Publications by authors named "Muhammad Mirza"

108 Publications

Structural probing of HapR to identify potent phytochemicals to control Vibrio cholera through integrated computational approaches.

Comput Biol Med 2021 11 9;138:104929. Epub 2021 Oct 9.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China; Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nashan District, Shenzhen, Guangdong, PR China; State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China. Electronic address:

Cholera is a severe small intestine bacterial disease caused by consumption of water and food contaminated with Vibrio cholera. The disease causes watery diarrhea leading to severe dehydration and even death if left untreated. In the past few decades, V. cholerae has emerged as multidrug-resistant enteric pathogen due to its rapid ability to adapt in detrimental environmental conditions. This research study aimed to design inhibitors of a master virulence gene expression regulator, HapR. HapR is critical in regulating the expression of several set of V. cholera virulence genes, quorum-sensing circuits and biofilm formation. A blind docking strategy was employed to infer the natural binding tendency of diverse phytochemicals extracted from medicinal plants by exposing the whole HapR structure to the screening library. Scoring function criteria was applied to prioritize molecules with strong binding affinity (binding energy < -11 kcal/mol) and as such two compounds: Strychnogucine A and Galluflavanone were filtered. Both the compounds were found favourably binding to the conserved dimerization interface of HapR. One rare binding conformation of Strychnogucine A was noticed docked at the elongated cavity formed by α1, α4 and α6 (binding energy of -12.5 kcal/mol). The binding stability of both top leads at dimer interface and elongated cavity was further estimated using long run of molecular dynamics simulations, followed by MMGB/PBSA binding free energy calculations to define the dominance of different binding energies. In a nutshell, this study presents computational evidence on antibacterial potential of phytochemicals capable of directly targeting bacterial virulence and highlight their great capacity to be utilized in the future experimental studies to stop the evolution of antibiotic resistance evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.compbiomed.2021.104929DOI Listing
November 2021

Determination of pesticide residues in dates using UHPLC-QqQ-MS/MS: method development and validation.

Environ Monit Assess 2021 Sep 1;193(9):613. Epub 2021 Sep 1.

Ecotoxicology Research Program (ERP), National Agricultural Research Center (NARC), Islamabad, 44000, Pakistan.

A modified, efficient, and sensitive acetate-buffered QuEChERS extraction method was developed for the quantitative study of 16 commonly applied multiclass pesticides on date palm fruit. The date palm fruit samples were rehydrated by adding water during comminution. Samples were extracted with acidified acetonitrile, buffered with acetate salt. To minimize the matrix interferences, clean-up of the rehydrated samples was optimized by comparison with different sorbents (alumina, silica gel, florisil, primary secondary amine (PSA), and chitosan). The method validation parameters were evaluated as per European Union (EU) guidelines (SANTE/12682/2019). For 16 pesticides, % recovery of 69 to 121.8% with an associated precision (RSD ≤ 20%) was achieved at the fortification levels that were 0.5 to 2 times of European Union maximum residue limits (EU-MRLs). The validated method was successfully employed for the analysis of date palm fruit samples (n = 20) collected from various markets. Forty percent (40%) of samples (n = 8) were found to be contaminated with various pesticides. The most frequently detected residues were carbofuran, carbaryl, metalaxyl, tebuconazole, triazophos, and pyriproxyfen. The concentration of all the detected pesticides in real samples was below the EU-MRLs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10661-021-09361-yDOI Listing
September 2021

A rare report of Rothia dentocariosa endocarditis.

J Community Hosp Intern Med Perspect 2021 10;11(3):413-415. Epub 2021 May 10.

Department of Internal Medicine, Trinitas Regional Medical Center, Elizabeth NJ.

Rothia species are gram positive, round to rod-shaped bacteria that are normally oral and respiratory tract flora. They were first isolated in 1967 from dental caries. We present a 69-year-old male with no risk factors for aforementioned bacteria however was found to have thickened anterior leaflet of the mitral valve with a small isoechoic lesion consistent with vegetation on Transthoracic echocardiogram. Blood cultures grew pan sensitive Rothia dentocariosa. Patient was treated with long-term antibiotics. This case adds to the limited number of cases of Rothia dentocariosa Endocarditis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/20009666.2021.1880539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118413PMC
May 2021

Development of a Novel Multi-Epitope Vaccine Against Crimean-Congo Hemorrhagic Fever Virus: An Integrated Reverse Vaccinology, Vaccine Informatics and Biophysics Approach.

Front Immunol 2021 16;12:669812. Epub 2021 Jun 16.

College of Life Science and Technology, Guangxi University, Nanning, China.

Crimean-Congo hemorrhagic fever (CCHF) is a highly severe and virulent viral disease of zoonotic origin, caused by a tick-born CCHF virus (CCHFV). The virus is endemic in many countries and has a mortality rate between 10% and 40%. As there is no licensed vaccine or therapeutic options available to treat CCHF, the present study was designed to focus on application of modern computational approaches to propose a multi-epitope vaccine (MEV) expressing antigenic determinants prioritized from the CCHFV genome. Integrated computational analyses revealed the presence of 9 immunodominant epitopes from Nucleoprotein (N), RNA dependent RNA polymerase (RdRp), Glycoprotein N (Gn/G2), and Glycoprotein C (Gc/G1). Together these epitopes were observed to cover 99.74% of the world populations. The epitopes demonstrated excellent binding affinity for the B- and T-cell reference set of alleles, the high antigenic potential, non-allergenic nature, excellent solubility, zero percent toxicity and interferon-gamma induction potential. The epitopes were engineered into an MEV through suitable linkers and adjuvating with an appropriate adjuvant molecule. The recombinant vaccine sequence revealed all favorable physicochemical properties allowing the ease of experimental analysis and . The vaccine 3D structure was established . Furthermore, the vaccine displayed excellent binding affinity for critical innate immune receptors: TLR2 (-14.33 kcal/mol) and TLR3 (-6.95 kcal/mol). Vaccine binding with these receptors was dynamically analyzed in terms of complex stability and interaction energetics. Finally, we speculate the vaccine sequence reported here has excellent potential to evoke protective and specific immune responses subject to evaluation of downstream experimental analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.669812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242340PMC
October 2021

Use of simulation based technology in pre-clinical years improves confidence and satisfaction among medical students.

J Pak Med Assoc 2021 Apr;71(4):1296-1302

Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan.

Objective: To determine perception of medical students about learning from integrated simulated clinical skill sessions as part of the undergraduate curriculum.

Methods: The cross-sectional study was conducted at the Centre for Innovation in Medical Education, Aga Khan University (AKU), Karachi, from July 2018 to February 2019, and comprised first year medical students undertaking the Respiration and Circulation module of the curriculum. Quantitative data was collected using a questionnaire and the responses were assessed on a five-point Likert scale. Data was analysed using SPSS 21. Qualitative data was gathered through focused group discussion with students and an in-depth interview with the facilitator conducting the sessions. The data was subjected to thematic analyses.

Results: Of the 161 subjects, 71(44%) participated in the session I and 90(56%) in the session II. Altogether 68(96%) students in session I and 81(90%) in session II believed integrated sessions to be effective in achieving learning objectives, and 65(92%) in session I and 79(88 %) in session II found them motivating, while 61(86%) in session I and 76(84%) in session II expressed the confidence that they had accomplished learning objectives and felt they had learned practical clinical skills; session I, 59(84%), session II, 73(81%). Qualitative analysis revealed that these sessions enhanced understanding of the subject matter and student engagement.

Conclusions: Integrated clinical skills sessions improved students' interest, engagement and confidence. It should be implemented in undergraduate medical teaching curriculum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.47391/JPMA.1152DOI Listing
April 2021

Toxicological Screening of 4-Phenyl-3,4-dihydrobenzo[]quinolin-2(1)-one: A New Potential Candidate for Alzheimer's Treatment.

ACS Omega 2021 Apr 16;6(16):10897-10909. Epub 2021 Apr 16.

Drug Design and Development Research Group (DDDRG), Department of Chemistry, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia.

Toxicity studies are necessary for the development of a new drug. Naphthalene is a bicyclic molecule and is easy to derivatize. In our previous study, a derivative of naphthalene (4-phenyl,3,4-dihydrobenzoquinoline-2()one) was synthesized and reported its in vitro activity on different enzymes. This study was a probe to investigate the toxicity potential of that compound (SF3). Acute oral (425), subacute (407), and teratogenicity (414) studies were planned according to their respective guidelines given by organization of economic cooperation and development (OECD). Acute oral, subacute, and teratogenicity studies were carried out on 2000, 5-40, and 40 mg/kg doses. Blood samples were collected for hematological and biochemical analyses. Vital organs were excised for oxidative stress (superoxide dismutase, catalase, glutathione, and malondialdehyde) and histopathological analysis. of SF3 was higher than 2000 mg/kg. In acute and subacute studies, levels of alkaline phosphates and aspartate transaminase were increased. Teratogenicity showed no resorptions, no skeletal or soft tissue abnormalities, and no cleft pallet. Oxidative stress biomarkers were close to the normal, and no increase in the malondialdehyde level was seen. Histopathological studies revealed normal tissue architecture of the selected organs, except kidney, in acute oral and subacute toxicity studies at 40 mg/kg. The study concluded that SF3 is safer if used as a drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.1c00654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153932PMC
April 2021

Toxicity Evaluation of the Naphthalen-2-yl 3,5-Dinitrobenzoate: A Drug Candidate for Alzheimer Disease.

Front Pharmacol 2021 10;12:607026. Epub 2021 May 10.

Department of Chemistry, Faculty of Science, Universiti Malaya, Kuala Lumpur, Malaysia.

The presented study was designed to probe the toxicity potential of newly identified compound naphthalen-2-yl 3,5-dinitrobenzoate (SF1). Acute, subacute toxicity and teratogenicity studies were performed as per Organization of economic cooperation and development (OECD) 425, 407, and 414 test guidelines, respectively. An oral dose of 2000 mg/kg to rats for acute toxicity. Furthermore, 5, 10, 20, and 40 mg/kg doses were administered once daily for 28 days in subacute toxicity study. Teratogenicity study was performed with 40 mg/kg due to its excellent anti-Alzheimer results at this dose. SF1 induced a significant rise in Alkaline Phosphatases (ALP), bilirubin, white blood cells (WBC), and lymphocyte levels with a decrease in platelet count. Furthermore, the reduction in urea, uric acid, and aspartate transaminase (AST) levels and an increase in total protein levels were measured in subacute toxicity. SF1 increased spermatogenesis at 5 and 10 mg/kg doses. Teratogenicity study depicted no resorptions, early abortions, cleft palate, spina bifida and any skeletal abnormalities in the fetuses. Oxidative stress markers (Superoxide dismutase (SOD), Catalase (CAT), and glutathione (GSH) were increased in all the experiments, whereas the effect on melanoaldehyde Malondialdehyde (MDA) levels was variable. Histopathology further corroborated these results with no change in the architectures of selected organs. Consequently, a 2000 mg/kg dose of SF1 tends to induce minor liver dysfunction along with immunomodulation, and it is well below its . Moreover, it can be safely used in pregnancy owing to its no detectable teratogenicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.607026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141749PMC
May 2021

Postoperative biliary anastomotic strictures after pancreaticoduodenectomy.

HPB (Oxford) 2021 11 27;23(11):1716-1721. Epub 2021 Apr 27.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Biliary anastomotic stricture (BAS) is an uncommon complication of pancreaticoduodenectomy (PD). As PDs are performed more frequently, BAS may become a more common pathologic entity requiring clinical engagement. The aim of this study was to report the incidence of BAS in the modern era of pancreatic surgery and identify risk factors associated with it.

Methods: Patients undergoing PD at the Johns Hopkins Hospital between 2007 and 2016 were identified using an institutional registry and clinicopathological features were analyzed to identify risk factors associated with BAS.

Results: Of 2125 patients identified, 103 (4.9%) developed BAS. Factors independently associated with BAS included laparoscopic approach (HR:2.83,95%CI:1.35-5.92, p = 0.006), postoperative pancreatic fistula (HR:2.45,95%CI:1.56-4.16,p < 0.001), postoperative bile leak (BL) (HR:5.26,95%CI:2.45-11.28,p < 0.001), and administration of adjuvant radiation therapy (HR:6.01,95%CI:3.19-11.34,p < 0.001). Malignant pathology was associated with lower rates of BAS (HR:0.52,95%CI:0.30-0.92, p = 0.025). BL was associated with higher rates of early-BAS (HR:16.49,95%CI:3.28-82.94, p = 0.001) while use of Vicryl suture for biliary enteric anastomosis was associated with lower rates of early-BAS (HR:0.20,95%CI:0.05-0.93, p = 0.041).

Conclusion: Approximately 5% of patients undergoing PD experience BAS. Multiple factors are associated with the development and timing of BAS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hpb.2021.04.008DOI Listing
November 2021

New isolate from Salvinia molesta with antioxidant and urease inhibitory activity.

Drug Dev Res 2021 Dec 13;82(8):1169-1181. Epub 2021 May 13.

Drug Design Development Research Group, Department of Chemistry, Universiti Malaya, Kuala Lumpur, Malaysia.

Urease plays a significant role in the pathogenesis of urolithiasis pyelonephritis, urinary catheter encrustation, hepatic coma, hepatic encephalopathy, and peptic acid duodenal ulcers. Salvinia molesta was explored to identify new bioactive compounds with particular emphasis on urease inhibitors. The aqueous methanol extract was fractionated using solvents of increasing polarity. A series of column chromatography and later HPLC were performed on butanol extract. The structures of the resulting pure compounds were resolved using NMR (1D and 2D), infrared, and mass spectroscopy. The novel isolate was evaluated for antioxidant activity (using DPPH, superoxide anion radical scavenging, oxidative burst, and Fe chelation assays), anti-glycation behavior, anticancer activity, carbonic anhydrase inhibition, phosphodiesterase inhibition, and urease inhibition. One new glucopyranose derivative 6'-O-(3,4-dihydroxybenzoyl)-4'-O-(4-hydroxybenzoyl)-α/β-D-glucopyranoside (1) and four known glycosides were identified. Glycoside 1 demonstrated promising antioxidant potential with IC values of 48.2 ± 0.3, 60.3 ± 0.6, and 42.1 ± 1.8 μM against DPPH, superoxide radical, and oxidative burst, respectively. Its IC in the Jack bean urease inhibition assay was 99.1 ± 0.8 μM. The mechanism-based kinetic studies presented that compound 1 is a mixed-type inhibitor of urease with a K value of 91.8 ± 0.1 μM. Finally, molecular dynamic simulations exploring the binding mode of compound 1 with urease provided quantitative agreement between estimated binding free energies and the experimental results. The studies corroborate the use of compound 1 as a lead for QSAR studies as an antioxidant and urease inhibitor. Moreover, it needs to be further evaluated through the animal model, that is, in vivo or tissue culture-based ex-vivo studies, to establish their therapeutic potential against oxidative stress phosphodiesterase-II and urease-induced pathologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ddr.21831DOI Listing
December 2021

Designing multi-epitope vaccine against Staphylococcus aureus by employing subtractive proteomics, reverse vaccinology and immuno-informatics approaches.

Comput Biol Med 2021 05 15;132:104389. Epub 2021 Apr 15.

College of Life Science and Technology, Guangxi University, Nanning, PR China. Electronic address:

Staphylococcus aureus is a deadly human bacterial pathogen that causes a wide variety of clinical manifestations. Invasive S. aureus infections in hospitals and the community are one of the main causes of mortality and morbidity, as virulent and multi-drug-resistant strains have evolved. There is an unmet and urgent clinical need for immune-based non-antibiotic approaches to treat these infections as the growing antibiotic resistance poses a significant public health danger. Subtractive proteomics assisted reverse vaccinology-based immunoinformatics pipeline was used in this study to target the suitable antigenic proteins for the development of multi-epitope vaccine (MEV). Three essential virulent and antigenic proteins were identified including Glycosyltransferase, Elastin Binding Protein, and Staphylococcal secretory antigen. A variety of immunoinformatics tools have been used to forecast T-cell and B-cell epitopes from target proteins. Seven CTL, five HTL, and eight LBL epitopes, connected through suitable linkers and adjuvant, were employed to design 444 amino acids long MEV construct. The vaccine was paired with the TLR4 agonist 50S ribosomal protein L7/L12 adjuvant to enhance the immune response towards the vaccine. The predicted MEV structure was assessed to be highly antigenic, non-toxic, non-allergenic, flexible, stable, and soluble. Molecular docking simulation of the MEV with the human TLR4 (toll-like receptor 4) and major histocompatibility complex molecules (MHCI and MHCII) was performed to validate the interactions with the receptors. Molecular dynamics (MD) simulation and MMGBSA binding free energy analyses were carried out for the stability evaluation and binding of the MEV docked complexes with TLR4, MHCI and MHCII. To achieve maximal vaccine protein expression with optimal post-translational modifications, MEV was reverse translated, its mRNA structure was analyzed, and finally in silico cloning was performed into E. coli expression host. These rigorous computational analyses supported the effectivity of proposed MEV in protection against infections associated with S. aureus. However, further experimental validations are required to fully evaluate the potential of proposed vaccine candidate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.compbiomed.2021.104389DOI Listing
May 2021

Development of a hybrid framework for inventory leanness in Technical Services Organizations.

PLoS One 2021 19;16(2):e0247144. Epub 2021 Feb 19.

Department of Engineering Management, College of Electrical and Mechanical Engineering, National University of Sciences & Technology (NUST), Islamabad, Pakistan.

Inherent uncertainties in demand and supply make it problematic for supply chains to accomplish optimum inventory replenishment, resulting in loss of sales or keeping excessive inventories. To cope with erratic demands, organizations have to maintain excessive inventory levels, sometimes taking up to one-third of an organization's annual budget. The two most pressing concerns to handle in inventory management are: how much to order and when to order. Therefore, an organization ought to make the correct and timely decisions based on precise demand information to avoid excessive inventory accumulation resulting in enhanced competitive advantage. Owing to the significance of inventory control and analysis, this paper reports on developing and successfully implementing a hybrid framework for optimum level inventory forecasting in Technical Services Organizations. The proposed framework is based on a case study of one of Pakistan's leading Technical Services Organization. The paper presents a statistical analysis of historical data and a comprehensive fault trend analysis. Both these analyses set a solid foundation for the formulation of a comparative analysis matrix based upon price and quantity based analysis of inventory. Finally, a decision criterion (Forecasting Model) is proposed using three primary forecasting techniques with minimum error calculations. The study's finding shows a forecast error of 142.5 million rupees in the last five years, resulting in the accumulation of more than 25 thousand excessive inventory stock. Application of price and quantity based analysis identifies that 65% of the annual budget is significantly dependent upon only 9% (in terms of quantity) of "High Price and Small Quantity" Items (HS). These HS items are forecasted through three different forecasting methods, i.e., Weighted Moving Average, Exponential Smoothing, and Trend Projection, with Minimum Absolute Deviation to significantly reduce the forecasting error while predicting the future required quantity. The research work aims to contribute to the inventory management literature in three ways. First, a new comparative analysis matrix concept for identifying the most critical items is introduced. Second, a Multi-Criteria Forecasting Model is developed to capture a wide range of operations. Third, the paper suggests how these forecasting criteria can be integrated into a single interactive DSS to maintain optimum inventory level stock. Even though the DSS framework is based on data from a single organization, the application is expected to manage inventory stock in a wide range of manufacturing and services industries. This study's proposed hybrid framework is the first of its kind that encapsulates all four dimensions of inventory classification criteria, forming a multi-criteria hybrid model within a DSS framework.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247144PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895359PMC
August 2021

Seed inoculation of desert-plant growth-promoting rhizobacteria induce biochemical alterations and develop resistance against water stress in wheat.

Physiol Plant 2021 Jun 18;172(2):990-1006. Epub 2021 Feb 18.

National Institute for Biotechnology and Genetic Engineering (NIBGE) P.O. Box 577 Jhang Road, Faisalabad, Pakistan.

Water shortage limits agricultural productivity, so strategies to get higher yields in dry agricultural systems is vital to circumvent the effect of climate change and land-shortage. The plant rhizosphere harbors beneficial bacteria able to confer biotic/abiotic tolerance along with a positive impact on plant growth. Herein, three bacterial strains, Proteus mirabilis R2, Pseudomonas balearica RF-2 and Cronobacter sakazakii RF-4 (accessions: LS975374, LS975373, LS975370, respectively) isolated from native desert-weeds were investigated for their response to improve wheat growth under drought stress. The bacteria showed drought tolerance up to 20% polyethylene glycol (PEG; -0.6 MPa), and salt (65-97 g l ), 1-aminocyclopropane-1-carboxylate (ACC)-deaminase activity, P/Zn/K-solubilization, calcite degradation, IAA, and siderophore production. The plant growth-promoting rhizobacteria (PGPR) were evaluated on wheat under water stress. The P. balearica strain RF-2 primed seeds showed a maximum promptness index and germination index under PEG-stress, that is, 68% and 100%, respectively. Inoculation significantly improved plant growth, leaf area, and biomass under water stress. P. mirabilis R2 inoculated plant leaves showed the highest water contents as compared to the plants inoculated with other strains. C. sakazakii RF-4 inoculated plants showed minimum cell injury, electrolyte leakage, and maximum cell membrane stability at PEG stress. After 13 days exposure to drought, C. sakazakii RF-4 treated plants showed an overall higher expression of cytosolic ascorbate peroxidase (cAPX) and ribulose-bisphosphate carboxylase (rbcL) genes. The activity of stress-induced catalase and polyphenol oxidase was reduced, while that of peroxidase and superoxide dismutase increased after inoculation but the response was temporal. Taken together, this data explains that different PGPR (especially C. sakazakii RF-4) modulate differential responses in wheat that eventually leads towards drought tolerance, hence, it has the potential to enhance crop production in arid regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ppl.13362DOI Listing
June 2021

Effect of multi-pronged interventions in reducing low birth weight and maternal anaemia among pregnant women. A community-based interventions research in non-agrarian resource constrained setting of rural Pakistan.

J Pak Med Assoc 2020 Dec;70(12(A)):2092-2101

Health and Nutrition Development Society, Karachi, Pakistan.

Objective: To investigate the effect on maternal and infant health of iron plus folate and multiple micronutrient supplements, along with deworming and health education session provided to pregnant women in rural, nonagrarian and food-insecure areas.

Methods: The quasi-experimental study was conducted in Tharparker and Umerkot districts, Sindh, Pakistan, in 2013-14, and comprised pregnant women in their earlier weeks of pregnancy. The enrolment and follow-up phase entailed 3 visits to each subject. Areas covered by lady health workers were designated as intervention areas, and those with non-LHW population were labelled as non-intervention areas.

Results: Of the 1204 subjects, 600(49.8%) were in the intervention group and 604(50.2%) were in the nonintervention group. By the end of the follow-up phase, significantly more women had increased number of meals in the intervention group compared to the non-intervention group (p<0.001). There was a significantly higher increase in mean haemoglobin levels and body mass index of women in the intervention arm after 3 and 6 months of interventions (p<0.05). Significantly higher mean birth weight was recorded in intervention areas compared to nonintervention areas (p<0.05).

Conclusions: Community-based provision of multiple micronutrients to women along with deworming, health education and dietary counselling significantly reduced the prevalence of anaemia and reduced the incidence of low birth weight.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.47391/JPMA.1218DOI Listing
December 2020

Effect of Berberis vulgaris L. root extract on ifosfamide-induced in vivo toxicity and in vitro cytotoxicity.

Sci Rep 2021 01 18;11(1):1708. Epub 2021 Jan 18.

Drug Design and Development Research Group, Department of Chemistry, Faculty of Science, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.

Ifosfamide is a widely used chemotherapeutic agent having broad-spectrum efficacy against several tumors. However, nephro, hepato, neuro cardio, and hematological toxicities associated with ifosfamide render its use limited. These side effects could range from organ failure to life-threatening situations. The present study aimed to evaluate the attenuating efficiency of Berberis vulgaris root extract (BvRE), a potent nephroprotective, hepatoprotective, and lipid-lowering agent, against ifosfamide-induced toxicities. The study design comprised eight groups of Swiss albino rats to assess different dose regimes of BvRE and ifosfamide. Biochemical analysis of serum (serum albumin, blood urea nitrogen, creatinine, alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase, total cholesterol, and triglycerides) along with complete blood count was performed. Kidney, liver, brain, and heart tissue homogenates were used to find malondialdehyde, catalase, and glutathione S-transferase levels in addition to the acetylcholinesterase of brain tissue. The results were further validated with the help of the histopathology of the selected organs. HeLa cells were used to assess the effect of BvRE on ifosfamide cytotoxicity in MTT assay. The results revealed that pre- and post-treatment regimens of BvRE, as well as the combination therapy exhibited marked protective effects against ifosfamide-induced nephro, hepato, neuro, and cardiotoxicity. Moreover, ifosfamide depicted a synergistic in vitro cytotoxic effect on HeLa cells in the presence of BvRE. These results corroborate that the combination therapy of ifosfamide with BvRE in cancer treatment can potentiate the anticancer effects of ifosfamide along with the amelioration of its conspicuous side effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-80579-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814047PMC
January 2021

New naphthalene derivative for cost-effective AChE inhibitors for Alzheimer's treatment: In silico identification, in vitro and in vivo validation.

Comput Biol Chem 2020 Dec 18;89:107378. Epub 2020 Sep 18.

Drug Design and Development Research Group (DDDRG), Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia. Electronic address:

Neurodegenerative diseases have complex etiology and pose a challenge to scientists to develop simple and cost-effective synthetic compounds as potential drug candidates for such diseases. Here, we report an extension of our previously published in silico screening, where we selected four new compounds as AChE inhibitors. Further, based on favorable binding possess, MD simulation and MMGBSA, two most promising compounds (3a and 3b) were selected, keeping in view the ease of synthesis and cost-effectiveness. Due to the critical role of BChE, LOX and α-glucosidase in neurodegeneration, the selected compounds were also screened against these enzymes. The IC values of 3a against AChE and BChE found to be 12.53 and 352.42 μM, respectively. Moderate to slight inhibitions of 45.26 % and 28.68 % were presented by 3a against LOX and α-glucosidase, respectively, at 0.5 mM. Insignificant inhibitions were observed with 3b against the four selected enzymes. Further, in vivo trial demonstrated that 3a could significantly diminish AChE levels in the mice brain as compared to the control. These findings were in agreement with the histopathological analysis of the brain tissues. The results corroborate that selected compounds could serve as a potential lead for further development and optimization as AChE inhibitors to achieve cost-effective anti-Alzheimer's drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.compbiolchem.2020.107378DOI Listing
December 2020

Identification of novel human USP2 inhibitor and its putative role in treatment of COVID-19 by inhibiting SARS-CoV-2 papain-like (PLpro) protease.

Comput Biol Chem 2020 Dec 13;89:107376. Epub 2020 Sep 13.

Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Medicinal Chemistry, University of Leuven, B-3000, Leuven, Belgium. Electronic address:

Human ubiquitin carboxyl-terminal hydrolase-2 (USP2) inhibitors, such as thiopurine analogs, have been reported to inhibit SARS-CoV papain-like proteases (PLpro). The PLpro have significant functional implications in the innate immune response during SARS-CoV-2 infection and considered an important antiviral target. Both proteases share strikingly similar USP fold with right-handed thumb-palm-fingers structural scaffold and conserved catalytic triad Cys-His-Asp/Asn. In this urgency situation of COVID-19 outbreak, there is a lack of in-vitro facilities readily available to test SARS-CoV-2 inhibitors in whole-cell assays. Therefore, we adopted an alternate route to identify potential USP2 inhibitor through integrated in-silico efforts. After an extensive virtual screening protocol, the best compounds were selected and tested. The compound Z93 showed significant IC value against Jurkat (9.67 μM) and MOTL-4 cells (11.8 μM). The binding mode of Z93 was extensively analyzed through molecular docking, followed by MD simulations, and molecular interactions were compared with SARS-CoV-2. The relative binding poses of Z93 fitted well in the binding site of both proteases and showed consensus π-π stacking and H-bond interactions with histidine and aspartate/asparagine residues of the catalytic triad. These results led us to speculate that compound Z93 might be the first potential chemical lead against SARS-CoV-2 PLpro, which warrants in-vitro evaluations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.compbiolchem.2020.107376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487165PMC
December 2020

A Putative Prophylactic Solution for COVID-19: Development of Novel Multiepitope Vaccine Candidate against SARS-COV-2 by Comprehensive Immunoinformatic and Molecular Modelling Approach.

Biology (Basel) 2020 Sep 18;9(9). Epub 2020 Sep 18.

Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore 54590, Punjab, Pakistan.

The outbreak of 2019-novel coronavirus (SARS-CoV-2) that causes severe respiratory infection (COVID-19) has spread in China, and the World Health Organization has declared it a pandemic. However, no approved drug or vaccines are available, and treatment is mainly supportive and through a few repurposed drugs. The urgency of the situation requires the development of SARS-CoV-2-based vaccines. Immunoinformatic and molecular modelling are time-efficient methods that are generally used to accelerate the discovery and design of the candidate peptides for vaccine development. In recent years, the use of multiepitope vaccines has proved to be a promising immunization strategy against viruses and pathogens, thus inducing more comprehensive protective immunity. The current study demonstrated a comprehensive in silico strategy to design stable multiepitope vaccine construct (MVC) from B-cell and T-cell epitopes of essential SARS-CoV-2 proteins with the help of adjuvants and linkers. The integrated molecular dynamics simulations analysis revealed the stability of MVC and its interaction with human Toll-like receptors (TLRs), which trigger an innate and adaptive immune response. Later, the in silico cloning in a known pET28a vector system also estimated the possibility of MVC expression in . Despite that this study lacks validation of this vaccine construct in terms of its efficacy, the current integrated strategy encompasses the initial multiple epitope vaccine design concepts. After validation, this MVC can be present as a better prophylactic solution against COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biology9090296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563440PMC
September 2020

Discovery of HIV entry inhibitors via a hybrid CXCR4 and CCR5 receptor pharmacophore-based virtual screening approach.

Eur J Pharm Sci 2020 Dec 2;155:105537. Epub 2020 Sep 2.

Medicinal Chemistry, Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium. Electronic address:

Chemokine receptors are key regulators of cell migration in terms of immunity and inflammation. Among these, CCR5 and CXCR4 play pivotal roles in cancer metastasis and HIV-1 transmission and infection. They act as essential co-receptors for HIV and furnish a route to the cell entry. In particular, inhibition of either CCR5 or CXCR4 leads very often the virus to shift to a more virulent dual-tropic strain. Therefore, dual receptor inhibition might improve the therapeutic strategies against HIV. In this study, we aimed to discover selective CCR5, CXCR4, and dual CCR5/CXCR4 antagonists using both receptor- and ligand-based computational methods. We employed this approach to fully incorporate the interaction attributes of the binding pocket together with molecular dynamics (MD) simulations and binding free energy calculations. The best hits were evaluated for their anti-HIV-1 activity against CXCR4- and CCR5-specific NL4.3 and BaL strains. Moreover, the Ca mobilization assay was used to evaluate their antagonistic activity. From the 27 tested compounds, three were identified as inhibitors: compounds 27 (CCR5), 6 (CXCR4) and 3 (dual) with IC values ranging from 10.64 to 64.56 μM. The binding mode analysis suggests that the active compounds form a salt bridge with the glutamates and π-stacking interactions with the aromatic side chains binding site residues of the respective co-receptor. The presented hierarchical virtual screening approach provides essential aspects in identifying potential antagonists in terms of selectivity against a specific co-receptor. The compounds having multiple heterocyclic nitrogen atoms proved to be relatively more specific towards CXCR4 inhibition as compared to CCR5. The identified compounds serve as a starting point for further development of HIV entry inhibitors through synthesis and quantitative structure-activity relationship studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2020.105537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467125PMC
December 2020

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches.

J Pharm Anal 2020 Dec 28;10(6):546-559. Epub 2020 Aug 28.

College of Life Science and Technology, Guangxi University, Nanning, China.

The papain-like protease (PL) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PL, which can be further developed as potential pan-PL based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PL were explored, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease inhibitors database composed of ∼7,000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PL, and showed consistent interaction profile with SARS-CoV PL and MERS-CoV PL as well. Conclusively, the reported SARS-CoV-2 PL specific compounds could serve as seeds for developing potent pan-PL based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpha.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453225PMC
December 2020

Enhanced Thermostability and Enzymatic Activity of Cel6A Variants from by Empirical Domain Engineering (Short Title: Domain Engineering of Cel6A).

Biology (Basel) 2020 Aug 7;9(8). Epub 2020 Aug 7.

Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Medicinal Chemistry, University of Leuven, B-3000 Leuven, Belgium.

Cellulases are a set of lignocellulolytic enzymes, capable of producing eco-friendly low-cost renewable bioethanol. However, low stability and hydrolytic activity limit their wide-scale applicability at the industrial scale. In this work, we report the domain engineering of endoglucanase (Cel6A) of to improve their catalytic activity and thermal stability. Later, enzymatic activity and thermostability of the most efficient variant named as Cel6A.CBC was analyzed by molecular dynamics simulations. This variant demonstrated profound activity against soluble and insoluble cellulosic substrates like filter paper, alkali-treated bagasse, regenerated amorphous cellulose (RAC), and bacterial microcrystalline cellulose. The variant Cel6A.CBC showed the highest catalysis of carboxymethyl cellulose (CMC) and other related insoluble substrates at a pH of 6.0 and a temperature of 60 °C. Furthermore, a sound rationale was observed between experimental findings and molecular modeling of Cel6A.CBC which revealed thermostability of Cel6A.CBC at 26.85, 60.85, and 74.85 °C as well as structural flexibility at 126.85 °C. Therefore, a thermostable derivative of Cel6A engineered in the present work has enhanced biological performance and can be a useful construct for the mass production of bioethanol from plant biomass.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biology9080214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464639PMC
August 2020

Isolation of Antidiabetic Withanolides from Dunal and Their In Vitro and In Silico Validation.

Biology (Basel) 2020 Jul 30;9(8). Epub 2020 Jul 30.

Department of Chemistry, Faculty of Sciences, University Malaya, Kuala Lumpur 50603, Malaysia.

() is well-known in herbal medicinal systems for its high biological potential. Different parts of the plant are used against insomnia, liver complications, asthma, and biliousness, as well as it is reported to be sedative, emetic, diuretic, antidiabetic antimicrobial, anti-inflammatory, antitumor, hepatoprotective, antihyperglycemic, cardiovascular, immuno-suppressive and central nervous system depressant. Withanolides present in have attracted an immense interest in the scientific field due to their diverse therapeutic applications. The current study deals with chemical and biological evaluation of chloroform, and -butanol fractions of . The activity-guided fractionation of both extracts via multiple chromatographic steps and structure elucidation of pure isolates using spectroscopies (NMR, mass spectrometry, FTIR and UV-Vis) led to the identification of a new withanolide glycoside, withacogulanoside-B () from -butanol extract and five known withanolides from chloroform extract [withanolid J (), coagulin E (), withaperuvin C (), 27-hydroxywithanolide I (), and ajugin E ()]. Among the tested compounds, compound was the most potent -glucosidase inhibitor with = 66.7 ± 3.6 µM, followed by compound (: 407 ± 4.5 µM) and compound (: 683 ± 0.94 µM), while no antiglycation activity was observed with the six isolated compounds. Molecular docking was used to predict the binding potential and binding site interactions of these compounds as -glucosidase inhibitors. Consequently, this study provides basis to discover specific antidiabetic compounds from .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biology9080197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464911PMC
July 2020

Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CL.

J Biomol Struct Dyn 2021 08 24;39(13):4936-4948. Epub 2020 Jun 24.

Structural Bioinformatics Laboratory, Faculty of Science and Engineering, Biochemistry, Åbo Akademi University, Turku, Finland.

The SARS-CoV-2 was confirmed to cause the global pandemic of coronavirus disease 2019 (COVID-19). The 3-chymotrypsin-like protease (3CLpro), an essential enzyme for viral replication, is a valid target to combat SARS-CoV and MERS-CoV. In this work, we present a structure-based study to identify potential covalent inhibitors containing a variety of chemical warheads. The targeted Asinex Focused Covalent (AFCL) library was screened based on different reaction types and potential covalent inhibitors were identified. In addition, we screened FDA-approved protease inhibitors to find candidates to be repurposed against SARS-CoV-2 3CLpro. A number of compounds with significant covalent docking scores were identified. These compounds were able to establish a covalent bond (C-S) with the reactive thiol group of Cys145 and to form favorable interactions with residues lining the substrate-binding site. Moreover, paritaprevir and simeprevir from FDA-approved protease inhibitors were identified as potential inhibitors of SARS-CoV-2 3CLpro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CLpro were characterized by molecular dynamics (MD) simulations. The identified compounds are potential inhibitors worthy of further development as COVID-19 drugs. Importantly, the identified FDA-approved anti-hepatitis-C virus (HCV) drugs paritaprevir and simeprevir could be ready for clinical trials to treat infected patients and help curb COVID-19. Communicated by Ramaswamy H. Sarma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07391102.2020.1782768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332866PMC
August 2021

Impact of IL-17F 7488T/C Functional Polymorphism on Progressive Rheumatoid Arthritis: Novel Insight from the Molecular Dynamic Simulations.

Immunol Invest 2021 May 16;50(4):416-426. Epub 2020 Jun 16.

Institute of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan.

Resorption of bones and cartilage coupled with structural changes in the inflamed joints are the major hallmark of rheumatoid arthritis (RA). Genetic polymorphisms in pro-inflammatory interleukins (ILs) appear to play an important role in the susceptibility towards progressive RA. We therefore aimed to investigate the association of single nucleotide polymorphisms (SNP), present in the hotspot coding/promoter regions of IL-6, -17 and -18, with RA susceptibility or severity in a larger study cohort from Pakistan together with finding clues as to how a functional SNP impacts the predisposition towards RA. TaqMan SNP genotyping approach was first used to assess IL-6 (rs1800795), IL-17 F (rs763780), IL-17A (rs2275913), and IL-18 (rs1946518) polymorphisms in 310 subjects (150 RA and 160 control). Molecular dynamic simulations (MDS) of wild- and mutant-type IL-17A with corresponding receptor were thereafter performed using AMBER-16; Chimera 1.13 was used for analyses. Our results showed the association of two SNPs, namely IL-6 - 174 G/C [allelic (OR = 0.960, 95% CI = 0.929-0.992, = .009)] and IL-17 F 7488 T/C [allelic (OR = 0.907, 95%CI = 0.861-0.954, = .000)] with increased RA risk in Pakistani subjects. When mapped, IL-17 F 7488 T/C was found involved in His→Arg change near the C-terminus of IL-17 F. Comparative MDS revealed enhanced stability of the mutant hence advocating a potential role of IL-17F functional SNP in RA susceptibility and/or severity. This study provides a novel structural insight for SNP-derived functional mutation and its overall impact on binding with heterotrimeric receptor complex of IL-17 receptor thereby opening new avenues for understanding the biochemical basis of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08820139.2020.1775642DOI Listing
May 2021

Correction to: 14 Years' experience of esophageal replacement surgeries.

Pediatr Surg Int 2020 07;36(7):843-844

The Children's Hospital and The Institute of Child Health, Lahore, Pakistan.

The quality of the images published in the original version was not satisfactory. The better version images are provided below.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00383-020-04677-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608206PMC
July 2020

Discovery of novel Hepatitis C virus inhibitor targeting multiple allosteric sites of NS5B polymerase.

Infect Genet Evol 2020 10 31;84:104371. Epub 2020 May 31.

Department of Pharmaceutical Sciences, REGA Institute for Medical Research, Medicinal Chemistry, University of Leuven, 3000 Leuven, Belgium.

HCV is a viral infection posing a severe global threat when left untreated progress to end-stage liver disease, including cirrhosis and HCC. The NS5B polymerase of HCV is the most potent target that harbors four allosteric binding sites that could interfere with the HCV infection. We present the discovery of a novel synthetic compound that harbors the potential of NS5B polymerase inhibition. All eight compounds belonging to the benzothiazine family of heterocycles displayed no cellular cytotoxicity in HepG2 cells at nontoxic dose concentration (200 μM). Subsequently, among eight compounds of the series, merely compound 5b exhibited significant inhibition of the expression of the HCV NS5B gene as compared to DMSO control in semi-quantitative PCR. Based on our western blot result, 5b at the range of 50, 100 and 200 μM induced 20, 40, and 70% inhibition of NS5B protein respectively. To estimate the binding potential, 5b was docked at respective allosteric sites followed by molecular dynamics (MD) simulations for a period of 20 ns. In addition, binding free energy calculation by MM-GB/PBSA method revealed a conserved interaction profile of residues lining the allosteric sites in agreement with the reported NS5B co-crystallized inhibitors. The presented results provide important information about a novel compound 5b which may facilitate the the discovery of novel inhibitors that tends to target multiple sites on NS5B polymerase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.meegid.2020.104371DOI Listing
October 2020

Gastrointestinal trichobezoar: An experience with 17 cases.

J Pediatr Surg 2020 Nov 5;55(11):2504-2509. Epub 2020 May 5.

Department of Pediatric Surgery, The Children's Hospital and the Institute of Child Health, Lahore, Pakistan.

Background: Trichobezoar is an exceedingly rare entity in children and mimics other chronic ailments such as abdominal tuberculosis or malignancy. Delayed diagnosis and management result in various complications. The study was conducted to describe our experience with 17 consecutive cases of gastrointestinal tract (GIT) trichobezoars.

Materials And Methods: We reviewed medical records of 17 consecutive cases of GIT trichobezoar managed in our department between January 2005 and December 2018.

Results: There were 3 males and 14 females. The median age of presentation was 7 years. Fifteen patients (88%) presented with abdominal pain and vomiting, while 8 (47%) had abdominal distension. Seven (41%) patients developed complications secondary to the GIT trichobezoar (intussusception and gangrene in 1, small bowel obstruction in 4, gastric perforation and massive bleeding per rectum in 1, acute transient pancreatitis and hypertension in 1). At operation, 9 (54%) patients had Rapunzel syndrome, 6 (35%) had gastric trichobezoar, and 2 (12%) had small bowel trichobezoars. One patient presented with massive bleeding per rectum and gastric perforation, succumbed postoperatively. One patient developed a recurrent trichobezoar.

Conclusion: GIT trichobezoar is rare in children and simulates chronic gastrointestinal ailments. Trichobezoars may reside in the alimentary tract, remain unnoticed for years, and become overt with the onset of complications. The majority of trichobezoars had a tail in our series. Life threatening complications can occur with delayed presentations.

Type Of Study: Case series.

Level Of Evidence: Level IV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpedsurg.2020.04.020DOI Listing
November 2020

Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase.

J Pharm Anal 2020 Aug 28;10(4):320-328. Epub 2020 Apr 28.

Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Medicinal Chemistry, University of Leuven, B-3000, Leuven, Belgium.

Recently emerged SARS-CoV-2 caused a major outbreak of coronavirus disease 2019 (COVID-19) and instigated a widespread fear, threatening global health safety. To date, no licensed antiviral drugs or vaccines are available against COVID-19 although several clinical trials are under way to test possible therapies. During this urgent situation, computational drug discovery methods provide an alternative to tiresome high-throughput screening, particularly in the hit-to-lead-optimization stage. Identification of small molecules that specifically target viral replication apparatus has indicated the highest potential towards antiviral drug discovery. In this work, we present potential compounds that specifically target SARS-CoV-2 vital proteins, including the main protease, Nsp12 RNA polymerase and Nsp13 helicase. An integrative virtual screening and molecular dynamics simulations approach has facilitated the identification of potential binding modes and favourable molecular interaction profile of corresponding compounds. Moreover, the identification of structurally important binding site residues in conserved motifs located inside the active site highlights relative importance of ligand binding based on residual energy decomposition analysis. Although the current study lacks experimental validation, the structural information obtained from this computational study has paved way for the design of targeted inhibitors to combat COVID-19 outbreak.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpha.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187848PMC
August 2020

14 Years' experience of esophageal replacement surgeries.

Pediatr Surg Int 2020 Jul 31;36(7):835-841. Epub 2020 Mar 31.

The Children's Hospital and The Institute of Child Health, Lahore, Pakistan.

Background: Esophageal replacement is a challenge to the therapeutic skills of surgeons and a technically demanding operation in the pediatric age group. Various conduits and routes have been described in the literature, each with their specific advantages and disadvantages. We carried out this retrospective study to share our experience of esophageal replacement.

Methodology: This study was conducted at the department of pediatric surgery The Children's Hospital and The Institute of Child Health, Lahore. The records of patients treated for esophageal replacement were reviewed. The patients under follow-up were called for clinical evaluation and assessed of long terms complications if any.

Results: A total of 93 patients with esophageal replacement were included in the study. Esophageal replacement was done with gastric transposition in 84 cases (90%), colon interposition in 7 cases (7.5%) including one case of redo colonic interposition, and jejunal interposition in 2 cases (2%). Routes of esophageal replacement were trans-hiatal in 71 (76%), retrosternal in 13 (14%), and trans-hiatal with thoracotomy in 9 (10%) patients. Postoperatively, all of the conduits maintained viability. Wound infection was seen in 10 (11%), wound dehiscence in 5 (5%), anastomotic leak in 9 (10%), anastomotic stenosis in 12 (13%), fistula formation in 4 (4%), aortic injury 1 (1%), dumping syndrome 8 (9%), reflux 18 (19%), dysphagia 15 (16%) and death occurred in 12 patients (13%).

Conclusion: There are problems with esophageal replacement in developing countries. In this context, gastric conduit appeared as the best conduit for esophageal replacement, using the trans-hiatal route for replacement, in the authors' experience.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00383-020-04649-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223057PMC
July 2020

3D LIDAR imaging using Ge-on-Si single-photon avalanche diode detectors.

Opt Express 2020 Jan;28(2):1330-1344

We present a scanning light detection and ranging (LIDAR) system incorporating an individual Ge-on-Si single-photon avalanche diode (SPAD) detector for depth and intensity imaging in the short-wavelength infrared region. The time-correlated single-photon counting technique was used to determine the return photon time-of-flight for target depth information. In laboratory demonstrations, depth and intensity reconstructions were made of targets at short range, using advanced image processing algorithms tailored for the analysis of single-photon time-of-flight data. These laboratory measurements were used to predict the performance of the single-photon LIDAR system at longer ranges, providing estimations that sub-milliwatt average power levels would be required for kilometer range depth measurements.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OE.383243DOI Listing
January 2020
-->