, technology, and content knowledge. Some of the challenges include; lack of technological skill, poor time management and lack of infrastructure. As technology rapidly advances, health care education systems must also advance in tandem. To implement the new competency-based system and online education, the institutions and the individuals must realize the importance of online education, identify the barriers and quickly work on solutions for success. METHODS: This review was conducted based on various research papers on the topic of online medical education, the challenges faced by faculty members, and the opinion of students on this dilemma. Search terms included online medical education, COVID19, competency-based medical education. CONCLUSION: This review identified various challenges posed by online education on the current medical curriculum, faced by both faculty members and students, especially under the light of the Competency-Based Undergraduate Curriculum for Indian Graduates. Different solutions were proposed to overcome these challenges.

19.
EMBO J ; 40(6): e105543, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586810

RESUMO

Influenza A virus (IAV) and SARS-CoV-2 (COVID-19) cause pandemic infections where cytokine storm syndrome and lung inflammation lead to high mortality. Given the high social and economic cost of respiratory viruses, there is an urgent need to understand how the airways defend against virus infection. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that ATG16L1-dependent targeting of LC3 to single-membrane, non-autophagosome compartments - referred to as non-canonical autophagy - protects mice from lethal IAV infection. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV was controlled within epithelial barriers where non-canonical autophagy reduced IAV fusion with endosomes and activation of interferon signalling. Conditional mouse models and ex vivo analysis showed that protection against IAV infection of lung was independent of phagocytes and other leucocytes. This establishes non-canonical autophagy in airway epithelial cells as a novel innate defence that restricts IAV infection and lethal inflammation at respiratory surfaces.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Vírus da Influenza A/patogenicidade , Proteínas Associadas aos Microtúbulos/metabolismo , Infecções por Orthomyxoviridae/genética , Deleção de Sequência , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/virologia , Animais , Autofagia , Proteínas Relacionadas à Autofagia/química , Proteínas Relacionadas à Autofagia/metabolismo , Embrião de Galinha , Citocinas/metabolismo , Cães , Células Madin Darby de Rim Canino , Camundongos , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/mortalidade , Domínios Proteicos , Replicação Viral
20.
J Pharm Biomed Anal ; 197: 113953, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33618130

RESUMO

Stress degradation studies were carried out on celiprolol hydrochloride under the ICH prescribed hydrolysis (acidic, basic and neutral), photolytic, oxidative and thermal conditions. Maximum degradation was observed upon hydrolysis, especially in the basic condition. In oxidative condition, the drug degraded only upon severe exposure to H2O2, but it remained stable when challenged with AIBN. It also degraded significantly under photolytic conditions. However, the drug was stable to thermal stress. A total of seven degradation products were formed, whose separation was successfully achieved on an Inertsil ODS-3V C-18 HPLC column employing a gradient mobile phase. A comprehensive mass fragmentation pattern of the drug was initially established through the support of high resolution mass spectrometry (HR-MS), multi-stage tandem mass spectrometry (MSn) and on-line H/D exchange MS data. The same approach was then extended to characterization of the degradation products. Additionally, two degradation products were isolated and subjected to 1D/2D NMR studies for their structural confirmation. One of the degradation products showed instability during isolation, therefore, it was subjected to LC-NMR studies for its structural confirmation.


Assuntos
Celiprolol , Peróxido de Hidrogênio , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Hidrólise , Oxirredução , Fotólise , Espectrometria de Massas em Tandem
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