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Background: Hereditary motor and sensory neuropathy (HMSN) refers to a group of inherited progressive peripheral neuropathies characterized by reduced nerve conduction velocity with chronic segmental demyelination and/or axonal degeneration. HMSN is highly clinically and genetically heterogeneous with multiple inheritance patterns and phenotypic overlap with other inherited neuropathies and neurodegenerative diseases. Due to this high complexity and genetic heterogeneity, this study aimed to elucidate the genetic causes of HMSN in Pakistani families using Whole Exome Sequencing (WES) for variant identification and Sanger sequencing for validation and segregation analysis, facilitating accurate clinical diagnosis., Methods: Families from Khyber Pakhtunkhwa with at least two members showing HMSN symptoms, who had not previously undergone genetic analysis, were included. Referrals for genetic investigations were based on clinical features suggestive of HMSN by local neurologists. WES was performed on affected individuals from each family, with Sanger sequencing used to validate and analyze the segregation of identified variants among family members. Clinical data including age of onset were assessed for variability among affected individuals, and the success rate of genetic diagnosis was compared with existing literature using proportional differences and Cohen's h., Results: WES identified homozygous pathogenic variants in GDAP1 (c.310 + 4 A > G, p.?), SETX (c.5948_5949del, p.(Asn1984Profs*30), IGHMBP2 (c.1591 C > A, p.(Pro531Thr) and NARS1 (c.1633 C > T, p.(Arg545Cys) as causative for HMSN in five out of nine families, consistent with an autosomal recessive inheritance pattern. Additionally, in families with HMSN, a SETX variant was found to cause cerebellar ataxia, while a NARS1 variant was linked to intellectual disability. Based on American College of Medical Genetics and Genomics criteria, the GDAP1 variant is classified as a variant of uncertain significance, while variants in SETX and IGHMBP2 are classified as pathogenic, and the NARS1 variant is classified as likely pathogenic. The age of onset ranged from 1 to 15 years (Mean = 5.13, SD = 3.61), and a genetic diagnosis was achieved in 55.56% of families with HMSN, with small effect sizes compared to previous studies., Conclusions: This study expands the molecular genetic spectrum of HMSN and HMSN plus type neuropathies in Pakistan and facilitates accurate diagnosis, genetic counseling, and clinical management for affected families., (© 2024. The Author(s).)

When high energetic heavy ions interact with any target, short range, high linear energy transfer (LET) target fragments are produced. These target fragments (TFs) can give a significant dose to the healthy tissue during heavy ion cancer therapy, and when cosmic radiation interacts with astronauts. This paper presents Monte Carlo simulations, using the Particle and Heavy Ion Transport code System (PHITS), to characterize target fragments from reactions of helium and carbon ions with water. The calculated ranges, LET, doses, and production cross sections are presented. It is shown that protons, deuterons, tritons, alpha particles, 3 He, 6 He, nitrogen, oxygen, and fluorine ions are the most probable target fragments when carbon and helium ions collide with water. Among the produced target fragments, alpha particles and nitrogen ions give the highest dose to the targets, since the combination of fluence and LETs of these TFs are highest among the produced fragments. The production cross sections of proton and oxygen are the highest among the target fragments cross sections when helium and carbon ions imping on water, because these TFs can be produced through more reaction channels compared to other fragments. These findings are helpful for accurate dose measurement during heavy ion cancer therapy and for shielding of space radiation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Hereditary Spastic Paraplegias (HSPs) and Hereditary Cerebellar Ataxias (HCAs) are progressive neurodegenerative disorders encompassing a spectrum of neurogenetic conditions with significant overlaps of clinical features. Spastic ataxias are a group of conditions that have features of both cerebellar ataxia and spasticity, and these conditions are frequently clinically challenging to distinguish. Accurate genetic diagnosis is crucial but challenging, particularly in resource-limited settings. This study aims to investigate the genetic basis of HSPs and HCAs in Pakistani families., Methods: Families from Khyber Pakhtunkhwa with at least two members showing HSP or HCA phenotypes, and who had not previously been analyzed genetically, were included. Families were referred for genetic analysis by local neurologists based on the proband's clinical features and signs of a potential genetic neurodegenerative disorder. Whole Exome Sequencing (WES) and Sanger sequencing were then used to identify and validate genetic variants, and to analyze variant segregation within families to determine inheritance patterns. The mean age of onset and standard deviation were calculated to assess variability among affected individuals, and the success rate was compared with literature reports using differences in proportions and Cohen's h., Results: Pathogenic variants associated with these conditions were identified in five of eight families, segregating according to autosomal recessive inheritance. These variants included previously reported SACS c.2182 C > T, p.(Arg728*), FA2H c.159_176del, p.(Arg53_Ile58del) and SPG11 c.2146 C > T, p.(Gln716*) variants, and two previously unreported variants in SACS c.2229del, p.(Phe743Leufs*8) and ZFYVE26 c.1926_1941del, p.(Tyr643Metfs*2). Additionally, FA2H and SPG11 variants were found to have recurrent occurrences, suggesting a potential founder effect within the Pakistani population. Onset age among affected individuals ranged from 1 to 14 years (M = 6.23, SD = 3.96). The diagnostic success rate was 62.5%, with moderate effect sizes compared to previous studies., Conclusions: The findings of this study expand the genotypic and phenotypic spectrum of HSPs and HCAs in Pakistan and emphasize the importance of utilizing exome/genome sequencing for accurate diagnosis or support accurate differential diagnosis. This approach can improve genetic counseling and clinical management, addressing the challenges of diagnosing neurodegenerative disorders in resource-limited settings., (© 2024. The Author(s).)

Pesticides are widely used to control weeds and pests in agricultural settings but harm non-target aquatic organisms. In this study, our objective was to evaluate the effect of short-term exposure (one week) to environmentally relevant concentrations of pesticides mixture (low concentration: 0.4 μg/l atrazine, 0.5 μg/l Roundup®, and 0.5 μg/l 2,4-D; high concentration: 0.8 μg/l atrazine, 1 μg/l Roundup®, and 1 μg/l 2,4-D) on tissue architecture, body fluid conditions, and 3-nitrotyrosine protein (NTP) and Na + /K + -ATPase, expressions in tissues of American oyster (Crassostrea virginica) under controlled laboratory conditions. Histological analysis demonstrated the atrophy in the gills and digestive glands of oysters exposed to pesticides mixture. Periodic acid-Schiff (PAS) staining showed the number of hemocytes in connective tissue increased in low- and high-concentration pesticides exposure groups. However, pesticides treatment significantly (P < 0.05) decreased the amount of mucous secretion in the gills and digestive glands of oysters. The extrapallial fluid (i.e., body fluid) protein concentrations and glucose levels were dropped significantly (P < 0.05) in oysters exposed to high-concentration pesticides exposure groups. Moreover, immunohistochemical analysis showed significant upregulations of NTP and Na + /K + -ATPase expressions in the gills and digestive glands in pesticides exposure groups. Our results suggest that exposure to environmentally relevant pesticides mixture causes morphological changes in tissues and alters body fluid conditions and NTP and Na + /K + -ATPase expressions in tissues, which may lead to impaired physiological functions in oysters., Competing Interests: Declaration of competing interest There are no competing interests in this research work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Different types of diseases have been treated by restricted caloric intake or fasting. Although during this long time, fasting protective measures, for example, supplements, are given to the patients to protect vital organs such as the liver and kidney, little attention is given to the brain. The current research aims to investigate hypoglycemia due to prolonged fasting disrupts blood-brain barrier (BBB) in mice., Materials and Methods: Immunohistochemistry (IHC) and in situ hybridization (ISH) techniques were used to examine the expression of different genes. Evans blue extravasation and wet-dry technique were performed to evaluate the integrity of BBB and the formation of brain edema, respectively., Results: We confirmed that hypoglycemia affected mice fasting brain by examining the increased expression of glucose transporter protein 1 and hyperphosphorylation of tau protein. We subsequently found downregulated expression of some genes, which are involved in maintaining BBB such as vascular endothelial growth factor ( VEGF ) in astrocytes and claudin-5 (a vital component of BBB) and VEGF receptor ( VEGFR1 ) in endothelial cells by ISH. We also found that prolonged fasting caused the brain endothelial cells to express lipocalin-2, an inflammatory marker of brain endothelial cells. We performed Evans blue extravasation to show more dye was retained in the brain of fasted mice than in control mice as a result of BBB disruption. Finally, wet-dry method showed that the brain of prolonged fasted mice contained significantly higher amount of water confirming the formation of brain edema. Therefore, special attention should be given to the brain during treatment with prolonged fasting for various diseases., Conclusions: Our results demonstrated that hypoglycemia due to prolonged fasting disrupts BBB and produces brain edema in wild-type mice, highlighting the importance of brain health during treatment with prolonged fasting., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Brain Circulation.)

Background: Epilepsy, a challenging neurological condition, is often present with comorbidities that significantly impact diagnosis and management. In the Pakistani population, where financial limitations and geographical challenges hinder access to advanced diagnostic methods, understanding the genetic underpinnings of epilepsy and its associated conditions becomes crucial., Methods: This study investigated four distinct Pakistani families, each presenting with epilepsy and a spectrum of comorbidities, using a combination of whole exome sequencing (WES) and Sanger sequencing. The epileptic patients were prescribed multiple antiseizure medications (ASMs), yet their seizures persist, indicating the challenging nature of ASM-resistant epilepsy., Results: Identified genetic variants contributed to a diverse range of clinical phenotypes. In the family 1, which presented with epilepsy, developmental delay (DD), sleep disturbance, and aggressive behavior, a homozygous splice site variant, c.1339-6 C > T, in the COL18A1 gene was detected. The family 2 exhibited epilepsy, intellectual disability (ID), DD, and anxiety phenotypes, a homozygous missense variant, c.344T > A (p. Val115Glu), in the UFSP2 gene was identified. In family 3, which displayed epilepsy, ataxia, ID, DD, and speech impediment, a novel homozygous frameshift variant, c.1926&#95;1941del (p. Tyr643MetfsX2), in the ZFYVE26 gene was found. Lastly, family 4 was presented with epilepsy, ID, DD, deafness, drooling, speech impediment, hypotonia, and a weak cry. A homozygous missense variant, c.1208 C > A (p. Ala403Glu), in the ATP13A2 gene was identified., Conclusion: This study highlights the genetic heterogeneity in ASM-resistant epilepsy and comorbidities among Pakistani families, emphasizing the importance of genotype-phenotype correlation and the necessity for expanded genetic testing in complex clinical cases., (© 2024. The Author(s).)

Background Hypophosphatemia, defined as a serum phosphate level less than 2.5 mg/dL, is a frequent finding in patients with chronic obstructive pulmonary disease (COPD) and has been speculated to negatively affect weaning outcomes. This study aimed to determine the incidence of hypophosphatemia in COPD patients requiring mechanical ventilation and evaluate the predictive role of hypophosphatemia as an indicator of successful weaning from mechanical ventilation in such patients admitted to the intensive care unit (ICU) in a tertiary care hospital in eastern India. Methodology This prospective observational study included 60 adult patients aged 18 to 75 years with acute exacerbations of COPD on mechanical ventilation in the ICU who were planned to undergo a weaning trial. Serum phosphate levels were assessed at the time of admission and before each weaning attempt. Weaning outcomes at each attempt, length of ventilator and ICU stay, and mortality were recorded. Data collection was initiated after approval of the Institutional Ethics Committee. Receiver operating curve (ROC) analysis was done to identify the cut-off value of serum phosphate which predicted successful weaning. Results Of 60 participants, hypophosphatemia on admission was present in 15 (25%) patients. Despite the correction, 13 (21.7%) patients had hypophosphatemia before the first weaning attempt. Only 22 patients out of 60 were successfully weaned off from mechanical ventilation in the first trial, accounting for a success rate of 36.7%, of whom 20 were normophosphatemic (90.9%). In the second and third weaning trials, hypophosphatemia was significantly associated with weaning failure. Overall differences in mean serum phosphate levels among those who failed to wean in each weaning trial and the successful attempt were statistically significant (p < 0.001). On ROC analysis of serum phosphate level before the first weaning trial, a cut-off value of ≥3.0 mg/dL was identified to have 86.4% sensitivity, 55.3% specificity, 52.8% positive predictive value, 87.5% negative predictive value, and 66.7% diagnostic accuracy in predicting weaning success. Five patients died, accounting for a mortality rate of 8.3%. Lower mean serum phosphate levels before the first weaning trial, higher mean age, and longer ventilator and ICU days were significantly associated with mortality among our study participants (p < 0.05). Conclusions Our findings suggest that maintaining normal serum phosphate levels is critical to successfully weaning off patients with COPD from ventilator support., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Kundu et al.)

This paper presents a custom made small rover based surveying, mapping and building information modeling solution. Majority of the commercially available mobile surveying systems are larger in size which restricts their maneuverability in the targeted indoor vicinities. Furthermore their functional cost is unaffordable for low budget projects belonging to developing markets. Keeping in view these challenges, an economical indigenous rover based scanning and mapping system has developed using orthogonal integration of two low cost RPLidar A1 laser scanners. All the instrumentation of the rover has been interfaced with Robot Operating System (ROS) for online processing and recording of all sensorial data. The ROS based pose and map estimations of the rover have performed using Simultaneous Localization and Mapping (SLAM) technique. The perceived class 1 laser scans data belonging to distinct vicinities with variable reflective properties have been successfully tested and validated for required structural modeling. Systematically the recorded scans have been used in offline mode to generate the 3D point cloud map of the surveyed environment. Later the structural planes extraction from the point cloud data has been done using Random Sampling and Consensus (RANSAC) technique. Finally the 2D floor plan and 3D building model have been developed using point cloud processing in appropriate software. Multiple interiors of existing buildings and under construction indoor sites have been scanned, mapped and modelled as presented in this paper. In addition, the validation of the as-built models have been performed by comparing with the actual architecture design of the surveyed buildings. In comparison to available surveying solutions present in the local market, the developed system has been found faster, accurate and user friendly to produce more enhanced structural results with minute details., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jafri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The impact of COVID-19 infection on individuals with small cell lung cancer (SCLC) poses a serious threat. Unfortunately, the molecular basis of this severe comorbidity has yet to be elucidated. The present study addresses this gap utilizing publicly available omics data of COVID-19 and SCLC to explore the key molecules and associated pathways involved in the convergence of these diseases. Findings revealed 402 genes, that exhibited differential expression patterns in SCLC patients and also play a pivotal role in COVID-19 pathogenesis. Subsequent functional enrichment analyses identified relevant ontologies and pathways that are significantly associated with these genes, revealing important insights into their potential biological, molecular and cellular functions. The protein-protein interaction network, constructed under four combinatorial topological assessments, highlighted SMAD3, CAV1, PIK3R1, and FN1 as the primary components to this comorbidity. Our results suggest that these components significantly regulate this cross-talk triggering the PI3K-AKT and TGF-β signaling pathways. Lastly, this study made a multi-step computational attempt and identified corylifol A and ginkgetin from natural sources that can potentially inhibit these components. Therefore, the outcomes of this study offer novel perspectives on the common molecular mechanisms underlying SCLC and COVID-19 and present future opportunities for drug development.Communicated by Ramaswamy H. Sarma.

Lung cancer (LC) is one of the major and risky health defects even the serious cause for death in concurrent era. But no potential drugs even chemotherapeutic agents have been discovered with approval of health safety although some non-toxic biological macromolecules, such as polysaccharides and polysaccharide-protein complexes, have obtained as anti-lung cancer properties. This study conveys the anti-lung cancer properties of 45 polysaccharide derivatives collected from PubChem database. Primarily, the PASS prediction was performed to depict their anti-cancer activity, and 37 compounds showed the desired results. Next, the chemical descriptors, such as HOMO, LUMO, softness, and hardness etc, were calculated through the density functional theory (DFT) for quantum properties. Secondly, the auto molecular docking was executed to delineate the protein-ligand interactions, binding ability and inhibition of active sites of proteins. Additionally, the compounds showed docking score more than -6.40 kcal/mol, and the highest binding affinity was at -10.00 kcal/mol even 15 compounds have higher binding score (-8.6 to -10.0) than approved drugs, Gemcitabine. Succeeding, the most common protein residue, VAL 647, was blocked by ligands for the main protein (1X2J). In addition, five protein's active sites were determined to make the relative study of protein-ligand interactions. As a result, the target docking against five proteins was performed, and it was found that the targeted docking score as the binding affinity is lower than auto docking. Finally, a comparative study between auto docking and targeted docking was performed for the most common five lung cancer proteins founded in three organisms.Communicated by Ramaswamy H. Sarma.

Self-compacting mortar (SCM) has superior workability and long-term durable performance compared to traditional mortar. The strength of SCM, including both its compressive and flexural strengths, is a crucial property that is determined by appropriate curing conditions and mix design parameters. In the context of materials science, predicting the strength of SCM is challenging because of multiple influencing factors. This study employed machine learning techniques to establish SCM strength prediction models. Based on ten different input parameters, the strength of SCM specimens were predicted using two different types of hybrid machine learning (HML) models, namely Extreme Gradient Boosting (XGBoost) and the Random Forest (RF) algorithm. HML models were trained and tested by experimental data from 320 test specimens. In addition, the Bayesian optimization method was utilized to fine tune the hyperparameters of the employed algorithms, and cross-validation was employed to partition the database into multiple folds for a more thorough exploration of the hyperparameter space while providing a more accurate assessment of the model's predictive power. The results show that both HML models can successfully predict the SCM strength values with high accuracy, and the Bo-XGB model demonstrated higher accuracy (R 2 = 0.96 for training and R 2 = 0.91 for testing phases) for predicting flexural strength with low error. In terms of compressive strength prediction, the employed BO-RF model performed very well, with R 2 = 0.96 for train and R 2 = 0.88 testing stages with minor errors. Moreover, the SHAP algorithm, permutation importance and leave-one-out importance score were used for sensitivity analysis to explain the prediction process and interpret the governing input variable parameters of the proposed HML models. Finally, the outcomes of this study might be applied to guide the future mix design of SCM specimens.

Musculoskeletal (MS) pain is widely prevalent and is an important health issue for desk-based employees which has a negative impact on both personal and work life. This study aimed to determine the MS pain status and its association with mental health and other individual factors among desk-based officials of Dhaka, Bangladesh. This cross-sectional study comprised a sample of 526 desk-based officials from Dhaka, Bangladesh. Data were collected between November 2020 to March 2021. MS pain was determined by the visual analog scale (VAS) and depression and anxiety were screened by Hospital Anxiety and Depression Scale (HADS). Logistic regression analyses were employed to estimate the adjusted effect of independent factors on MS pain. The overall prevalence of MS pain was 64% among desk-based officials. The corresponding prevalence were 19% severe, 21% moderate and 24% mild MS pain. In the adjusted model, gender (AOR: 0.19, 95% CI: 0.07-0.46), BMI (AOR: 0.28, 95% CI: 0.14-0.59), monthly income (AOR: 5.17, 95% CI: 2.18-12.25), organization type (AOR: 4.3, 95% CI:1.8-10.1), floor living (AOR: 4.7, 95% CI:2.1-10.8), physical activity (AOR: 0.16, 95% CI: 0.06-0.45), and lift facility in the house (AOR: 4.11, 95% CI: 2.06-8.23) were associated with MS pain. In addition, the prevalence of anxiety and depression was 17.7% and 16.4%, respectively. Depression was identified as a significant predictor for severe MS pain (AOR: 2.44, 95%CI:1.29-4.63). This study has revealed a relatively high prevalence of MS pain and mental health problems among Bangladeshi desk-based officials. Preventive measures need to be taken from both organizational and personal sides to delimitate MS pain and mental health problems., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Iqbal Ahmed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Conventional convolutional neural networks (CNNs) present a high computational workload and memory access cost (CMC). Spectral domain CNNs (SpCNNs) offer a computationally efficient approach to compute CNN training and inference. This paper investigates CMC of SpCNNs and its contributing components analytically and then proposes a methodology to optimize CMC, under three strategies, to enhance inference performance. In this methodology, output feature map (OFM) size, OFM depth or both are progressively reduced under an accuracy constraint to compute performance-optimized CNN inference. Before conducting training or testing, it can provide designers guidelines and preliminary insights regarding techniques for optimum performance, least degradation in accuracy and a balanced performance-accuracy trade-off. This methodology was evaluated on MNIST and Fashion MNIST datasets using LeNet-5 and AlexNet architectures. When compared to state-of-the-art SpCNN models, LeNet-5 achieves up to 4.2× (batch inference) and 4.1× (single-image inference) higher throughputs and 10.5× (batch inference) and 4.2× (single-image inference) greater energy efficiency at a maximum loss of 3% in test accuracy. When compared to the baseline model used in this study, AlexNet delivers 11.6× (batch inference) and 5× (single-image inference) increased throughput and 25× (batch inference) and 8.8× (single-image inference) more energy-efficient inference with just 4.4% reduction in accuracy., Competing Interests: Competing interestsThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.)

Epigenetic modifications by toxic heavy metals are one of the intensively investigated fields of modern genomic research. Among a diverse group of heavy metals, lead (Pb) is an extensively distributed toxicant causing an immense number of abnormalities in the developing fetus via a wide variety of epigenetic changes. As a divalent cation, Pb can readily cross the placental membrane and the fetal blood brain barrier leading to far-reaching alterations in DNA methylation patterns, histone protein modifications, and micro-RNA expression. Over recent years, several human cohorts and animal model studies have documented hypermethylation and hypomethylation of developmental genes along with altered DNA methyl-transferase expression by in utero Pb exposure in a dose-, duration-, and sex-dependent manner. Modifications in the expression of specific histone acetyltransferase enzymes along with histone acetylation and methylation levels have been reported in rodent and murine models. Apart from these, down-regulation and up-regulation of certain microRNAs crucial for fetal development have been shown to be associated with in utero Pb exposure in human placenta samples. All these modifications in the developing fetus during the prenatal and perinatal stages reportedly caused severe abnormalities in early or adult age, such as impaired growth, obesity, autism, diabetes, cardiovascular diseases, risks of cancer development, and Alzheimer's disease. In this review, currently available information on Pb-mediated alterations in the fetal epigenome is summarized. Further research on Pb-induced epigenome modification will help to understand the mechanisms in detail and will enable us to formulate safety guidelines for pregnant women and developing children., (© 2022 John Wiley & Sons, Ltd.)

This paper presents the comparative evaluation of multiple compact and lightweight 2D laser scanners for their possible backpack based scanning and mapping applications. These scanners include Hokuyo URG-04LX, Slamtec RPLidar A1-M8 and Hokuyo UTM-30LX-EW scanners. Since the technical datasheets provide general information and limited working details, this research presents a thorough study on the performance of each scanner related explicitly to indoor mapping operations. A series of scanning experiments have been performed for the characterization of each scanner using statistical analysis. During the testing, all the scanning data has been recorded using Robot Operating System (ROS) and then computed in offline processing. In initial tests, each scanner's drift effect on range measurements has been tested and presented in the relevant section of the paper. In continuation, the effect of various scanning distances on measurement accuracy has been evaluated and discussed. Later the impact of various materials typically found in indoor vicinities and their respective properties of color and smoothness have been tested and provided in the paper. Finally, a Kalman Filtering based mathematical formulation has been utilized to calibrate each scanner and to reduce the measuring uncertainties as observed in various tests for each scanner., Competing Interests: The authors have declared that no competing interests exist.

A metabolic network of energy-sensing molecular pathways drives the biological ageing process. Regulating certain network elements can help decelerate the ageing process and ameliorate ageing associated disorders. Bioactive phytopeptides are a prospective avenue for anti-ageing therapeutics and rejuvenation biotechnology. The present study investigates the potential of therapeutic plant peptides against cellular senescence by targeting three key proteins in the ageing network - target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). This investigation screened a library of reported bioactive peptides using standard cheminformatic methods including in-silico ADMET, molecular docking, molecular dynamics simulation and molecular mechanics calculation. The retrieved simulation data predict 25 diverse phytopeptides as potential safe and drug-like anti-ageing biologics with half-lives >20 h and bioavailability scores >0.40. The best docked peptide, Cycloleonuripeptide B, exhibited strong binding affinity and stable complex formation with mTOR (-17.5 kCal/mol), SIRT1 (-28.54 kCal/mol) and two active sites in AMPK (-41.8 kCal/mol; -36.0 kCal/mol) during molecular dynamics simulations. The computational study acts as a foundation for future laboratory and clinical research into the potential of repurposing therapeutic phytopeptides against cellular senescence and associated pathophysiology. Communicated by Ramaswamy H. Sarma.

Colorectal cancer remains one of the leading prevalent cancers in the world and is the fourth most common cause of death from cancer. Unfortunately, the currently utilized chemotherapies fail in selectively targeting cancer cells and cause harm to healthy cells, which results in profound side effects. Researchers are focused on developing anti-cancer targeted medications, which is essential to making them safer, more effective, and more selective and to maximizing their therapeutic benefits. Milk-derived extracellular vesicles (EVs) from camels and cows have attracted much attention as a natural substitute product that effectively suppresses a wide range of tumor cells. This review sheds light on the biogenesis, methods of isolation, characterization, and molecular composition of milk EVs as well as the therapeutic potentials of milk EVs on colorectal cancer.

Heritiera fomes is a mangrove plant with a rich history of ethnomedicinal usage against chronic inflammation. Biochemical analyses of H. fomes have exposed a plethora of bioactive phytochemicals that contribute to this therapeutic effect by perturbing enzymes of a complex inflammatory network mediated by arachidonic acid (AA) metabolism. This study is the first instance of utilizing cheminformatic approaches to elucidate a molecular linkage between these phytochemical interventions and the multi-enzyme AA metabolic network regulation. Analysis of the simulations reflects H. fomes as a functional reservoir of multiple safe and potent natural anti-inflammatory compounds. The investigation suggests two phytocompounds extracted from the plant: a sesquiterpene lactone and a flavone glycoside, as candidate inhibitors of multiple catalytic checkpoints of the inflammatory network. The outcomes of this research act as a primary guideline for future laboratory and clinical testing of anti-inflammatory potentials of H. fomes as an exploitable source of safe and potent drug-like molecules.Communicated by Ramaswamy H. Sarma.

Emerging data show that pregnant women with COVID-19 are at significantly higher risk of severe outcomes compared with non-pregnant women of similar age. This review discusses the invaluable insight revealed from vaccine clinical trials in women who were vaccinated and inadvertently became pregnant during the trial period. It further explores a number of clinical avenues in their management and proposes a drug development strategy in line with clinical trials for vaccines and drug treatments for the drug development community. Little is known of the long-term effects of COVID-19 on the mother and the baby. Our hypothesis that COVID-19 predisposes pregnant women to pre-eclampsia or hypertensive disorders during pregnancy is supported by a clinical study, and this may also adversely impact a woman's cardiovascular disease risk later in life. It may also increase a woman's risk of pre-eclampsia in subsequent pregnancy. This is an ever-evolving landscape, and early knowledge for healthcare providers and drug innovators is offered to ensure benefits outweigh the risks. COVID-19 mRNA vaccines appear to generate robust humoral immunity in pregnant and lactating women. This novel approach to vaccination also offers new ways to therapeutically tackle disorders of many unmet medical needs. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aim: To investigate the genetic basis of autosomal recessive retinitis pigmentosa (arRP) in two consanguineous/ endogamous Pakistani families., Methods: Whole exome sequencing (WES) was performed on genomic DNA samples of patients with arRP to identify disease causing mutations. Sanger sequencing was performed to confirm familial segregation of identified mutations, and potential pathogenicity was determined by predictions of the mutations' functions., Results: A novel homozygous frameshift mutation [NM&#95;000440.2:c.1054delG, p. (Gln352Argfs*4); Chr5:g.149286886del (GRCh37)] in the PDE6A gene in an endogamous family and a novel homozygous splice site mutation [NM&#95;033100.3:c.1168-1G>A, Chr10:g.85968484G>A (GRCh37)] in the CDHR1 gene in a consanguineous family were identified. The PDE6A variant p. (Gln352Argfs*4) was predicted to be deleterious or pathogenic, whilst the CDHR1 variant c.1168-1G>A was predicted to result in potential alteration of splicing., Conclusion: This study expands the spectrum of genetic variants for arRP in Pakistani families., (International Journal of Ophthalmology Press.)

The penetration of microwave power inside a human head model is improved by employing a dielectric loaded rectangular waveguide as the transmission source. A multi-layer reflection model is investigated to evaluate the combined material characteristics of different lossy human head tissues at 2.45 GHz. A waveguide loaded with a calculated permittivity of 3.62 is shown to maximise the microwave power penetration at the desired frequency. A Quartz (SiO 2 ) loaded rectangular waveguide fed by a microstrip antenna is designed to validate the power penetration improvement inside an inhomogeneous human head phantom. A measured 1.33 dB power penetration increment is observed for the dielectric loaded waveguide over a standard rectangular waveguide at 50 mm inside the head, with an 81.9% reduction in the size of the transmission source., (© 2021. The Author(s).)

Introduction: After the first case of Covid-19 was identified in Wuhan City, China, the numbers increased rapidly all over the world putting a huge burden on the entire healthcare system. Managing these cases posed a great challenge to the treating clinicians in the absence of targeted therapy. At this juncture, few modalities got approved as EUA (Emergency use under authorization) drugs namely Remdesivir, Convalescent Plasma (CP), and Tocilizumab (TCZ) to treat this deadly disease., Aim: To analyze the success rates of EUA therapies for Covid-19 pneumonia in our hospital., Materials and Methods: This was a prospective observational study conducted from April 2020 to October 2020 in the department of Medicine at Tata Main Hospital, Jamshedpur, Jharkhand. All adults with moderate to severe Covid-19 as per the WHO criteria were enrolled in the study with their informed consent. Patients with estimated glomerular filtration rate <30 mL/min, deranged liver function tests, electrocardiographic abnormalities, and deranged hematological parameters were excluded from the study. Thorough clinical evaluation was done in all cases. Routine investigations together with CRP, LDH, serum Ferritin, D Dimer and IL6, Chest X-Ray, and HRCT thorax were done in all cases. ECG was done in all cases and 2D-ECHO in selected ones. Depending on their clinical and radiological criteria, patients were treated with various modalities approved under EUA with close monitoring of clinical, biochemical, and radiological parameters. Presenting symptoms, clinical findings, co-morbidities, laboratory parameters, and radiological assessment were analyzed, and statistical analysis was done. The survival rate and in-hospital mortality was analyzed., Observations and Results: We had a total of 448 patients who were included in our study, out of which 326 were males and 122 were females with a male to female ratio of 2.7:1. Their age varied between 16 and 91 years with an average age of 51.4 years with a standard deviation (SD) of +/- 6.4 years. About 255 patients (57%) received only Remdesivir (176 males, 79 females), 139 (105 males, 35 females) patients (31%) received Remdesivir along with two units of CP, and 38 (32 males, 6 females) patients received a combination of Remdesivir, CP, and TCZ. All patients in our study tolerated the drugs well. About 5% of cases who received CP had minor transfusion reactions. One patient had TRALI and three patients had TACO, which was managed aggressively. Asymptomatic transaminitis was seen in 36% patients. The survival rate in patients treated with Remdesivir was 78%, those with Remdesivir and CP was 44%, and those with all three was 13%. The mean length of stay was 14.23 days with a SD of 9.06 days in patients treated with TCZ in comparison to other two modalities, which was 13.88 days with a standard variation of +/- 8.71 days in Remdesivir and 13.88 days with a SD of 8.73 days in patients treated with CP that was stastically significant., Conclusions: Though the success rate of various drugs under EUA varies in different studies from all over the world, the data to support their use are encouraging. We also observed satisfying results in our study specially with the use of Remdesivir. Therefore, EUA agents should be used early to fight against COVID-19 along with the other measures as per the protocol laid by ICMR and MoHFW., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

Recently developed medicated dressings target either bacterial or fungal infection only, which is not effective for the treatment of mixed infections common in diabetic foot ulcers (DFUs). This study aimed to develop advanced bioactive alginate-based dressings (films and wafers) to deliver therapeutically relevant doses of ciprofloxacin (CIP) and fluconazole (FLU) to target mixed bacterial and fungal infections in DFUs. The alginate compatibility with the drugs was confirmed by SEM, XRD, FTIR and texture analysis, while the medicated wafers showed better fluid handling properties than the films in the presence of simulated wound fluid. The dressings showed initial fast release of FLU followed by sustained release of CIP which completely eradicated E. coli, S. aureus, P. aeruginosa and reduced fungal load (C. albicans) by 10-fold within 24 h. Moreover, the medicated dressings were biocompatible (>70% cell viability over 72 h) with human primary adult keratinocytes and in-vitro scratch assay showed 65-68% wound closure within 7 days., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2) receptor. Other important proteins involved in this process include disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) also known as tumour necrosis factor-α-converting enzyme and transmembrane serine protease 2. ACE2 converts angiotensin II (Ang II) to angiotensin (1-7), to balance the renin angiotensin system. Membrane-bound ACE2 ectodomain shedding is mediated by ADAM17 upon viral spike binding, Ang II overproduction and in several diseases. The shed soluble ACE2 (sACE2) retains its catalytic activity, but its precise role in viral entry is still unclear. Therapeutic sACE2 is claimed to exert dual effects; reduction of excess Ang II and blocking viral entry by masking the spike protein. Nevertheless, the paradox is why SARS-CoV-2 comorbid patients struggle to attain such benefit in viral infection despite having a high amount of sACE2. In this review, we discuss the possible detrimental role of sACE2 and speculate on a series of events where protease primed or non-primed virus-sACE2 complex might enter the host cell. As extracellular virus can bind many sACE2 molecules, sACE2 level could be reduced drastically upon endocytosis by the host cell. A consequential rapid rise in Ang II level could potentially aggravate disease severity through Ang II-angiotensin II receptor type 1 (AT1R) axis in comorbid patients. Hence, monitoring sACE2 and Ang II level in coronavirus disease 2019 comorbid patients are crucial to ensure safe and efficient intervention using therapeutic sACE2 and vaccines., (© 2020 John Wiley & Sons Ltd.)

Placenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy., (© 2021. The Author(s).)

Background: Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4000 individuals worldwide. The most common form of syndromic RP is Usher syndrome (USH) accounting for approximately 20-30 % of RP cases. Mutations in the USH2A gene cause a significant proportion of recessive non-syndromic RP and USH type II (USH2). This study aimed to determine the causative role of the USH2A gene in autosomal recessive inherited ocular diseases and to establish genotype-phenotype correlation associated with USH2A variants., Methods: We performed direct Sanger sequencing and co-segregation analysis of the USH2A gene to identify disease causing variants in a non-syndromic RP family, two USH2 families and two Keratoconus (KC) families., Results: Disease causing variants in the USH2A gene were identified in two families displayed KC and USH2 phenotypes. A novel variant c.4029T > G, p.Asn1343Lys in the USH2A gene was detected in a Pakistani family with KC phenotype. In addition, a missense variant (c.7334 C > T, p. Ser2445Phe) in the USH2A gene was found segregating in another Pakistani family with USH2 phenotype. Homozygosity of identified missense USH2A variants was found associated with autosomal recessive inherited KC and USH2 phenotypes in investigated families. These variants were not detected in ethnically matched healthy controls. Moreover, the USH2A variants were predicted to be deleterious or potentially disease causing by PolyPhen-2, PROVEAN and SIFT., Conclusions: This study provided first evidence for association of a novel USH2A variant with KC phenotype in a Pakistani family as well as established the phenotype-genotype correlation of a USH2A variant (c.7334 C > T, p. Ser2445Phe) with USH2 phenotype in another Pakistani family. The phenotype-genotype correlations established in present study may improve clinical diagnosis of affected individuals for better management and counseling.

Preeclampsia affects one in twelve of the 130 million pregnancies a year. The lack of an effective therapeutic to prevent or treat it is responsible for an annual global cost burden of 100 billion US dollars. Preeclampsia also affects these women later in life as it is a recognised risk factor for cardiovascular disease, stroke and vascular dementia. Our laboratory demonstrated that preeclampsia is associated with high soluble fms-like tyrosine kinase 1 (sFlt-1) and low heme oxygenase-1 (HO1/Hmox1) expression. Here we sought to determine the therapeutic value of a novel H 2 S-releasing aspirin (MZe786) in HO-1 haploid deficient (Hmox1 +/- ) pregnant mice in a high sFlt-1 environment. Pregnant Hmox1 +/- mice were injected with adenovirus encoding sFlt-1 or control virus at gestation day E11.5. Subsequently, Hmox1 +/- dams were treated daily with a number of treatment regimens until E17.5, when maternal and fetal outcomes were assessed. Here we show that HO-1 compromised mice in a high sFlt-1 environment during pregnancy exhibit severe preeclampsia signs and a reduction in antioxidant genes. MZe786 ameliorates preeclampsia by reducing hypertension and renal damage possibly by stimulating antioxidant genes. MZe786 also improved fetal outcome in comparison with aspirin alone and appears to be a better therapeutic agent at preventing preeclampsia than aspirin alone., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

An imbalance in angiogenic growth factors and poor utero-placental perfusion are strongly associated with preeclampsia. The reduced utero-placental perfusion (RUPP) model that mimics insufficient placental perfusion is used to study preeclampsia. The aim of this study was to develop a refined RUPP model in C57Bl/6 J mice to test the efficacy of MZe786 as a potential inhibitor of soluble Flt-1 for preeclampsia therapy. Murine RUPP (mRUPP) was induced through bilateral ligation of the ovarian arteries at E11.5 that resulted in typical preeclampsia symptoms including increase in mean arterial pressure (MAP), kidney injury and elevated soluble Flt-1 (sFlt-1) levels in the maternal plasma and amniotic fluid. The murine RUPP kidneys showed tubular and glomerular damage along with increased oxidative stress characterised by increased nitrotyrosine staining. The mRUPP displayed abnormal placental vascular histology, reduced expression of placental cystathionine γ-lyase (CSE), the hydrogen sulfide (H 2 S) producing enzyme, and resulted in adverse fetal outcomes (FGR). Importantly, oral administration of hydrogen sulfide (H 2 S)-releasing compound MZe786 from E11.5 to E17.5 successfully prevented the development of preeclampsia. Specifically, MZe786 treatment reduced maternal MAP and kidney nitrotyrosine staining and improved fetal outcome. The circulation levels of sFlt-1 were dramatically decreased in MZe786 treated animals implying that H 2 S released from MZe786 offered protection by inhibiting sFlt-1 levels. MZe786 prevent preeclampsia and warrant a rapid move to randomised control clinical trial., (Copyright © 2020. Published by Elsevier B.V.)

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management., Objectives: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers., Design: This was an individual participant data meta-analysis of cohort studies., Setting: Source data from secondary and tertiary care., Predictors: We identified predictors from systematic reviews, and prioritised for importance in an international survey., Primary Outcomes: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia., Analysis: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C -statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I 2 and τ 2 . A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals., Results: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C -statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia., Limitations: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data., Conclusion: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings., Future Work: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate., Study Registration: This study is registered as PROSPERO CRD42015029349., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

Throughout history, the human race has often faced pandemics with substantial numbers of fatalities. As the COVID-19 pandemic has now affected the whole planet, even countries with moderate to strong healthcare support and expenditure have struggled to contain disease transmission and casualties. Countries affected by COVID-19 have different demographics, socioeconomic, and lifestyle health indicators. In this context, it is important to find out to what extent these parametric variations are modulating disease outcomes. To answer this, this study selected demographic, socioeconomic, and health indicators e.g., population density, percentage of the urban population, median age, health expenditure per capita, obesity, diabetes prevalence, alcohol intake, tobacco use, case fatality of non-communicable diseases (NCDs) as independent variables. Countries were grouped according to these variables and influence on dependent variables e.g., COVID-19 positive tests, case fatality, and case recovery rates were statistically analyzed. The results suggested that countries with variable median age had a significantly different outcome on positive test rate ( P < 0.01). Both the median age ( P = 0.0397) and health expenditure per capita ( P = 0.0041) showed a positive relation with case recovery. An increasing number of tests per 100 K of the population showed a positive and negative relationship with the number of positives per 100 K population ( P = 0.0001) and the percentage of positive tests ( P < 0.0001), respectively. Alcohol intake per capita in liter ( P = 0.0046), diabetes prevalence ( P = 0.0389), and NCDs mortalities ( P = 0.0477) also showed a statistical relation to the case fatality rate. Further analysis revealed that countries with high healthcare expenditure along with high median age and increased urban population showed more case fatality but also had a better recovery rate. Investment in the health sector alone is insufficient in controlling the severity of the pandemic. Intelligent and sustainable healthcare both in urban and rural settings and healthy lifestyle acquired immunity may reduce disease transmission and comorbidity induced fatalities, respectively., (Copyright © 2020 Ahmed, Haque and Rahman.)

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting., Methods: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis., Results: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%., Conclusions: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice., Trial Registration: PROSPERO ID: CRD42015029349 .

Endothelial dysfunction is a hallmark of preeclampsia, a life-threatening complication of pregnancy characterised by hypertension and elevated soluble Fms-Like Tyrosine Kinase-1 (sFlt-1). Dysregulation of hydrogen sulfide (H 2 S) by inhibition of cystathionine γ-lyase (CSE) increases sFlt-1 and soluble endoglin (sEng) release. We explored whether compromise in CSE/H 2 S pathway is linked to dysregulation of the mitochondrial bioenergetics and oxidative status. We investigated whether these effects were linked to CSE-induced sFlt-1 and sEng production in endothelial cells. Here, we demonstrate that CSE/H 2 S pathway sustain endothelial mitochondrial bioenergetics and loss of CSE increases the production of mitochondrial-specific superoxide. As a compensatory effect, low CSE environment enhances the reliance on glycolysis. The mitochondrial-targeted H 2 S donor, AP39, suppressed the antiangiogenic response and restored the mitochondrial bioenergetics in endothelial cells. AP39 revealed that upregulation of sFlt-1, but not sEng, is independent of the mitochondrial H 2 S metabolising enzyme, SQR. These data provide new insights into the molecular mechanisms for antiangiogenic upregulation in a mitochondrial-driven environment. Targeting H 2 S to the mitochondria may be of therapeutic benefit in the prevention of endothelial dysfunction associated with preeclampsia.

Objective: The aim of this systematic review was to evaluate the effectiveness of laser application in temporomandibular joint disorder., Methods: PubMed, SCOPUS, Science Direct, Web of Science, and Google Scholar electronic databases were searched systematically with restricting the languages to only English and year (January 2001 to March 2020), and studies were selected based on the inclusion criteria. Study quality and publication bias were assessed by using the Robvis, a software package of R statistical software., Results: This systematic review included 32 studies (1172 patients) based on the inclusion and exclusion criteria. Most of the studies reported significant reduction of pain by the use of the laser during TMD treatment. Two-thirds of the study (78.13%) found a better outcome comparing with conventional one. According to Robvis, 84.4% of the studies were high methodological studies with low risk of bias., Conclusion: TMD patients suffer with continuous pain for long time even after conventional treatment. Laser therapy shows a promising outcome of pain reduction for TMD patients. Therefore, laser therapy can be recommended for the TMD patients' better outcome. This trial is registered with PROSPERO (CRD42020177562)., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Abdalwhab Zwiri et al.)

Hypertensive disorder in pregnancy is a major cause of maternal and perinatal mortality worldwide. Women who have had preeclampsia are at three to four times higher risk in later life of developing high blood pressure and heart disease. Soluble Flt-1 (sFlt-1) is elevated in preeclampsia and may remain high postpartum in women with a history of preeclampsia. Heme oxygenase-1 (Hmox1/HO-1) exerts protective effects against oxidative stimuli and is compromised in the placenta of pregnant women with preeclampsia. We hypothesized that sFlt-1 inhibits cardiac mitochondrial activity in HO-1 deficient mice. HO-1 haplo-insufficient mice (Hmox1 +/- ) were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) or control virus (Ad-CMV). Subsequently, they were treated daily with either placebo or MZe786 for six days, when the heart tissue was harvested to assess cardiac mitochondrial activity. Here, we show that the loss of HO-1 disturbed cardiac mitochondrial respiration and reduced mitochondrial biogenesis. The overexpression of sFlt-1 resulted in the inhibition of the cardiac mitochondrial activity in Hmox1 +/- mice. The present study demonstrates that the hydrogen sulfide (H 2 S) releasing molecule, MZe786, rescues mitochondrial activity by stimulating cardiac mitochondrial biogenesis and antioxidant defense in Hmox1 -/- mice and in Hmox1 +/- mice exposed to a high sFlt-1 environment.

Background: Spiritual health forms the core of health and is associated with better physical and mental health. Spiritual health and wellbeing has been shown to be significantly associated with better mental outcomes, yet there's lack of understanding of the determinants of spiritual health. Religious practices have been shown to improve health and have been assumed to be associated with spirituality, yet there remains a gap between religious practices and spiritual health. It is therefore, crucial to understand the role of religious beliefs and practices in improving spiritual health., Purpose: To assess spiritual wellbeing between religious and non-religious professionals and assess how regional religious beliefs and practices are associated with spiritual wellbeing., Methods: We examined spiritual health among religious and non-religious professionals. A comparative cross sectional study was done with a sample size of 210. Differences of spiritual health and spiritual experiences, perceived spiritual traits and psychological parameters were observed., Results: Religious professionals were found to be more spiritually healthy than non-religious professionals (P < .05). Spiritual experiences weakly contribute to spiritual health (r = 0.39, P < .05). Perceived spiritual traits including frequency of prayer (β = 5.25, CI = 1.80-8.70, P < .01) and belief in the presence of Supreme Being (β = 1.001, CI = 0.120-1.883, P < .05) influenced spiritual wellbeing and spiritual wellbeing showed a negative association with psychological parameters including anger (OR = 0.95, CI = 0.929-0.987, P < .05)., Conclusion and Implications: The findings from this study show that religious professionals tend to be more spiritually healthy than non-religious professionals highlighting the importance of incorporating religious practices to ensure spiritual wellbeing. Improving spiritual wellbeing can provide an important tool for promoting holistic healing.

Numerous studies have been conducted in the previous years with an objective to determine the ideal biomarker or set of biomarkers in temporomandibular disorders (TMDs). It was recorded that tumour necrosis factor (TNF), interleukin 8 (IL-8), IL-6, and IL-1 were the most common biomarkers of TMDs. As of recently, although the research on TMDs biomarkers still aims to find more diagnostic agents, no recent study employs the biomarker as a targeting point of pharmacotherapy to suppress the inflammatory responses. This article represents an explicit review on the biomarkers of TMDs that have been discovered so far and provides possible future directions towards further research on these biomarkers. The potential implementation of the interactions of TNF with its receptor 2 (TNFR2) in the inflammatory process has been interpreted, and thus, this review presents a new hypothesis towards suppression of the inflammatory response using TNFR2-agonist. Subsequently, this hypothesis could be explored as a potential pain elimination approach in patients with TMDs.

The Solanaceae is an important plant family that has been playing an essential role in traditional medicine and human nutrition. Members of the Solanaceae are rich in bioactive metabolites and have been used by different tribes around the world for ages. Antimicrobial peptides (AMPs) from plants have drawn great interest in recent years and raised new hope for developing new antimicrobial agents for meeting the challenges of antibiotic resistance. This review aims to summarize the reported AMPs from plants of the Solanaceae with possible molecular mechanisms of action as well as to correlate their traditional uses with reported antimicrobial actions of the peptides. A systematic literature study was conducted using different databases until August 2019 based on the inclusion and exclusion criteria. According to literature, a variety of AMPs including defensins, protease inhibitor, lectins, thionin-like peptides, vicilin-like peptides, and snaking were isolated from plants of the Solanaceae and were involved in their defense mechanism. These peptides exhibited significant antibacterial, antifungal and antiviral activity against organisms for both plant and human host. Brugmansia, Capsicum , Datura , Nicotiana, Salpichora, Solanum , Petunia , and Withania are the most commonly studied genera for AMPs. Among these genera, Capsicum and the Solanum ranked top according to the total number of studies (35%-38% studies) for different AMPs. The mechanisms of action of the reported AMPs from Solanaceae was not any new rather similar to other reported AMPs including alteration of membrane potential and permeability, membrane pore formation, and cell aggregation. Whereas, induction of cell membrane permiabilization, inhibition of germination and alteration of hyphal growth were reported as mechanisms of antifungal activity. Plants of the Solanaceae have been used traditionally as antimicrobial, insecticidal, and antiinfectious agents, and as poisons. The reported AMPs from the Solanaceae are the products of chemical shields to protect plants from microorganisms and pests which unfold an obvious link with their traditional medicinal use. In summary, it is evident that AMPs from this family possess considerable antimicrobial activity against a wide range of bacterial and fungal pathogens and can be regarded as a potential source for lead molecules to develop new antimicrobial agents., (Copyright © 2020 Afroz, Akter, Ahmed, Rouf, Shilpi, Tiralongo, Sarker, Göransson and Uddin.)

Background/aims: The impact of a scientific article in its respective field is reflected by its citation count. The purpose of this review was to conduct a citation analysis in order to identify and analyze the top 50 most cited articles published in Dental Traumatology since its inception in order to highlight the contribution of the journal to the field of Dental Traumatology., Methods: Elsevier's Scopus was used to search and analyze the 50 most frequently cited scientific papers. After the screening process, two reviewers arranged the articles in a descending order based on their citation counts. Each article was then cross-matched with Google Scholar. The articles were analyzed, and information including citation counts, citation density, publication year, authorship, contributing institutions and countries, article topic, study design, and keywords was extracted., Results: The literature search identified 2421 articles. The citation counts of the 50 selected articles varied from 117 to 580 (Scopus) and 206 to 1130 (Google Scholar). The year in which most top 50 articles were published was 2002 (n = 5). Among 105 authors, the greatest contribution was made by JO Andreasen (n = 12). Most of the articles originated from the United States (n = 12) with the greatest contributions from the University Hospital (Rigshospitalet), Copenhagen, Denmark (n = 6). Original research article was the most frequent study design (n = 34). The majority of the top 50 articles were focused on traumatic dental injuries. Among 131 unique key words, root resorption (n = 6) was the most frequently used. A non-significant correlation occurred between citation count (correlation coefficient = 0.127, P = .378), citation density (correlation coefficient = 0.654, P = 2.493), and publication age., Conclusions: This study identified the top 50 most cited articles published in this journal in the specialty of Dental Traumatology. The publication year of an article was not significantly associated with citation count nor citation density., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We recently derived mouse expanded potential stem cells (EPSCs) from individual blastomeres by inhibiting the critical molecular pathways that predispose their differentiation. EPSCs had enriched molecular signatures of blastomeres and possessed developmental potency for all embryonic and extra-embryonic cell lineages. Here, we report the derivation of porcine EPSCs, which express key pluripotency genes, are genetically stable, permit genome editing, differentiate to derivatives of the three germ layers in chimeras and produce primordial germ cell-like cells in vitro. Under similar conditions, human embryonic stem cells and induced pluripotent stem cells can be converted, or somatic cells directly reprogrammed, to EPSCs that display the molecular and functional attributes reminiscent of porcine EPSCs. Importantly, trophoblast stem-cell-like cells can be generated from both human and porcine EPSCs. Our pathway-inhibition paradigm thus opens an avenue for generating mammalian pluripotent stem cells, and EPSCs present a unique cellular platform for translational research in biotechnology and regenerative medicine.

Aims: Randomized controlled trials have shown that cardiac resynchronization therapy (CRT) prolongs survival in patients with heart failure. No studies have explored survival after CRT in relation to individuals in the general population (relative survival, RS). We sought to determine observed and RS after CRT in a nationwide cohort undergoing CRT., Methods and Results: A national administrative database was used to quantify observed mortality for patients undergoing CRT. Relative survival (RS) was quantified using life tables. In 50 084 patients [age 72.1 ± 11.6 years (mean ± standard deviation)] undergoing CRT with (CRT-D) (n = 25 273) or without (CRT-P) defibrillation (n = 24 811) over 8.8 years (median follow-up 2.7 years, interquartile range 1.3-4.8), expected survival decreased with age. Device type, male sex, ischaemic heart disease, diabetes, and chronic kidney disease predicted excess mortality. In multivariate analyses, excess mortality (analogue of RS) was lower after CRT-D than after CRT-P in all patients [adjusted hazard ratio (aHR) 0.80, 95% confidence interval (CI) 0.76-0.84] as well as in subgroups with (aHR 0.79, 95% CI 0.74-0.84) or without (aHR 0.82, 95% CI 0.74-0.91) ischaemic heart disease. A Charlson Comorbidity Index (CCI) ≥3 portended a higher excess mortality (aHR 3.04, 95% CI 2.76-3.34). Relative survival was higher in 2015-2017 than in 2009-2011 (aHR 0.64, 95% CI 0.59-0.69)., Conclusion: Reference RS data after CRT is presented. Sex, ischaemic heart disease, diabetes, chronic kidney disease, and CCI were major determinants of RS after CRT. CRT-D was associated with a higher RS than CRT-P in patients with or without ischaemic heart disease. Relative survival after CRT improved from 2009 to 2017., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Nowadays, the electrical and electronic products are a crucial commodity for different purposes of daily life and they are multiplying five times faster than human like mobile phones, which has reached zero to 7.2 billion in only three decades. A 5-10% yearly increase in the amount of used electrical and electronic equipment that are disposed of prudently can cause environmental hazards that have an aversive effect on human health, marine life, contamination of groundwater, and reduces soil's fertility. Management of this enormous influx of electrical and electronic waste is a challenge for developing countries like Bangladesh with barebones solid waste management infrastructure. Inadequacy of public awareness, policies and poor budget in the field of waste management are few of the key factors behind this delineating scenario. In this study, the picture electrical and electronic waste productions in Bangladesh along with the recent E-waste management systems have been presented comprehensively. Based on the study, it was concluded that most of the adapted E-waste management methods are conversational and detached from current technological capability. A set of sustainable E-waste management system has been suggested along with the challenges, which might appear during the implementation of these strategies. Successful implementation of these suggested systems would advance the quality of E-waste management in Bangladesh increasing the current 35% overall E-waste recycling rate and offer enormous energy from the waste.

The use of travelling surface acoustic waves (TSAW) in a microfluidic system provides a powerful tool for the manipulation of particles and cells. In a TSAW driven system, acoustophoretic effects can cause suspended micro-objects to display three distinct responses: (1) swirling, driven by acoustic streaming forces, (2) migration, driven by acoustic radiation forces and (3) patterning in a spatially periodic manner, resulting from diffraction effects. Whilst the first two phenomena have been widely discussed in the literature, the periodic patterning induced by TSAW has only recently been reported and is yet to be fully elucidated. In particular, more in-depth understanding of the size-dependant nature of this effect and the factors involved are required. Herein, we present an experimental and numerical study of the transition in acoustophoretic behaviour of particles influenced by relative dominance of these three mechanisms and characterise it based on particle diameter, channel height, frequency and intensity of the TSAW driven microfluidic system. This study will enable better understanding of the performance of TSAW sorters and allow the development of TSAW systems for particle collection and patterning.

Calcium alginate (CA) wafer dressings were prepared by lyophilization of hydrogels to deliver ciprofloxacin (CIP) directly to the wound site of infected diabetic foot ulcers (DFUs). The dressings were physically characterized by scanning electron microscopy (SEM), texture analysis (for mechanical and in vitro adhesion properties), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Further, functional properties essential for wound healing, i.e., porosity, in vitro swelling index, water absorption (Aw), equilibrium water content (EWC), water vapor transmission rate (WVTR), evaporative water loss (EWL), moisture content, in vitro drug release and kinetics, antimicrobial activity, and cell viability (MTT assay) were investigated. The wafers were soft, of uniform texture and thickness, and pliable in nature. Wafers showed ideal wound dressing characteristics in terms of fluid handling properties due to high porosity (SEM). XRD confirmed crystalline nature of the dressings and FTIR showed hydrogen bond formation between CA and CIP. The dressings showed initial fast release followed by sustained drug release which can inhibit and prevent re-infection caused by both Gram-positive and Gram-negative bacteria. The dressings also showed biocompatibility (> 85% cell viability over 72 h) with human adult keratinocytes. Therefore, it will be a potential medicated dressing for patients with DFUs infected with drug-resistant bacteria.

Background: Throughout history, menopause has been regarded as a transition in a woman's life. With the increase in life expectancy, women now spend more than a third of their lives in menopause. During these years, women may experience intolerable symptoms both physically and mentally, leading them to seek clinical advice. It is imperative for healthcare providers to improve the quality of life by reducing bothersome menopausal symptoms and preventing disorders such as osteoporosis and atherosclerosis. The current treatment in the form of hormone replacement therapy (HRT) is sometimes inadequate with several limitations and adverse effects. Objective and rationale: The current review aims to discuss the need, efficacy, and limitations of current HRT; the role of other ovarian hormones, and where we stand in comparison with ovary-in situ; and finally, explore towards the preparation of an HRT model by regeneration of ovaries tissues through stem cells which can replicate a functional ovary., Search Methods: Four electronic databases (MEDLINE, Embase, Web of Science and CINAHL) were searched from database inception until 26 April 2018, using a combination of relevant controlled vocabulary terms and free-text terms related to 'menopause', 'hormone replacement therapy', 'ovary regeneration', 'stem cells' and 'ovarian transplantation'., Outcomes: We present a synthesis of the existing data on the efficacy and limitations of HRT. HRT is far from adequate in postmenopausal women with symptoms of hormone deprivation as it fails to deliver all hormones secreted by naïve ovarian tissue. Moreover, the pharmacokinetics of synthetic hormones makes them substantially different from natural ones. Not only does the number and type of hormones given in HRT matter, but the route of delivering and their release in circulation are also imperative. The hormones are delivered either orally or topically in a non-physiological uniform manner, which brings along with it several side effects. These identify the need for a hormone delivery system which replicates, integrates and reacts as per the requirement of the female body. Wider implications: The review outlines the strengths and weaknesses of HRT and highlights the potential areas for future research. There is a tremendous potential for research in this field to understand the collective roles of the various ovarian hormones and to devise an auto-regulated hormone delivery system which replicates the normal physiology. Its clinical applications can prove to be transformative for postmenopausal women helping them to lead a healthy and productive life.

We demonstrate a novel differential phase-shift-keying (DPSK) demodulator based on coherent perfect absorption (CPA). Our DPSK demodulator chip device, which incorporates a silicon ring resonator, two bus waveguide inputs, and monolithically integrated detectors, operates passively at a bit rate of 10 Gbps at telecommunication wavelengths, and fits within a mm-scale footprint. Critical coupling is used to achieve efficient CPA by tuning the gap between the ring and bus waveguides. The device has a vertical eye opening of 12.47 mV and a quality factor exceeding 3×10 4 . The fundamental principle behind this photonic circuit can be extended to other formats of integrated demodulators.

Preeclampsia is a maternal hypertensive disorder that affects up to 1 out of 12 pregnancies worldwide. It is characterized by proteinuria, endothelial dysfunction, and elevated levels of the soluble form of the vascular endothelial growth factor receptor-1 (VEGFR-1, known as sFlt-1). sFlt-1 effects are mediated in part by decreasing VEGF signaling. The direct effects of sFlt-1 on cellular metabolism and bioenergetics in preeclampsia, have not been established. The goal of this study was to evaluate whether sFlt-1 causes mitochondrial dysfunction leading to disruption of normal functioning in endothelial and placental cells in preeclampsia. Endothelial cells (ECs) and first-trimester trophoblast (HTR-8/SVneo) were treated with serum from preeclamptic women rich in sFlt-1 or with the recombinant protein. sFlt-1, dose-dependently inhibited ECs respiration and acidification rates indicating a metabolic phenotype switch enhancing glycolytic flux. HTR-8/SVneo displayed a strong basal glycolytic metabolism, remaining less sensitive to sFlt-1-induced mitochondrial impairment. Moreover, results obtained in ECs exposed to serum from preeclamptic subjects demonstrated that increased sFlt-1 leads to metabolic perturbations accountable for mitochondrial dysfunction observed in preeclampsia. sFlt-1 exacerbated mitochondrial reactive oxygen species (ROS) formation and mitochondrial membrane potential dissipation in ECs and trophoblasts exposed to serum from preeclamptic women. Forcing oxidative metabolism by culturing cells in galactose media, further sensitized cells to sFlt-1. This approach let us establish that sFlt-1 targets mitochondrial function in ECs. Effects of sFlt-1 on HTR-8/SVneo cells metabolism were amplified in galactose, demonstrating that sFlt-1 only target cells that rely mainly on oxidative metabolism. Together, our results establish the early metabolic perturbations induced by sFlt-1 and the resulting endothelial and mitochondrial dysfunction in preeclampsia.