Social determinants of respiratory health from birth: still of concern in the 21st century?

Respiratory symptoms are ubiquitous in children and, even though they may be the harbinger of poor long-term outcomes, are often trivialised. Adverse exposures pre-conception, antenatally and in early childhood have lifetime impacts on respiratory health. For the most part, lung function tracks from the pre-school years at least into late middle age, and airflow obstruction is associated not merely with poor respiratory outcomes but also early all-cause morbidity and mortality. Much would be preventable if social determinants of adverse outcomes were to be addressed. This review presents the perspectives of paediatricians from many different contexts, both high and low income, including Europe, the Americas, Australasia, India, Africa and China. It should be noted that there are islands of poverty within even the highest income settings and, conversely, opulent areas in even the most deprived countries. The heaviest burden of any adverse effects falls on those of the lowest socioeconomic status. Themes include passive exposure to tobacco smoke and indoor and outdoor pollution, across the entire developmental course, and lack of access even to simple affordable medications, let alone the new biologicals. Commonly, disease outcomes are worse in resource-poor areas. Both within and between countries there are avoidable gross disparities in outcomes. Climate change is also bearing down hardest on the poorest children. This review highlights the need for vigorous advocacy for children to improve lifelong health. It also highlights that there are ongoing culturally sensitive interventions to address social determinants of disease which are already benefiting children.

Genome and secretome insights: unravelling the lignocellulolytic potential of Myceliophthora verrucosa for enhanced hydrolysis of lignocellulosic biomass.

Lignocellulolytic enzymes from a novel Myceliophthora verrucosa (5DR) strain was found to potentiate the efficacy of benchmark cellulase during saccharification of acid/alkali treated bagasse by ~ 2.24 fold, indicating it to be an important source of auxiliary enzymes. The De-novo sequencing and analysis of M. verrucosa genome (31.7 Mb) revealed to encode for 7989 putative genes, representing a wide array of CAZymes (366) with a high proportions of auxiliary activity (AA) genes (76). The LC/MS QTOF based secretome analysis of M. verrucosa showed high abundance of glycosyl hydrolases and AA proteins with cellobiose dehydrogenase (CDH) (AA8), being the most prominent auxiliary protein. A gene coding for lytic polysaccharide monooxygenase (LPMO) was expressed in Pichia pastoris and CDH produced by M. verrucosa culture on rice straw based solidified medium were purified and characterized. The mass spectrometry of LPMO catalyzed hydrolytic products of avicel showed the release of both C1/C4 oxidized products, indicating it to be type-3. The lignocellulolytic cocktail comprising of in-house cellulase produced by Aspergillus allahabadii strain spiked with LPMO & CDH exhibited enhanced and better hydrolysis of mild alkali deacetylated (MAD) and unwashed acid pretreated rice straw slurry (UWAP), when compared to Cellic CTec3 at high substrate loading rate.

Unveiling the Role of PAR 1: A Crucial Link with Inflammation in Diabetic Subjects with COVID-19.

Inflammation is a distinguished clinical manifestation of COVID-19 and type 2 diabetes mellitus (T2DM), often associated with inflammatory dysfunctions, insulin resistance, metabolic dysregulation, and other complications. The present study aims to test the hypothesis that serum concentrations of PAR-1 levels differ between COVID-19 diabetic patients (T2DM) and non-diabetic COVID-19 patients and determine their association with different biochemical parameters and inflammatory biomarkers. T2DM patients with COVID-19 (n = 50) with glycated hemoglobin (HbA1c) levels of (9.23 ± 1.66) and non-diabetic COVID-19 patients (n = 50) with HbA1c levels (4.39 ± 0.57) were recruited in this study. The serum PAR-1 levels (ELISA method) were determined in both groups and correlated with parameters such as age, BMI, inflammatory markers including CRP, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), D-dimer, homocysteine, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Demographic variables such as BMI (29.21 ± 3.52 vs. controls 21.30 ± 2.11) and HbA1c (9.23 ± 1.66 vs. controls 4.39 ± 0.57) were found to be statistically elevated in COVID-19 T2DM patients compared to non-diabetic COVID-19 patients. The concentrations of several inflammatory biomarkers and PAR-1 were remarkably increased in the COVID-19 T2DM group when compared with the non-diabetic COVID-19 group. The univariate analysis revealed that increased serum PAR-1 estimations were positively correlated with enhanced HbA1c, BMI, inflammatory cytokines, D-dimer, homocysteine, and NT-proBNP. The findings in the current study suggest that increased levels of serum PAR-1 in the bloodstream could potentially serve as an independent biomarker of inflammation in COVID-19 patients with T2DM.

Retraction of 'Ameliorating the Role of Aripiprazole in Memory Deficits Induced by Intracerebroventricular Streptozotocin-Induced Dementia of Alzheimer's Type'.

[This retracts the article DOI: 10.1021/acsomega.3c02550.].

Doxorubicin catalyses self-assembly of p53 by phase separation.

Liquid-liquid phase separation plays a crucial role in cellular physiology, as it leads to the formation of membrane-less organelles in response to various internal stimuli, contributing to various cellular functions. However, the influence of exogenous stimuli on this process in the context of disease intervention remains unexplored. In this current investigation, we explore the impact of doxorubicin on the abnormal self-assembly of p53 using a combination of biophysical and imaging techniques. Additionally, we shed light on the potential mechanisms behind chemoresistance in cancer cells carrying mutant p53. Our findings reveal that doxorubicin co-localizes with both wild-type p53 (WTp53) and its mutant variants. Our in vitro experiments indicate that doxorubicin interacts with the N-terminal-deleted form of WTp53 (WTp53ΔNterm), inducing liquid-liquid phase separation, ultimately leading to protein aggregation. Notably, the p53 variants at the R273 position exhibit a propensity for phase separation even in the absence of doxorubicin, highlighting the destabilizing effects of point mutations at this position. The strong interaction between doxorubicin and p53 variants, along with its localization within the protein condensates, provides a potential explanation for the development of chemotherapy resistance. Collectively, our cellular and in vitro studies emphasize the role of exogenous agents in driving phase separation-mediated p53 aggregation.

A thermostable and inhibitor resistant ß-glucosidase from Rasamsonia emersonii for efficient hydrolysis of lignocellulosics biomass.

The present study reports a highly thermostable ß-glucosidase (GH3) from Rasamsonia emersonii that was heterologously expressed in Pichia pastoris. Extracellular ß-glucosidase was purified to homogeneity using single step affinity chromatography with molecular weight of ~ 110 kDa. Intriguingly, the purified enzyme displayed high tolerance to inhibitors mainly acetic acid, formic acid, ferulic acid, vanillin and 5-hydroxymethyl furfural at concentrations exceeding those present in acid steam pretreated rice straw slurry used for hydrolysis and subsequent fermentation in 2G ethanol plants. Characteristics of purified ß-glucosidase revealed the optimal activity at 80 °C, pH 5.0 and displayed high thermostability over broad range of temperature 50-70 °C with maximum half-life of ~ 60 h at 50 °C, pH 5.0. The putative transglycosylation activity of ß-glucosidase was appreciably enhanced in the presence of methanol as an acceptor. Using the transglycosylation ability of ß-glucosidase, the generated low cost mixed glucose disaccharides resulted in the increased induction of R. emersonii cellulase under submerged fermentation. Scaling up the recombinant protein production at fermenter level using temporal feeding approach resulted in maximal ß-glucosidase titres of 134,660 units/L. Furthermore, a developed custom made enzyme cocktail consisting of cellulase from R. emersonii mutant M36 supplemented with recombinant ß-glucosidase resulted in significantly enhanced hydrolysis of pretreated rice straw slurry from IOCL industries (India). Our results suggest multi-faceted ß-glucosidase from R. emersonii can overcome obstacles mainly high cost associated enzyme production, inhibitors that impair the sugar yields and thermal inactivation of enzyme.

Pesticides: An alarming detrimental to health and environment.

Pesticides are chemical substances of natural or synthetic origin that are used to eradicate pests and insects. These are indispensable in the agricultural processes for better crop production. Pesticide use aims to promote crop yield and protect the crops from diseases and damage. Pesticides must be handled carefully and disposed of appropriately because they are dangerous to people and other species by default. Environmental pollution occurs when pesticide contamination spreads away from the intended plants. Older pesticides such as lindane and dichlorodiphenyltrichloroethane (DDT) may remain in water and soil for a longer time. These accumulate in various parts of the food chain and cause damage to the ecosystem. Biological techniques in the management of pest control such as importation, augmentation, and conservation, and the accompanying procedures are more efficient, less expensive, and ecologically sound than other ways. This review mainly focuses on the consequences on the targeted and non-targeted organisms including the health and well-being of humans by the use of pesticides and their toxicity. The side effects that occur when a pesticide's LD50 exceeds the accepted limit through oral or skin penetration due to their binding to various receptors such as estrogen receptors, GABA, EGFR, and others. These pesticide classes include carbamates, pyrethroids, organochlorides, organophosphorus, and others. The current study seeks to highlight the urgent requirement for a novel agricultural concept that includes a major reduction in the use of chemical pesticides.

Evaluation of Pertussis Disease in Young Infants in India: A Hospital-Based Multicentric Observational Study.

OBJECTIVES: To evaluate the incidence of laboratory-confirmed pertussis (LCP) among infants hospitalized with acute respiratory infections (ARIs) and meeting the Centers for Disease Control and Prevention (CDC)-recommended clinical case definition. METHODS: An investigator-initiated active surveillance for clinically suspected cases (CSCs) of pertussis screened infants aged ≤6 mo hospitalized with ARIs during January 2020-April 2022 at seven centers across India. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect Bordetella pertussis in nasopharyngeal swabs. Infants were classified as having 'LCP' or 'probable pertussis' (PP). RESULTS: Among 1102 screened infants, 400 participants met the CDC-2020 clinical case definition for pertussis. Of these, 34/400 (8.5%) had LCP and 46/400 (11.5%) had PP. The proportion of participants with LCP and PP was similar among infants aged 0-3 and 4-6 mo [LCP: 0-3 mo, 21/248 (~9%); 4-6 mo, 13/152 (~9%); PP: 0-3 mo, 30/248 (~12%); 4-6 mo, 16/152 (~11%)]. Cough illness lasted ≥2 wk in 3/34 (~9%) and 34/46 (~74%) participants with LCP and PP, respectively. Notably, 80% CSCs had neither LCP nor PP, and a respiratory pathogen apart from B. pertussis was detected in ~32%. Ventilation was required in 12 participants with LCP/PP. CONCLUSIONS: In this first study from India based on revised CDC guidelines, the incidence of LCP was 8.5%; cough illness was not a predominant feature. Infants below the age appropriate for vaccination are prone to pertussis-related hospital admissions, ICU care, and ventilation. Maternal immunization may be evaluated for neonatal protection, in addition to other strategies, to decrease disease burden in this highly vulnerable group. CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2019/12/022449.

Morus Alba Fruit Extract and its Fractions Ameliorate Streptozotocin Induced Cognitive Deficit in Mice via Modulating Oxidative and Cholinergic Systems.

Increased oxidative stress and acetylcholinesterase (AChE) activity are key pathological characters contributing to the memory disorders. Thus, drugs targeting both oxidative stress and AChE are being explored for the management of cognitive dysfunction. Morus alba fruits (commonly consumed for its high nutritious value) are known to have antioxidant and AChE inhibitory effects. However, the role of Morus alba fruits in the management of memory disorders has not reported yet. This investigation was conducted to assess the antioxidant and AChE inhibitory potential of Morus alba fruit extracts in-vitro and to identify the components responsible for such effects. Further, the obtained bioactive component was studied for possible memory improvement effects against streptozotocin (STZ) induced dementia. To isolate the bioactive component in-vitro DPPH and AChE assays guided fractionation was performed. Memory functions in mice were determined using Morris Water Maze test while brain biochemical parameters were measured to understand the mechanism of action. In-vitro assays revealed strong AChE and DPPH inhibitory potential of methanol extract (ME), therefore, it was further fractionated. Among various fractions obtained, ethyl-acetate fraction (EAF) was found to possess marked AChE and DPPH inhibitory activities. On subsequent fractionation of EAF, bioactivity of obtained sub-fractions was found to be inferior to EAF. Further, both ME and EAF improved STZ (intracerebroventricular) induced cognitive dysfunction in animals by restoring endogenous antioxidant status (superoxide dismutase and reduced glutathione) and reducing thiobarbituric acid reactive species and nitric oxide levels along with brain AChE and myeloperoxidase activity. TLC densitometric studies showed appreciable levels of phenolic acids and quercetin in both EAF and ME. It can be concluded that Morus alba fruit extract has the ability to modulate cholinergic and oxidative system due to presence of phenolic and flavonoid compounds and hence, could aid in the management of memory disorders.

Computational Studies to Understand the Neuroprotective Mechanism of Action Basil Compounds.

Neurodegenerative diseases, such as Alzheimer's and Parkinson's, pose a significant global health challenge, emphasizing the need for novel neuroprotective agents. Basil (Ocimum spp.) has been recognized for its therapeutic potential, and numerous studies have reported neuroprotective effects. In this manuscript, we present a computational protocol to extricate the underlying mechanism of action of basil compounds in neuroprotective effects. Molecular docking-based investigation of the chemical interactions between selected bioactive compounds from basil and key neuroprotective targets, including AChE, GSK3ß, γ-secretase, and sirtuin2. Our results demonstrate that basil compound myricerone caffeoyl ester possesses a high affinity of -10.01 and -8.85 kcal/mol against GSK3ß and γ-secretase, respectively, indicating their potential in modulating various neurobiological processes. Additionally, molecular dynamics simulations were performed to explore the protein-ligand complexes' stability and to analyze the bound basil compounds' dynamic behavior. This comprehensive computational investigation enlightens the putative mechanistic basis for the neuroprotective effects of basil compounds, providing a rationale for their therapeutic use in neurodegenerative disorders after further experimental validation.

Clinical Significance of Adropin and Afamin in Evaluating Renal Function and Cardiovascular Health in the Presence of CKD-MBD Biomarkers in Chronic Kidney Disease.

AIM: The study aims to test the hypothesis that concentrations of adropin and afamin differ between patients in various stages of chronic kidney disease when compared with healthy controls. The study also investigates the association of the biomarkers (adropin and afamin) with CKD-MBD and traditional cardiovascular risk parameters in CKD patients. METHODOLOGY: The cross-sectional study includes the subjects divided into four groups comprising the control group (healthy volunteers = 50), CKD stages 1-2 patients (n = 50), CKD stages 3-4 patients (n = 50), CKD stage 5 patients (n = 50). Serum concentrations of adropin and afamin were determined using ELISA. Clinical variables (renal, lipid, and CKD-MBD parameters) were correlated to adropin and afamin concentrations. RESULTS: Afamin concentration was found to be higher in group IV, followed by groups III and II when compared to the control group, i.e., (83.243 ± 1.46, 64.233 ± 0.99, and 28.948 ± 0.72 vs. 14.476 ± 0.5) mg/L (p < 0.001), and adropin concentration was found to be lower in group IV as compared to groups III, II, and I (200.342 ± 8.37 vs. 284.682 ± 9.89 vs. 413.208 ± 12.32 vs. 706.542 ± 11.32) pg/mL (p < 0.001), respectively. Pearson correlation analysis showed that afamin was positively correlated with traditional cardiovascular risk biomarkers, while adropin showed a negative correlation. CONCLUSIONS: Adropin and afamin may potentially serve as futuristic predictors for the deterioration of renal function and may be involved in the pathological mechanisms of CKD and its associated complications such as CKD-MBD and high lipid levels.

In Silico Approaches to Developing Novel Glycogen Synthase Kinase 3ß (GSK-3ß).

Alzheimer's disease (AD) is caused by plaque agglomeration and entanglement in several areas of the neural cells, which leads to apoptosis. The main etiology of AD is senile dementia, which is linked to amyloid-beta (Aß) deregulation and tau perivascular pathogeny. Hyperphosphorylated tau has a propensity for microtubules, which elevate the instability and tau-protein congregates, leading to accumulation of neurofibrillary tangles (NFTs). Tau hyperphosphorylation is susceptible to GSK-3, which has led to an emerging hypothesis regarding the pathogenesis of AD. Accordingly, attempts have been made to conduct investigations and achieve further advancements on new analogues capable of inhibiting the GSK-3 protein, which are currently in the clinical trials. In this analysis, we have evaluated certain GSK-3 inhibitor variants utilising scaffolding and framework devised techniques with pharmacological characteristics, accompanied by computational screenings (pharmacokinetics and docking). The structure-based designed analogues interacted effectively with the active amino acids of GSK-3ß target protein. The in silico pharmacokinetic studies revealed their drug-like properties. The analogues with best interactions and binding scores will be considered in the future to completely demonstrate their potential relevance as viable GSK-3 inhibitors.

A system approach to improving guideline-directed therapy for cardio-renal-metabolic conditions: The "beyond diabetes" initiative.

Objective: Despite demonstrating improvements in cardiovascular disease, kidney disease, and survival outcomes, guideline-directed antihyperglycemic medications such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like-peptide-1 receptor agonists (GLP1-RA), are underutilized. Many obstacles constrain their use including lack of systematic provider and patient education, concern for medication side effects, and patient affordability. Methods: We designed a multimodality, systems-based approach to address these challenges with the goal of increasing medication utilization across the largest healthcare system in New York State. This multispecialty collaborative included provider and patient education, an electronic health record-enabled platform to identify eligible patients, and access to pharmacists for medication guidance and addressing insurance coverage barriers. Surveys were administered following grand rounds lectures and knowledge-based questionnaires were given before and after case-based sessions for housestaff, with results analyzed using a two-sided Student's t-test. Rates of first prescriptions of SGLT2i/GLP1-RA in combined and individual analyses were compared between the pre- and post-education periods (6 months prior to 3/31/2021 and 6 months post 8/19/2021), and the change in prescriptions per 100 eligible-visits was assessed using the incidence density approach. Results: Among grand rounds participants, 69.3% of respondents said they would make changes to their clinical practice. Knowledge increased by 14.7% (p-value <0.001) among housestaff following case-based sessions. An increase in SGLT2i/GLP1-RA prescribing was noted for eligible patients among internal medicine, cardiology, nephrology, and endocrinology providers, from 11.9 per 100 eligible visits in the pre-education period to 14.8 in the post-education period (absolute increase 2.9 [24.4%], incidence risk ratio 1.24 [95% CI 1.18-1.31]; p-value <0.001). Increases in prescribing rates were also seen among individual medical specialties. Conclusions: Our "Beyond Diabetes" initiative showed an improvement in provider knowledge-base and was associated with a modest, but statistically significant increase in the use of SGLT2i and GLP1-RA throughout our healthcare system.

Cystic lung tuberculosis in children: A series of five cases.

Frequent imaging manifestations of pulmonary tuberculosis are airspace or interstitial nodules with or without tree-in-bud nodules, consolidation, cavitation, ground glass opacity, miliary nodules, lymphadenopathy and pleural effusion. It is unusual to encounter cystic changes in patients with pulmonary tuberculosis, and these findings should be differentiated from other cystic lung diseases. This case series describes five cases of cystic lung disease in children with tuberculosis (TB) with illustrative chest radiography and CT findings. Contribution: The manuscript highlights the need to consider tuberculosis as a possible cause of acquired cystic lung disease in appropriate clinical settings, particularly in endemic regions.

An assessment of childhood cancer care services in India - gaps, challenges and the way forward.

Background: Childhood cancers are emerging as an essential concern in India where there is lack of a specific programme component or policy to address childhood cancer control. There is limited information on the status and quality of childhood cancer care services in India. This paper describes the childhood cancer care services available at secondary and tertiary-level hospitals in India through a cross sectional study design. Methods: The survey was conducted in 137 tertiary-level and 92 secondary-level hospitals in 26 states and 4 Union Territories (UTs), ensuring a uniform representation of public and private care hospitals. The study tool collected data on the organisational infrastructure, type of oncology services, health workforce, equipment, treatment and referral protocols, and treatment guidelines. Descriptive statistics was used to primarily present the health service status and data on childhood cancer care services in proportions and mean. Findings: A dedicated pediatric oncology department was available in 41.6% of the public, 48.6% of private, and 64% Non Government Organization (NGO) managed tertiary-level hospitals. In 36 (39%) of the 92 hospitals providing secondary care, childhood cancer care was provided. The availability of bone (41.5%) and positron emission tomography (PET) scans (25.9%) was lower in public tertiary hospitals, whereas histopathology, computerised tomography (CT scan), and magnetic resonance imaging (MRI) were lower in public secondary hospitals than private and NGO managed hospitals for the corresponding level of care. Most tertiary hospitals had the required supportive care facilities except for play therapy and hospice care. Less than 50% of the public tertiary hospitals had stocks of the four categories of cancer-treating drugs and essential infrastructure for radiotherapy and chemotherapy. Most secondary-level hospitals not treating childhood cancer had referral linkages with tertiary hospitals. Interpretation: The situational analysis of childhood cancer care services in India showed the concentration of availability of childhood cancer care services at the tertiary level of health care. There were gaps in the availability of specialised pediatric oncology care in all the tertiary hospitals. The availability of childhood cancer care services was higher in private and NGO-managed hospitals than in public hospitals. Integration of childhood cancer as a part of the national cancer control response should be taken up as a matter of priority. The need of the hour is to formulate a childhood cancer policy that will enable timely access to care universally. Funding: World Health Organization, India provided funding and technical support.

Recent Development of Novel Aminoethyl-Substituted Chalcones as Potential Drug Candidates for the Treatment of Alzheimer's Disease.

No drug on the market, as a single entity, participates in different pathways involved in the pathology of Alzheimer's disease. The current study is aimed at the exploration of multifunctional chalcone derivatives which can act on multiple targets involved in Alzheimer's disease. A series of novel aminoethyl-substituted chalcones have been developed using in silico approaches (scaffold morphing, molecular docking, and ADME) and reported synthetic methods. The synthesized analogs were characterized and evaluated biologically using different in vitro assays against AChE, AGEs, and radical formation. Among all compounds, compound PS-10 was found to have potent AChE inhibitory activity (IC50 = 15.3 nM), even more than the standard drug (IC50 = 15.68 nM). Further, the in vivo evaluation of PS-10 against STZ-induced dementia in rats showed memory improvement (Morris Water Maze test) in rats. Also, PS-10 inhibited STZ-induced brain AChE activity and oxidative stress, further strengthening the observed in vitro effects. Further, the molecular dynamic simulation studies displayed the stability of the PS-10 and AChE complex. The novel aminoethyl-substituted chalcones might be considered potential multifunctional anti-Alzheimer's molecules.

CRISPR/Cas9 mediated gene editing of transcription factor ACE1 for enhanced cellulase production in thermophilic fungus Rasamsonia emersonii.

BACKGROUND: The filamentous fungus Rasamsonia emersonii has immense potential to produce biorefinery relevant thermostable cellulase and hemicellulase enzymes using lignocellulosic biomass. Previously in our lab, a hyper-cellulase producing strain of R. emersonii was developed through classical breeding and system biology approaches. ACE1, a pivotal transcription factor in fungi, plays a crucial role in negatively regulating the expression of cellulase genes. In order to identify the role of ACE1 in cellulase production and to further improve the lignocellulolytic enzyme production in R. emersonii, CRISPR/Cas9 mediated disruption of ACE1 gene was employed. RESULTS: A gene-edited ∆ACE1 strain (GN11) was created, that showed 21.97, 20.70 and 24.63, 9.42, 18.12%, improved endoglucanase, cellobiohydrolase (CBHI), ß-glucosidase, FPase, and xylanase, activities, respectively, as compared to parental strain M36. The transcriptional profiling showed that the expression of global regulator (XlnR) and different CAZymes genes including endoglucanases, cellobiohydrolase, ß-xylosidase, xylanase, ß-glucosidase and lytic polysaccharide mono-oxygenases (LPMOs) were significantly enhanced, suggesting critical roles of ACE1 in negatively regulating the expression of various key genes associated with cellulase production in R. emersonii. Whereas, the disruption of ACE1 significantly down-regulated the expression of CreA repressor gene as also evidenced by 2-deoxyglucose (2-DG) resistance phenotype exhibited by edited strain GN11 as well as appreciably higher constitutive production of cellulases in the presence of glucose and mixture of glucose and disaccharide (MGDs) both in batch and flask fed batch mode of culturing. Furthermore, ∆ACE1 strains were evaluated for the hydrolysis of biorefinery relevant steam/acid pretreated unwashed rice straw slurry (Praj Industries Ltd; 15% substrate loading rate) and were found to be significantly superior when compared to the benchmark enzymes produced by parent strain M36 and Cellic Ctec3. CONCLUSIONS: Current work uncovers the crucial role of ACE1 in regulating the expression of the various cellulase genes and carbon catabolite repression mechanism in R. emersonii. This study represents the first successful report of utilizing CRISPR/Cas9 genome editing technology to disrupt the ACE1 gene in the thermophlic fungus R. emersonii. The improved methodologies presented in this work might be applied to other commercially important fungal strains for which genetic manipulation tools are limited.

N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation.

The series of N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfuctional agents against Alzheimer's disease that have been designed, synthesized and then evaluated biologically using in vitro assays for the inhibition of acetylcholinesterase (AChE) activity, AGEs, and free radical formation. The majority of synthesized compounds inhibited AChE & AGEs with additional free radical scavenging activities at nanomolar concentrations. Among these, compound 5k was found to have potent AChE inhibitory activity (IC50 = 11.6 nM), superior than the reference compound donepezil (15.68 nM) along with the good anti-AGEs and free radical formation effect. Its potency was justified by docking studies that revealed its dual binding characteristic with both catalytic active site and peripheral anionic site of AChE, simultaneously. Furthermore, the in vivo evaluation of 5k against streptozotocin (STZ)-induced dementia in rats also showed improvement of memory functions (Morris water maze test) in animals. Also, 5k inhibited STZ-inudced brain AChE activity and oxidative stress which further strengthen the observed in vitro effects. The stability of the ligand-protein complex was then analyzed using a simulation-based interaction protocol. The results revealed that these N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives could be considered for potential polyfunctional anti-Alzheimer's molecules.

Neurologic Complications in Patients With Lymphoreticular Malignancy: A Descriptive Cohort Study.

OBJECTIVES: The objectives of this study were to study the spectrum of neurologic complications in children with lymphoreticular malignancy (acute lymphoblastic leukemia, Hodgkin, and non-Hodgkin lymphoma) at diagnosis and during treatment and to determine the etiology of these complications. MATERIALS AND METHODS: In this descriptive cohort study, conducted between November 2018 and March 2020, 204 children with a diagnosis of lymphoreticular malignancy were enrolled. The baseline investigations were done in all the cases. Those who developed neurological symptoms were evaluated with cerebrospinal fluid examination and radiologic and electrophysiologic studies as per indication and were managed according to standard management guidelines. RESULTS: Of the 204 patients, 30 (14.7%) developed neurological complications. The majority of these complications (n=20/30; 87%) occurred during the intensive chemotherapy period. Common complications included acute methotrexate neurotoxicity (n=7), vincristine-induced neurotoxicity (n=7), central nervous system (CNS) relapse (n=4), and posterior reversible encephalopathy syndrome (n=2). L-asparaginase-induced thrombosis (n=1), intramedullary compression syndrome (n=1), CNS infection (n=2), CNS hemophagocytic lymphohistiocytosis (n=1), and steroid-induced myopathy (n=1) were also observed. The complications resolved in 21/30 (70%) patients after receiving appropriate treatment while the neurological complication persisted in 2/30 (6.7%) patients. Three patients (10%) abandoned the treatment, and 4 (13.3%) patients expired. CONCLUSIONS: Neurologic complications in patients with lymphoreticular malignancy are quite variable, having common presenting symptoms but varying imaging abnormalities. By close follow-up and effective treatment, the morbidity and mortality of these complications can be minimized.