Naringenin as a potent inhibitor molecule for targeting microtubule affinity-regulating kinase 4 (mark4): a molecular docking and in vitro study for therapeutics of Alzheimer's disease

Background: The targeted inhibition of Microtubule Affinity-Regulating Kinase 4 (MARK4) using small molecule inhibitors has emerged as a promising therapeutic approach for diverse diseases, including neurological disorders such as Alzheimer’s disease. Ongoing research endeavors aim to develop novel and more effective MARK4 inhibitors with enhanced target specificity and reduced off-target effects. In the present study, we sought to investigate the binding affinity and impact of Naringenin on the activity of MARK4. Methods: We employed a combination of molecular docking and other bioinformatics methods, a fluorescence-based inhibition assay, as well as a kinase activity assay to assess the binding affinity and inhibition potential of Naringenin against MARK4. Additionally, we utilized the MTT assay to examine the effect of Naringenin on the viability of two cell lines: the normal human cell line HEK-293 and the neuronal cell line SH-SY5Y. The IC50 dose of Naringenin, determined from the MTT assay, provided a valuable reference point for subsequent neuronal cell line experiments.Results: The results of the molecular docking demonstrated a robust binding affinity of Naringenin (-7.8 kcal/mol) to MARK4, affirming its potency as an inhibitor. Moreover, the fluorescence inhibition and kinase activity assays confirmed the inhibitory effect of Naringenin on MARK4. Interestingly, the MTT assay outcomes indicated that increasing concentrations of Naringenin did not significantly impact the viability of HEK 293 cells, while exhibiting a pronounced effect on SH-SY5Y neuronal cells. The IC50 concentration of Naringenin was determined to be 10.0 ± 1.33 μM for SH-SY5Y neuronal cells.Conclusion: In conclusion, this study reported Naringenin as a potential inhibitor molecule for MARK4, offering promising prospects for future therapeutic interventions in neuronal disorders specifically for Alzheimer’s disease.Keywords: Inhibition; Microtubule Affinity-Regulating Kinase 4 (MARK4); Molecular docking; Naringenin; Neuronal disorders  Editorial Note: You are viewing the latest version of this manuscript having correction in abstract section, which is different from the originally published copy

Mucosal immunity to poliovirus in children 0-15 years of age: A community-based study in Karachi, Pakistan in 2019

This study assesses poliovirus type 1 (PV1) immunity in children to inform the contribution of mucosal immunity in and preventing poliovirus circulation. A community-based study was conducted in peri-urban Karachi, Pakistan. Randomly selected children (0-15 years) received oral poliovirus vaccine (OPV) challenge dose. Blood and stool samples were collected at several time points and evaluated for polio-neutralizing antibodies and serotype-specific poliovirus, respectively. 81/589 (14%) children excreted PV1 7 days post-OPV-challenge; 70/81 (86%) were seropositive at baseline. 12/610 (2%) were asymptomatic Wild Poliovirus Type 1 (WPV1) excretors. Most poliovirus excretors had humoral immunity, suggesting mucosal immunity in these children likely waned or never developed. Without mucosal immunity, they are susceptible to poliovirus infection, shedding, and transmission. Asymptomatic WPV1 excretion suggests undetected poliovirus circulation within the community

Incidence of acute diarrhea-associated death among children < 5 years of age in Bangladesh, 2010-12

Although acute diarrheal deaths have declined globally among children = 13.6 km. Diarrhea contributes to childhood death at a higher proportion than when considering it only as the sole underlying cause of death. These data support the use of interventions aimed at preventing acute diarrhea, especially available vaccinations for common etiologies, such as rotavirus

Crossing the Frontiers: Transdisciplinary Research and the Negotiated Approach for Peri-Urban Groundwater Management in the Indo-Gangetic Delta

In this publication, we share our experiences with combining transdisciplinary research with the Negotiated Approached to address the challenges in groundwater management in peri-urban villages near Khulna, Bangladesh and near Kolkata, India. From 2014 – 2019, our team of researchers and civil society organizations has been executing the Shifting Grounds project. The project was developed as a transdisciplinary research project under the Urbanising Deltas of the World programme of the Netherlands Organisation for Scientific Research (NWO). The Negotiated Approach, an approach for community empowerment, was used to combine research with capacity development within peri-urban communities. In this report, we capture our experiences as an interdisciplinary and international team, covering successes as well as challenges we faced in the process.Policy Analysi

Evaluation of prognostic risk models for postoperative pulmonary complications in adult patients undergoing major abdominal surgery: a systematic review and international external validation cohort study

Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society