Surface-normal illuminated pseudo-planar Ge-on-Si avalanche photodiodes with high gain and low noise.

Germanium-on-Silicon (Ge-on-Si) avalanche photodiodes (APDs) are of considerable interest as low intensity light detectors for emerging applications. The Ge absorption layer detects light at wavelengths up to ≈ 1600 nm with the Si acting as an avalanche medium, providing high gain with low excess avalanche noise. Such APDs are typically used in waveguide configurations as growing a sufficiently thick Ge absorbing layer is challenging. Here, we report on a new vertically illuminated pseudo-planar Ge-on-Si APD design utilizing a 2 µm thick Ge absorber and a 1.4 µm thick Si multiplication region. At a wavelength of 1550 nm, 50 µm diameter devices show a responsivity of 0.41 A/W at unity gain, a maximum avalanche gain of 101 and an excess noise factor of 3.1 at a gain of 20. This excess noise factor represents a record low noise for all configurations of Ge-on-Si APDs. These APDs can be inexpensively manufactured and have potential integration in silicon photonic platforms allowing use in a variety of applications requiring high-sensitivity detectors at wavelengths around 1550 nm.

Association of Surgical Approaches and Outcomes in Total Mesorectal Excision and Margin Status for Rectal Cancer.

INTRODUCTION: Despite being a key metric with a significant correlation with the outcomes of patients with rectal cancer, the optimal surgical approach for total mesorectal excision (TME) has not yet been identified. The aim of this study was to assess the association of the surgical approach on the quality of TME and surgical margins and to characterize the surgical and long-term oncologic outcomes in patients undergoing robotic, laparoscopic, and open TME for rectal cancer. METHODS: Patients with primary, nonmetastatic rectal adenocarcinoma who underwent either lower anterior resection or abdominoperineal resection via robotic (Rob), laparoscopic (Lap), or open approaches were selected from the US Rectal Cancer Consortium database (2007-2017). Quasi-Poisson regression analysis with backward selection was used to investigate the relationship between the surgical approach and outcomes of interest. RESULTS: Among the 664 patients included in the study, the distribution of surgical approaches was as follows: 351 (52.9%) underwent TME via the open approach, 159 (23.9%) via the robotic approach, and 154 (23.2%) via the laparoscopic approach. There were no significant differences in baseline demographics among the three cohorts. The laparoscopic cohort had fewer patients with low rectal cancer (<6 cm from the anal verge) than the robotic and open cohorts (Lap 28.6% versus Rob 59.1% versus Open 45.6%, P = 0.015). Patients who underwent Rob and Lap TME had lower intraoperative blood loss compared with the Open approach (Rob 200 mL [Q1, Q3: 100.0, 300.0] versus Lap 150 mL [Q1, Q3: 75.0, 250.0] versus Open 300 mL [Q1, Q3: 150.0, 600.0], P < 0.001). There was no difference in the operative time (Rob 243 min [Q1, Q3: 203.8, 300.2] versus Lap 241 min [Q1, Q3: 186, 336] versus Open 226 min [Q1, Q3: 178, 315.8], P = 0.309) between the three approaches. Postoperative length of stay was shorter with robotic and laparoscopic approach compared to open approach (Rob 5.0 d [Q1, Q3: 4, 8.2] versus Lap 5 d [Q1, Q3: 4, 8] versus Open 7.0 d [Q1, Q3: 5, 9], P < 0.001). There was no statistically significant difference in the quality of TME between the robotic, laparoscopic, and open approaches (79.2%, 64.9%, and 64.7%, respectively; P = 0.46). The margin positivity rate, a composite of circumferential margin and distal margin, was higher with the robotic and open approaches than with the laparoscopic approach (Rob 8.2% versus Open 6.6% versus Lap 1.9%, P = 0.17), Rob versus Lap (odds ratio 0.21; 95% confidence interval 0.05, 0.83) and Rob versus Open (odds ratio 0.5; 95% confidence interval 0.22, 1.12). There was no difference in long-term survival, including overall survival and recurrence-free survival, between patients who underwent robotic, laparoscopic, or open TME (Figure 1). CONCLUSIONS: In patients undergoing surgery with curative intent for rectal cancer, we did not observe a difference in the quality of TME between the robotic, laparoscopic, or open approaches. Robotic and open TME compared to laparoscopic TME were associated with higher margin positivity rates in our study. This was likely due to the higher percentage of low rectal cancers in the robotic and open cohorts. We also reported no significant differences in overall survival and recurrence-free survival between the aforementioned surgical techniques.

Structural and functional implications of SLC13A3 and SLC9A6 mutations: an in silico approach to understanding intellectual disability.

BACKGROUND: Intellectual disability (ID) is a condition that varies widely in both its clinical presentation and its genetic underpinnings. It significantly impacts patients' learning capacities and lowers their IQ below 70. The solute carrier (SLC) family is the most abundant class of transmembrane transporters and is responsible for the translocation of various substances across cell membranes, including nutrients, ions, metabolites, and medicines. The SLC13A3 gene encodes a plasma membrane-localized Na+/dicarboxylate cotransporter 3 (NaDC3) primarily expressed in the kidney, astrocytes, and the choroid plexus. In addition to three Na + ions, it brings four to six carbon dicarboxylates into the cytosol. Recently, it was discovered that patients with acute reversible leukoencephalopathy and a-ketoglutarate accumulation (ARLIAK) carry pathogenic mutations in the SLC13A3 gene, and the X-linked neurodevelopmental condition Christianson Syndrome is caused by mutations in the SLC9A6 gene, which encodes the recycling endosomal alkali cation/proton exchanger NHE6, also called sodium-hydrogen exchanger-6. As a result, there are severe impairments in the patient's mental capacity, physical skills, and adaptive behavior. METHODS AND RESULTS: Two Pakistani families (A and B) with autosomal recessive and X-linked intellectual disorders were clinically evaluated, and two novel disease-causing variants in the SLC13A3 gene (NM 022829.5) and the SLC9A6 gene (NM 001042537.2) were identified using whole exome sequencing. Family-A segregated a novel homozygous missense variant (c.1478 C > T; p. Pro493Leu) in the exon-11 of the SLC13A3 gene. At the same time, family-B segregated a novel missense variant (c.1342G > A; p.Gly448Arg) in the exon-10 of the SLC9A6 gene. By integrating computational approaches, our findings provided insights into the molecular mechanisms underlying the development of ID in individuals with SLC13A3 and SLC9A6 mutations. CONCLUSION: We have utilized in-silico tools in the current study to examine the deleterious effects of the identified variants, which carry the potential to understand the genotype-phenotype relationships in neurodevelopmental disorders.

Engineering processive cellulase of Clostridium thermocellum to divulge the role of the carbohydrate-binding module.

The processive cellulase (CelO) is an important modular enzyme of Clostridium thermocellum. To study the effect of the carbohydrate-binding module (CBM3b) on the catalytic domain of CelO (GH5), four engineered derivatives of CelO were designed by truncation and terminal fusion of CBM3b. These are CBM at the N-terminus, native form (CelO-BC, 62 kDa); catalytic domain only (CelO-C, 42 kDa); CBM at the C-terminus (CelO-CB, 54 kDa) and CBM attached at both termini (CelO-BCB, 73 kDa). All constructs were cloned into pET22b (+) and expressed in Escherichia coli BL21 (DE3) star. The expression levels of CelO-C, CelO-CB, CelO-BC, and CelO-BCB were 35%, 35%, 30%, and 20%, respectively. The enzyme activities of CelO-C, CelO-CB, CelO-BC, and CelO-BCB against 1% regenerated amorphous cellulose (RAC) were 860, 758, 985, and 1208 units per µmole of the enzyme, respectively. The enzymes were partially purified from the lysate of E. coli cells by heat treatment followed by anion exchange FPLC purification. Against RAC, CelO-C, CelO-CB, CelO-BC, and CelO-BCB showed KM values of 32, 33, 45, and 43 mg⋅mL-1 and Vmax values of 3571, 3846, 3571, and 4545 U⋅min-1 , respectively. CBM3b at the N-terminus of GH5 linked through a P/T-rich linker was found to enhance the catalytic activity and thermostability of the enzyme.

Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche.

We have described multipotent progenitor-like cells within the major pancreatic ducts (MPDs) of the human pancreas. They express PDX1, its surrogate surface marker P2RY1, and the bone morphogenetic protein (BMP) receptor 1A (BMPR1A)/activin-like kinase 3 (ALK3), but not carbonic anhydrase II (CAII). Here we report the single-cell RNA sequencing (scRNA-seq) of ALK3bright+-sorted ductal cells, a fraction that harbors BMP-responsive progenitor-like cells. Our analysis unveiled the existence of multiple subpopulations along two major axes, one that encompasses a gradient of ductal cell differentiation stages, and another featuring cells with transitional phenotypes toward acinar tissue. A third potential ducto-endocrine axis is revealed upon integration of the ALK3bright+ dataset with a single-cell whole-pancreas transcriptome. When transplanted into immunodeficient mice, P2RY1+/ALK3bright+ populations (enriched in PDX1+/ALK3+/CAII- cells) differentiate into all pancreatic lineages, including functional ß-cells. This process is accelerated when hosts are treated systemically with an ALK3 agonist. We found PDX1+/ALK3+/CAII- progenitor-like cells in the MPDs of types 1 and 2 diabetes donors, regardless of the duration of the disease. Our findings open the door to the pharmacological activation of progenitor cells in situ.

Reliability and validity of Urdu PARENTS for assessing non-technical skills of paediatric residents in a teaching hospital in Pakistan.

PURPOSE: The primary objective of our study is twofold. First, we assessed nontechnical skills (NTSs), such as the cognitive, social, and personal skills of postgraduate residents (PGRs), from paediatric caregivers' perspectives in a paediatric emergency department (PED) of a tertiary care hospital. Second, we evaluated the reliability and validity of the 'Parents' Assessment of Residents Enacting Non-Technical Skills' (PARENTS) instrument in its Urdu-translated version, ensuring its applicability and accuracy in the Pakistani context. MATERIALS AND METHODS: This mixed-method study used an instrument translation and validation design. We translated an existing instrument, PARENTS, into Urdu, the national language of Pakistan, and administered it to paediatric caregivers in the PED of a tertiary care hospital. We collected data from 471 paediatric caregivers and coded them for analysis in AMOS and SPSS. RESULTS: The Urdu-translated version of the PARENTS demonstrated reliability and internal validity in our study. The findings from the assessment revealed that paediatric caregivers expressed satisfaction with the knowledge and skill of residents. However, there was comparatively lower satisfaction regarding the residents' display of patience or empathy towards the children under their care. CONCLUSION: The study findings support the validity and reliability of the PARENTS as an effective instrument for assessing the NTS of PGRs from the perspective of paediatric caregivers. With its demonstrated efficacy, medical educators can utilize PARENTS to pinpoint specific areas that require attention regarding the NTS of PGRs, thus facilitating targeted interventions for enhanced patient care outcomes.

Production performance, protein digestibility, gut health and economic efficiency in sexed broilers with super dozing of lysine.

Modern commercial broiler is growing very rapidly and its amino acid requirement is not fulfilling. An experimental trial was conducted to study the effect of super-dosing of lysine in fish meal-based diets (50% fish meal and 50% SBM) on production performance, protein digestibility and economic efficiency in male and female broiler chickens. Four hundred and eighty (480) one-day-old male and female broiler chicks were divided into forty experimental units of 12 birds each. Five levels of dietary lysine i.e. 90, 100, 110, 120 and 130% of Ross-308 recommendation in male and female birds were separately used. Weight gain and feed intake were higher (p < 0.05) in birds received 100 and 110% recommended lysine than other levels. Feed conversion ratio and EPEF were improved (p < 0.05) in birds received 100% recommended lysine than other levels. Higher (p < 0.05) CP digestibility and lower production cost per kg live weight were noted for birds fed diet containing lysine 100, 110 and 120% than 90 and 130%. Male birds had higher (p < 0.05) WG, FI, EPEF, protein digestibility and lower production cost per kg live weight than female birds. In conclusion, lysine levels below 100% and above 110% of Ross recommended levels had poor production performance, protein digestibility and economic efficiency.

Risk factors of previously undiagnosed and known untreated hypertension among patients with Type-2 diabetes mellitus.

Objectives: To find the risk factors of previously undiagnosed and known untreated hypertension among patients with Type- 2 diabetes mellitus. Methods: The cross-sectional analytical study was conducted at Diabetes Clinic of Sir Ganga Ram Hospital Lahore during Oct-Dec 2021. Total 153 known diabetics were enrolled using convenience sampling. Patients (n=24) with ischemic heart disease, hepatitis or missing information excluded. Data from 129 cases of Type-2 diabetes presenting with and without hypertension analyzed using SPSS. Binary logistic regression analyses were performed to calculate the adjusted odds ratios. Result: Mean age of all diabetics (n=129) was 49.0±10.7 years. The participation of females was higher than males (65.1% vs. 34.9%). The frequency of hypertension, previously undiagnosed hypertension and known untreated hypertension was 58.1%, 25.3% and 19.6%, respectively. Among risk factors, frequency of high intake of salt was 67.4%, sedentary lifestyle was 65.1%, obesity was 37.2%, and poor glycemic control was 58.9%. Young age [aOR=2.01, 95.0% CI 0.53-7.61], low family income <20000 PKR/month [aOR=2.70, 95.0% CI 0.92-7.96], high intake of salt [aOR=3.22, 95.0% CI 0.98-10.61], elevated total cholesterol [aOR=3.68, 95.0% CI 0.85-15.85], poor glycemic control [aOR=3.28, 95.0% CI 0.51-21.13], and overweight/ obesity [aOR=9.07, 95.0% CI 1.6-51.39] had higher risk of previously undiagnosed or known untreated HTN. Conclusions: Prevalence of previously undiagnosed and known untreated hypertension is high among Type-2 diabetics. Strict compliance to diabetes care guidelines is much needed to minimize the risk of undiagnosed and untreated hypertension.

Late-onset pulmonary complications among survivors of coronavirus Disease 2019.

Objectives: To assess the late-onset pulmonary complications among survivors of coronavirus disease 2019. Methods: The cross-sectional analytical study was conducted in the department of Pulmonology, Sir Ganga Ram Hospital Lahore between October 2020 and March 2021. Total 288 patients visiting the hospital 12-week after recovery from COVID-19 enrolled using convenience sampling. After excluding patients (n=61) with a history of previous respiratory symptoms before the development of COVID-19, data from 227 patients was subjected to final analysis. Chest X-ray (CXR) was used to evaluate lung condition. Results: Participation of middle-aged adults (54.6%) was higher than older (38.3%) and young adults (7.0%). The percentage of males was 55.5% and smokers was 29.1%. Dyspnea was the most common complication as 80.0% patients had moderate to severe dyspnea while chronic cough was 78.0% and lung fibrosis (LF) was 13.2%. The chances of LF increased with the rise in age (p-value 0.033). However, the distribution of LF was similar between males and females. The frequency of lung fibrosis in smokers was 3-time higher than among non-smokers (24.2 vs. 8.7%; p-value 0.003). The patients with LF were more dependent on O2 as compared to the patients without LF (p-value < 0.001). The frequency of tachycardia was significantly different between patients with and without LF (all p-values < 0.05). Conclusion: LF is a common late-onset pulmonary complication of COVID-19 and is associated with old age, smoking, O2 dependency, tachycardia, and severe dyspnea.

Folate Conjugated Polyethylene Glycol Probe for Tumor-Targeted Drug Delivery of 5-Fluorouracil.

A targeted delivery system is primarily intended to carry a potent anticancer drug to specific tumor sites within the bodily tissues. In the present study, a carrier system has been designed using folic acid (FA), bis-amine polyethylene glycol (PEG), and an anticancer drug, 5-fluorouracil (5-FU). FA and PEG were joined via an amide bond, and the resulting FA-PEG-NH2 was coupled to 5-FU producing folate-polyethylene glycol conjugated 5-fluorouracil (FA-PEG-5-FU). Spectroscopic techniques (UV-Vis, 1HNMR, FTIR, and HPLC) were used for the characterization of products. Prodrug (FA-PEG-5-FU) was analyzed for drug release profile (in vitro) up to 10 days and compared to a standard anticancer drug (5-FU). Folate conjugate was also analyzed to study its folate receptors (FR) mediated transport and in vitro cytotoxicity assays using HeLa cancer cells/Vero cells, respectively, and antitumor activity in tumor-bearing mice models. Folate conjugate showed steady drug release patterns and improved uptake in the HeLa cancer cells than Vero cells. Folate conjugate treated mice group showed smaller tumor volumes; specifically after the 15th day post-treatment, tumor sizes were decreased significantly compared to the standard drug group (5-FU). Molecular docking findings demonstrated importance of Trp138, Trp140, and Lys136 in the stabilization of flexible loop flanking the active site. The folic acid conjugated probe has shown the potential of targeted drug delivery and sustained release of anticancer drug to tumor lesions with intact antitumor efficacy.

Impact of Age, Gender, post infection and post vaccination status on antibody response in COVID 19 patients.

OBJECTIVE: To evaluate severe acute respiratory syndrome coronavirus-2 spike protein antibodies against coronavirus disease-2019 in post-infection and post-vaccinated individuals. METHODS: The cross-sectional study was conducted from June, 1 to July 31, 2021 at the Rehman Medical Institute, Peshawar, Pakistan, and comprised subjects of either gender in whom immunogenicity was checked 35 days post-vaccination and 90 days post-infection. Correlation with age and gender was checked. Specimens were collected and investigated for severe acute respiratory syndrome coronavirus-2 spike protein antibodies by consuming electro-chemiluminescence immunoassay. Data was analysed using SPSS 23. RESULTS: Of the total 256 patients enrolled, 70(27.34%) were included; 49(69%) males and 21(29.6%) females. The overall mean age was 44±7.75 years. Among 30(42.8%) patients with positive polymerase chain reaction test, the mean time between the positive test and antibody screening was 90±30 days. Among the 40(57.2%) vaccinated individuals, the time between vaccination and antibody screening was 35±9.74 days. Overall, 68(97%) patients revealed robust positive findings to severe acute respiratory syndrome coronavirus-2 spike proteins antibodies >50IU/mL. Male subjects had significantly higher immunogenic response compared to females (p=0.001), and immunogenicity decreased with advancing age (p<0.001). Also, post-vaccinated patients' antibody response was significant compared to post-infection patients' response (p=0.001). Conclusion: Majority of the patients had significantly higher antibody titers against severe acute respiratory syndrome coronavirus-2 post-infection and post-vaccination. Males and younger individuals developed a significant humoral immunity compared to females and the elderly.

B-type natriuretic peptide as diagnostic and prognostic marker in various forms of acute coronary syndrome.

Objectives: This study was conducted to evaluate the diagnostic and prognostic value of B-type natriuretic peptide (BNP) in different categories of acute coronary syndrome (ACS) patients on arrival. Methods: This cohort study included 197 patients admitted in Coronary Care Unit (CCU) of Rehman Medical Institute (RMI) Peshawar from January 2020 to June 2020. Patients were categorized in two subgroups. Subgroup-I with BNP below 100pg/mL. Subgroup-II having BNP above 100pg/mL. Samples were obtained on admission from these patients for Cardiac Troponin I (Trop-i), BNP and serum creatinine. BNP samples were analyzed on Cobas® using chemiluminescence method. Descriptive statistics were derived for age; gender and cardiac biomarkers. Receiver-operating characteristic curves (ROC) were generated. Diagnostic accuracy parameters were determined for Non ST- segment elevation myocardial infarction (STEMI), ST- segment elevation myocardial infarction (STEMI) and unstable angina (UA). Result: One hundred fourteen patients (58.2%) were males and 82 were females (41.8%).Our of this 89 patients were NSTEMI in group II. Mean BNP was 1438±1463.Age distribution shows 120 individuals were over 55 years (61.2%). Hypertension, diabetes, smoking and previous infarcts were the risk factors for ACS. Sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive value (NPV), likelihood ratios, and overall accuracy of BNP at admission for the entire sub categories in ACS (cut-off value 100 pg/mL) were determined by using Trop-i the gold standard. ROC curve showed AUC = 0.557, (95% confidence interval: 0.476-0.638). When Pearson correlation was applied, BNP was found to be a noteworthy independent predictor. Conclusion: BNP can be a useful Biomarker along with standard cardiac biomarkers in various categories of patients with ACS.

Controlled release floating drug delivery system for proton pump inhibitors lansoprazole: In-vitro, In-vivo floating and pharmacokinetic evaluation.

Lansoprazole (LPZ) show poor bioavailability because of first pass effect and absorption factors. The floating delivery systems could reduce fluctuations in plasma drug concentration through maintaining desirable plasma drug concentration. The objective of present study was to enhance bioavailability despite first pass effect through continuous availability of drug from floating system. Gum tragacanth (GT) and itaconic acid (IA) based floating hydrogels (FH) were synthesized. Parameters optimized were; microwave radiation exposure time, pH, GT:IA ratio and concentration of the glutaraldehyde. Optimized FH were evaluated for entrapment efficiency (% EE), in-vitro release, FTIR, SEM, and in- vitro and in-vivo floating study. Finally, pharmacokinetic was evaluated in ulcer-induced SD rats. Grafting percentage, swelling ratio and %EE of LPZ was 115%, Ì´250% and 90%, respectively. Microwave radiation exposure time, pH of reaction medium, GT:IA ratios and cross linker concentration were 2 min, pH 5, ratios 2:1 and 0.02%, respectively. The optimized FH showed acceptable floating behavior. The X-ray images revealed that hydrogels remained floated over gastric contents up to 24 hours. The in-vitro release and pharmacokinetics revealed availability of LPZ upto to 24h in-vitro and in ulcer-induced SD rats, respectively. The present hydrogels based floating system of lansoprazole is capable to extend the gastric residence time upto 24 hours.

Therapeutic approach for global myocardial injury using bone marrow-derived mesenchymal stem cells by cardiac support device in rats.

Bone marrow-derived mesenchymal stem cells (BMSCs) have been considered a promising therapeutic approach to cardiovascular disease. This study intends to compare the effect of BMSCs through a standard active cardiac support device (ASD) and intravenous injection on global myocardial injury induced by isoproterenol. BMSCs were cultured in vitro, and the transplanted cells were labeled with a fluorescent dye CM-Dil. Isoproterenol (ISO) was injected into the rats; 2 weeks later, the labeled cells were transplanted into ISO-induced heart-jury rats through the tail vein or ASD device for 5 days. The rats were sacrificed on the first day, the third day, and the fifth day after transplantation to observe the distribution of cells in the myocardium by fluorescence microscopy. The hemodynamic indexes of the left ventricle were measured before sacrificing. H&E staining and Masson's trichrome staining were used to evaluate the cardiac histopathology. In the ASD groups, after 3 days of transplantation, there were a large number of BMSCs on the epicardial surface, and after 5 days of transplantation, BMSCs were widely distributed in the ventricular muscle. But in the intravenous injection group, there were no labeled-BMSCs distributed. In the ASD + BMSCs-three days treated group and ASD + BMSCs -five days-treated group, left ventricular systolic pressure (LVSP), the maximum rate of left ventricular pressure rise (+dP/dt), the maximum rate of left ventricular pressure decline (-dP/dt) increased compared with model group and intravenous injection group (P < 0.05). By giving BMSCs through ASD device, cells can rapidly and widely distribute in the myocardium and significantly improve heart function.

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

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 ), 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.

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

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, p = .009)] and IL-17 F 7488 T/C [allelic (OR = 0.907, 95%CI = 0.861-0.954, p = .000)] with increased RA risk in Pakistani subjects. When mapped, IL-17 F 7488 T/C was found involved in His161→Arg161 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.

Factors influencing treatment outcomes of tuberculosis patients attending health facilities in Galkayo Puntland, Somalia.

AIM: This study evaluated the underlying factors associated with poor tuberculosis (TB) treatment outcomes among patients attending health care facilities in Galkayo, Puntland, Somalia. METHODS: An institution-based cross-sectional study was conducted between 2016 and 2017 in three selected TB clinics. Data were collected from 400 TB patients, through medical record review and structured questionnaire. Multivariate logistic regression analyses were performed. RESULTS: Of the 400 TB respondents, 57.3% were new cases, 12.3% had smear-negative TB and 12.5% had extrapulmonary TB. The median age was (35.66 ± 13.16) with majority being male (65.5%). Overall, 85% of patients were successfully treated, 9.7% failed and 5.3% defaulted. Multivariate analysis revealed that patient's body weight (odds ratio [OR]: 1.078); diabetes (OR: 8.022); family size (OR: 3.851); patients' delay in diagnosis (OR: 11.946); frequency of receiving anti-TB medication (OR: 9.068); smoker (OR: 5.723); category of patients (retreatment versus new, OR: 5.504; retreatment versus transfer in, OR: 4.957); health facilities (OR: 6.716) and treatment duration (OR: 132.091) were independent factors associated with poor TB outcomes. CONCLUSIONS: Our findings highlight the need to improve TB services for vulnerable groups. They also emphasize the need for health system strengthening, public awareness and risk of treatment interruption. This may reduce both patients' delay in seeking care and TB treatment failure in Galkayo district.

Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins.

Xenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes such as polymerases, ligases and nucleases. Here, we present a structure-guided modelling-based strategy for the rational design of those enzymes essential for the development of XNA molecular biology. Docking of protein domains to unbound double-stranded nucleic acids is used to generate a first approximation of the extensive interaction of nucleic acid processing enzymes with their substrate. Molecular dynamics is used to optimise that prediction allowing, for the first time, the accurate prediction of how proteins that form toroidal complexes with nucleic acids interact with their substrate. Using the Chlorella virus DNA ligase as a proof of principle, we recapitulate the ligase's substrate specificity and successfully predict how to convert it into an XNA-templated XNA ligase.

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

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+2 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/ß-D-glucopyranoside (1) and four known glycosides were identified. Glycoside 1 demonstrated promising antioxidant potential with IC50 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 IC50 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 Ki 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.

Chemical characterization and anti-arthritic appraisal of Monotheca buxifolia methanolic extract in Complete Freund's Adjuvant-induced arthritis in Wistar rats.

The current study was designed to evaluate the anti-oxidant and anti-arthritic potential of a traditionally used herb, Monotheca buxifolia. The M. buxifolia methanolic extract (MBME) was prepared from the aerial parts of the plant followed by chemical characterization with GC-MS. The anti-oxidant potential of the MBME was demonstrated by DPPH scavenging activity. The effects of MBME on protein denaturation and membrane stabilization were determined by inhibition of egg albumin denaturation and RBC membrane stabilization assays, respectively. The in vivo anti-arthritic potential of the MBME at 50, 100, and 150 mg/kg/day was evaluated in Complete Freund's Adjuvant-induced polyarthritis in Wistar rats treated for 21 days. Phytochemicals, such as linolenic acid methyl ester, n-hexadecanoic acid, vitamin E, α-amyrin, and ß-amyrin were detected in the GC-MS analysis. The plant extract exhibited a 55.20 ± 0.69% scavenging of free radicals at 100 µg/ml concentration. It significantly (p < 0.05) stabilized human RBC membrane (65.06 ± 0.22%) and inhibited protein denaturation (70.53 ± 0.34%) at 100 mg/ml concentration. The diclofenac sodium (DS) and MBME at 150,100, and 50 mg/kg reduced the paw edema, restored the body weight, and altered blood parameters including CRP. The MBME significantly reduced the MDA and increased the SOD, CAT, and GSH levels in liver tissue homogenate in treated rats. The serum concentration of TNF-α and PGE2 was remarkably (p < 0.01-< 0.0001) restored by the DS and MBME dose dependently. The histopathological study showed that MBME 150 mg/kg commendably restored the ankle joint inflammation, bone erosion, and cartilage damage in polyarthritic rats. It was concluded that the anti-oxidant, anti-inflammatory and anti-arthritic effects of MBME might be attributed to phenols, flavonoids, triterpenoids, vitamin E, phytol, and other fatty acids. This study showed the anti-arthritic potential of Monotheca buxifolia and thus validates its traditional claim.