| 1. |
- Ademuyiwa, Adesoji O., et al.
(författare)
-
Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
-
Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
|
|
| 2. |
- Hassan, Sameer, et al.
(författare)
-
MSALigMap-A Tool for Mapping Active-Site Amino Acids in PDB Structures onto Known and Novel Unannotated Homologous Sequences with Similar Function
- 2022
-
Ingår i: Life-Basel. - : MDPI AG. ; 12:12
-
Tidskriftsartikel (refereegranskat)abstract
- MSALigMap (Multiple Sequence Alignment Ligand Mapping) is a tool for mapping active-site amino-acid residues that bind selected ligands on to target protein sequences of interest. Users can also provide novel sequences (unavailable in public databases) for analysis. MSALigMap is written in Python. There are several tools and servers available for comparing and mapping active-site amino-acid residues among protein structures. However, there has not previously been a tool for mapping ligand binding amino-acid residues onto protein sequences of interest. Using MSALigMap, users can compare multiple protein sequences, such as those from different organisms or clinical strains, with sequences of proteins with crystal structures in PDB that are bound with the ligand/drug and DNA of interest. This allows users to easily map the binding residues and to predict the consequences of different mutations observed in the binding site. The MSALigMap server can be accessed at https://albiorix.bioenv.gu.se/MSALigMap/HomePage.py.
|
|
| 3. |
- Bhargavi, G., et al.
(författare)
-
Protein-protein interaction of Rv0148 with Htdy and its predicted role towards drug resistance in Mycobacterium tuberculosis
- 2020
-
Ingår i: Bmc Microbiology. - : Springer Science and Business Media LLC. - 1471-2180. ; 20:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background Mycobacterium tuberculosis resides inside host macrophages during infection and adapts to resilient stresses generated by the host immune system. As a response, M. tuberculosis codes for short-chain dehydrogenases/reductases (SDRs). These SDRs are nicotinamide adenine dinucleotide-reliant oxidoreductases involved in cell homeostasis. The precise function of oxidoreductases in bacteria especially M. tuberculosis were not fully explored. This study aimed to know the detail functional role of one of the oxidoreductase Rv0148 in M. tuberculosis. Results In silico analysis revealed that Rv0148 interacts with Htdy (Rv3389) and the protein interactions were confirmed using far western blot. Gene knockout mutant of Rv0148 in M. tuberculosis was constructed by specialized transduction. Macrophage cell line infection with this knockout mutant showed increased expression of pro-inflammatory cytokines. This knockout mutant is sensitive to oxidative, nitrogen, redox and electron transport inhibitor stress agents. Drug susceptibility testing of the deletion mutant showed resistance to first-line drugs such as streptomycin and ethambutol and second-line aminoglycosides such as amikacin and kanamycin. Based on interactorme analysis for Rv0148 using STRING database, we identified 220 most probable interacting partners for Htdy protein. In the Rv0148 knockout mutants, high expression of htdy was observed and we hypothesize that this would have perturbed the interactome thus resulting in drug resistance. Finally, we propose that Rv0148 and Htdy are functionally interconnected and involved in drug resistance and cell homeostasis of M. tuberculosis. Conclusions Our study suggests that Rv0148 plays a significant role in various functional aspects such as intermediatory metabolism, stress, homeostasis and also in drug resistance.
|
|
| 4. |
- Dadar, M., et al.
(författare)
-
Investigation of mutations in the rifampin-resistance-determining region of the rpob gene of brucella melitensis by gene analysis
- 2021
-
Ingår i: Jundishapur Journal of Microbiology. - : Briefland. - 2008-3645 .- 2008-4161. ; 14:2
-
Tidskriftsartikel (refereegranskat)abstract
- Background: RNA polymerase beta subunit (rpoB) gene analysis in bacterial communities is known as a method for determining rifampin sensitivity and genetic diversity among Brucella spp. Detection of antibiotic resistance among Brucella isolates can be a critical approach to control brucellosis. However, rpoB gene analysis of Brucella melitensis for assessing rifampicin resistance has not yet been performed in Iran, which is considered an endemic area for brucellosis. Objectives: The aim of this study was to analyze the whole sequence of rpoB genes of different B. melitensis isolates from humans to identify the single-nucleotide polymorphisms (SNPs) and mutations related to rifampin resistance and to analyze the genetic diversity of these bacteria in Iran. Methods: Between 2017 and 2019, a total of 156 blood samples along with 12 synovial fluid specimens were collected from brucellosis patients in different Iranian provinces and subjected to bacterial culture in Brucella selective media. Brucella identification was carried out using classical biotyping and molecular examinations. Polymerase chain reaction (PCR)-based amplification of the rpoB gene was performed by specific rpoB primers for whole gene sequencing. The antimicrobial susceptibility of Brucella isolates was assessed using disk diffusion susceptibility tests and minimal inhibitory concentration (MIC) methods. The presence of rifampinbinding sites and SNPs were investigated through rpoB whole gene sequencing. Results: Clinical B. melitensis isolates were obtained from blood (13) and synovial fluid (1) samples of patients from different regions of Iran. The results of MIC and disk diffusion susceptibility tests showed that all the isolates were sensitive to rifampin except for one isolate showing intermediate rifampin resistance based on the standards defined for slow-growing bacteria by the Clinical and Laboratory Standards Institute (CLSI). Gene analysis for identifying the mutations related to rifampin resistance and investigating genetic diversity showed that none of the B. melitensis isolates had missense mutations, confirming the susceptibility of all the studied isolates to rifampin. Conclusions: The present study revealed that rpoB gene analysis could be used for the efficient and precise identifying of the mutations related to rifampin resistance, investigating rifampin binding sites, and genotyping Brucella species. Furthermore, the identification of B. melitensis isolates with intermediate resistance to rifampicin highlighted the importance of periodically carrying out antibiotic susceptibility testing. The molecular detection of rpoB mutations in different Brucella isolates may help to prevent the spread of rifampin-resistant Brucella spp. among humans and livestock. © 2021, Author(s).
|
|
| 5. |
|
|
| 6. |
- Griswold, Max G., et al.
(författare)
-
Alcohol use and burden for 195 countries and territories, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016
- 2018
-
Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 392:10152, s. 1015-1035
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older.Methods: Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health.Findings: Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2.2% (95% uncertainty interval [UI] 1.5-3.0) of age-standardised female deaths and 6.8% (5.8-8.0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3.8% (95% UI 3.2-4-3) of female deaths and 12.2% (10.8-13-6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2.3% (95% UI 2.0-2.6) and male attributable DALYs were 8.9% (7.8-9.9). The three leading causes of attributable deaths in this age group were tuberculosis (1.4% [95% UI 1. 0-1. 7] of total deaths), road injuries (1.2% [0.7-1.9]), and self-harm (1.1% [0.6-1.5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27.1% (95% UI 21.2-33.3) of total alcohol-attributable female deaths and 18.9% (15.3-22.6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0.0-0.8) standard drinks per week.Interpretation: Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption.
|
|
| 7. |
- Hassan, Sameer, et al.
(författare)
-
Computational approach identifies protein off-targets for Isoniazid-NAD adduct: hypothesizing a possible drug resistance mechanism in Mycobacterium tuberculosis
- 2020
-
Ingår i: Journal of Biomolecular Structure & Dynamics. - : Informa UK Limited. - 0739-1102 .- 1538-0254. ; 38:6
-
Tidskriftsartikel (refereegranskat)abstract
- Isoniazid is an important antitubercular molecule identified as a drug of choice in tuberculosis treatment. As such, INH is an inactive prodrug; it acquires an active conformation by forming an adduct with NAD. The adduct targets inhA protein, a reductase responsible for fatty acid chain elongation in the cell wall of Mycobacterium tuberculosis. Resistance to INH is majorly contributed by mutations in inhA, katG and geneic and non-geneic regions associated with efflux genes. Despite being widespread, the mechanism of resistance remains unknown in similar to 15% of INH-resistant strains. Studies report that an intracellular increase in NADH concentration prevents inhA inhibition, leading to INH resistance. In the pursuit of finding possible resistance mechanisms, we set out to find NAD binding proteins to explore similarities in structure and NAD binding property of these proteins with that of inhA. We identified 172 NAD binding proteins, of which 53 were identified to have sequence or structural similarity to inhA. By performing docking analysis on selected proteins, we identified INH-adduct to have good binding affinity despite very minimal structural similarity to inhA. This analysis was further supported by principal component analysis, which identified 65 proteins with NAD binding conformation similar to that of inhA. These findings prompt us to hypothesize that upon exposure to INH, bacteria tries to reduce inhA susceptibility by inducing expression of these NAD binding proteins through increase in NADH concentration. This in turn favours off-target binding and leads to decreased binding and potency of INH, thus contributing indirectly to INH resistance.
|
|
| 8. |
- Hassan, Sameer, et al.
(författare)
-
Elucidation of ligand binding and dimerization of NADPH:protochlorophyllide (Pchlide) oxidoreductase from pea (Pisum sativum L.) by structural analysis and simulations
- 2021
-
Ingår i: Proteins-Structure Function and Bioinformatics. - : Wiley. - 0887-3585 .- 1097-0134. ; 89:10, s. 1300-1314
-
Tidskriftsartikel (refereegranskat)abstract
- NADPH:protochlorophyllide (Pchlide) oxidoreductase (POR) is a key enzyme of chlorophyll biosynthesis in angiosperms. It is one of few known photoenzymes, which catalyzes the light-activated trans-reduction of the C17-C18 double bond of Pchlide's porphyrin ring. Due to the light requirement, dark-grown angiosperms cannot synthesize chlorophyll. No crystal structure of POR is available, so to improve understanding of the protein's three-dimensional structure, its dimerization, and binding of ligands (both the cofactor NADPH and substrate Pchlide), we computationally investigated the sequence and structural relationships among homologous proteins identified through database searches. The results indicate that alpha 4 and alpha 7 helices of monomers form the interface of POR dimers. On the basis of conserved residues, we predicted 11 functionally important amino acids that play important roles in POR binding to NADPH. Structural comparison of available crystal structures revealed that they participate in formation of binding pockets that accommodate the Pchlide ligand, and that five atoms of the closed tetrapyrrole are involved in non-bonding interactions. However, we detected no clear pattern in the physico-chemical characteristics of the amino acids they interact with. Thus, we hypothesize that interactions of these atoms in the Pchlide porphyrin ring are important to hold the ligand within the POR binding site. Analysis of Pchlide binding in POR by molecular docking and PELE simulations revealed that the orientation of the nicotinamide group is important for Pchlide binding. These findings highlight the complexity of interactions of porphyrin-containing ligands with proteins, and we suggest that fit-inducing processes play important roles in POR-Pchlide interactions.
|
|
| 9. |
- Hassan, Sameer, et al.
(författare)
-
Evolution and identification of DREB transcription factors in the wheat genome: modeling, docking and simulation of DREB proteins associated with salt stress
- 2022
-
Ingår i: Journal of Biomolecular Structure & Dynamics. - : Informa UK Limited. - 0739-1102 .- 1538-0254. ; 40:16, s. 7191-7204
-
Tidskriftsartikel (refereegranskat)abstract
- Soil salinity and the resulting salt stress it imposes on crop plants is a major problem for modern agriculture. Understanding how salt tolerance mechanisms in plants are regulated is therefore important. One regulatory mechanism is the APETALA2/Ethylene Responsive Factor (AP2/ERF) transcription factor family, including dehydration responsive element binding (DREB) transcription factors. By binding to DNA, specifically upstream of genes that play roles in salt tolerance pathways, DREB proteins upregulate expression of these genes. DREB in Triticum aestivum (wheat) cluster in sub-groups and in this study by scanning the recently extended predicted proteome of wheat for DREB, we increased the number of members of this sub-family. Using the wheat genome, we identified 576 genes coding for the AP2 domain of which 508 were identified to have one AP2 domain, a characteristic of the DREB/ERF subfamily. We confirmed the existing four sub-groups by sequence-based phylogenetic analyses but also identified 32 new DREB subfamily members, not belonging to any known sub-group. Transcription factor profile inference analysis identified two genes, TraesCS2B02G002700 and TraesCS2D02G015200, being homologous to DREB1A of Arabidopsis thaliana. Based on molecular simulation (25 ns) analysis, TraesCS2B02G002700 with a CCGAC motif was observed to interact very stably with DNA. In silico mutational analysis at the 19(th) position in the DREB domain of TraesCS2B02G002700-DNA complex indicated this as a stable part for recognizing and forming interaction with DNA. Moreover, six target genes were predicted having an upstream CCGAC motif regulated by TraesCS2B02G002700. Our study provides an overall framework for exploring the transcription factors in plants and identifying e.g. potential salt stress target genes. Communicated by Ramaswamy H. Sarma
|
|
| 10. |
- Hassan, Sameer, et al.
(författare)
-
In silico based screening of WRKY genes for identifying functional genes regulated by WRKY under salt stress
- 2019
-
Ingår i: Computational Biology and Chemistry. - : Elsevier BV. - 1476-9271. ; 83
-
Tidskriftsartikel (refereegranskat)abstract
- Soil salinization is an increasing global threat to economically important agricultural crops such as bread wheat (Triticum aestivum L.). A main regulator of plants’ responses to salt stress is WRKY transcription factors, a protein family that binds to DNA and alters the rate of transcription for specific genes. In this study, we identified 297 WRKY genes in the Chinese Spring wheat genome (Ensembl Plants International Wheat Genome Sequencing Consortium (IWGSC)), of which 126 were identified as putative. We classified 297 WRKY genes into three Groups: I, II (a–e) and III based on phylogenetic analysis. Principal component analysis (PCA) of WRKY proteins using physicochemical properties resulted in a very similar clustering as that observed through phylogenetic analysis. The 5‘ upstream regions (−2 000 bp) of 107 891 sequences from the wheat genome were used to predict WRKY transcription factor binding sites, and from this we identified 31 296 genes with putative WRKY binding motifs using the Find Individual Motif Occurrences (FIMO) tool. Among these predicted genes, 47 genes were expressed during salt stress according to a literature survey. Thus, we provide insight into the structure and diversity of WRKY domains in wheat and a foundation for future studies of DNA-binding specificity and for analysis of the transcriptional regulation of plants’ response to different stressors, such as salt stress, as addressed in this study. © 2019 Elsevier Ltd
|
|
