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Here, integrated functional components into a hybrid heterostructure via highly stabilized network-like interconnected electronic nanoarchitecture of 1D N-doped holey-carbon nanotube (NHCNT) with 2D nickel─metal-organic framework (Ni─MOF) nanosheets are developed as high-performance electrocatalyst for overall water splitting. The NHCNT promoting electron transport pathways in electrocatalyst, and formation of holes in nanotubes further enables excellent diffusion of ions for promoting the overall reaction rate. An excellent combination of 1D/2D structure of NHCNT/Ni─MOF-4 electrocatalyst exhibits excellent oxygen evolution reaction (η 10 = 207.8 mV, and Tafel = 62.6 mV dec -1 ) and reasonable hydrogen evolution reaction (η 10 = 159.8 mV, and Tafel = 107.69 mV dec -1 ) activity with consistent and stable performance in a 1 m KOH. The highly interconnected network structure contains Ni 2+ and Ni 3+ species in the NHCNT/Ni─MOF-4 electrocatalyst, which possesses high specific surface area (SSA) (235.53 m 2 g -1 ), electrochemically active surface area (ECSA) (796.2 cm 2 ), mass activity (4.76 mA mg -1 ), and turnover frequency (3.99 × 10 -2 s -1 ), which provide remarkable electrocatalytic performance via generating synergy between the NHCNT and Ni─MOF. For overall water splitting, NHCNT/Ni─MOF-4 attains a low cell voltage (1.77 V@10 mA cm -2 )., (© 2024 Wiley‐VCH GmbH.)

Metal-Organic Frameworks (MOFs) have garnered significant attention in the development of electrochemical glucose sensors due to their unique and advantageous properties. The highly tunable pore channels of MOFs facilitate optimal diffusion of glucose molecules, while their large specific surface area provides abundant active sites for electrochemical reactions. Furthermore, the well-dispersed metallic active sites within MOFs enhance electrocatalytic activity, thereby improving the sensitivity and selectivity of glucose detection. These features make MOF-based nanoarchitectures promising candidates for the development of efficient and sensitive glucose sensors, which are crucial for diabetes management and monitoring. The integration of enzymatic biosensors with nanotechnology continues to drive advancements in glucose monitoring, offering the potential for more accurate, convenient, and user-friendly tools for diabetes management. Current research explores non-invasive glucose monitoring methods, such as using sweat, saliva, or interstitial fluid instead of blood, aiming to reduce the discomfort and inconvenience associated with frequent blood sampling. A review of the advancements and applications of MOF-based enzyme-mimic electrochemical sensors for glucose monitoring can provide valuable insights for young researchers, inspiring future research in biomedical device fabrication. Such reviews not only offer a comprehensive understanding of the current state of the art but also highlight existing challenges and future opportunities in the field of enzyme-less glucose sensing, particularly in the surface modification techniques of highly porous MOFs. This fosters innovation and new research directions. By understanding the advantages, challenges, and opportunities, researchers can contribute to the development of more effective and innovative enzyme-mimic glucose sensing transducers, which are essential for advancing biomedical devices.

Olfml3 is a microglia-specific protein whose role in neuroinflammation is elusive. In silico analysis was conducted to characterize the Olfml3 protein, followed by molecular docking and MD simulation to check possible interaction with Iba1. Further, expression and co-localization analysis was performed in the LPS-induced neuroinflammatory mice brains. Results suggest that Olfml3 physically interacts with Iba1. Olfml3 and Iba1 expression increases during neuroinflammation in mice brains. Olfml3 was observed to co-localize with Iba1, and the number of Olfml3 and Iba1 dual-positive cells increased in the brain of the neuroinflammatory mice model. Thus, Olfml3 could potentially participate in microglia functions by interacting with Iba1., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Quantum dots (QDs), a novel category of semiconductor materials, exhibit extraordinary capabilities in tuning optical characteristics. Their emergence in biophotonics has been noteworthy, particularly in bio-imaging, biosensing, and theranostics applications. Although conventional QDs such as PbS, CdSe, CdS, and HgTe have garnered attention for their promising features, the presence of heavy metals in these QDs poses significant challenges for biological use. To address these concerns, the development of Ag chalcogenide QDs has gained prominence owing to their near-infrared emission and exceptionally low toxicity, rendering them suitable for biological applications. This review explores recent advancements in Ag chalcogenide QDs, focusing on their synthesis methodologies, surface chemistry modifications, and wide-ranging applications in biomedicine. Additionally, it identifies future directions in material science, highlighting the potential of these innovative QDs in revolutionizing the field., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Neurodegenerative diseases (NDDs) refer to a complex heterogeneous group of diseases which are associated with the accumulation of amyloid fibrils or plaques in the brain leading to progressive loss of neuronal functions. Alzheimer's disease is one of the major NDD responsible for 60-80 % of all dementia cases. Currently, there are no curative or disease-reversing/modifying molecules for many of the NDDs except a few such as donepezil, rivastigmine, galantamine, carbidopa and levodopa which treat the disease-associated symptoms. Similarly, there are very few FDA-approved tracers such as flortaucipir (Tauvid) for tau fibril imaging and florbetaben (Neuraceq), flutemetamol (Vizamyl), and florbetapir (Amyvid) for amyloid imaging available for diagnosis. Recent advances in the cryogenic electron microscopy reported distinctly different microstructures for tau fibrils associated with different tauopathies highlighting the possibility to develop tauopathy-specific imaging agents and therapeutics. In addition, it is important to identify the proteins that are associated with disease development and progression to know about their 3D structure to develop various diagnostics, therapeutics and theranostic agents. The current article discusses in detail the disease-associated amyloid and non-amyloid proteins along with their structural insights. We comprehensively discussed various novel proteins associated with NDDs and their implications in disease pathology. In addition, we document various emerging chemical compounds developed for diagnosis and therapy of different NDDs with special emphasis on theranostic agents for better management of NDDs., (© 2024 Wiley-VCH GmbH.)

According to the World Health Organization, infectious diseases, particularly those caused by multidrug-resistant bacteria (MDR), are projected to claim the lives of 15 million people by 2050. Septicemia carries a higher morbidity and mortality rate than infections caused by susceptible Pseudomonas aeruginosa, and MDR-mediated ocular infections can lead to impaired vision and blindness. To identify and develop a potential drug against MDR P. aeruginosa, we employed in silico reverse genetics-based target mining, drug prioritization, and evaluation. Rare Lipoprotein A (RlpA) was selected as the target protein, and its crystal structure was geometrically optimized. Molecular docking and virtual screening analyses revealed that RlpA exhibits strong binding affinity with 11 compounds. Among these, 3-chlorophthalic acid was evaluated, and subsequent in vitro assays demonstrated significant anti-Pseudomonas activity with negligible cytotoxicity. The compound was further evaluated against both drug-susceptible and MDR P. aeruginosa strains in vitro, with cytotoxicity assessed using an MTT assay. The study demonstrated that 3-chlorophthalic acid exhibits potent anti-Pseudomonas activity with minimal toxicity to host cells. Consequently, this compound emerges as a promising candidate against MDR P. aeruginosa, warranting further investigation., 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 Elsevier B.V. All rights reserved.)

In this study, we report a small molecule optical marker BI-CyG derived from the structural engineering of a cyanine scaffold. The developed probe offers suitable advantages over existing cyanine-based albumin specific probes in terms of its excitation and emission wavelengths, which are 760 and 830-832 nm, respectively. Structural tuning of the cyanine architecture leading to extended π-conjugation and resulting in a suitable bathochromic shift in the emission wavelength of the probe is represented in this study. The probe besides emitting in the NIR region, also possesses the desirable characteristics of being a potential target selective optical marker, as established from various biophysical studies. Molecular modelling and simulation studies provided critical insights into the binding of the probe in the protein microenvironment, which was further supported by experimental studies. The probe displayed intracellular albumin selectivity and was utilized for demonstrating alteration in albumin levels in pathological states such as hyperglycemia in hepatic cells. The present study also sheds some light on using BI-CyG as an imaging probe and on the role of metformin as a suitable drug for balancing hyperglycemia-induced reduced intra-hepatic albumin levels. The study, thus, attempts to highlight the structural derivatization of cyanine to afford a potential probe for serum albumin and its deployment to image altering albumin levels in an induced pathological condition, hyperglycemia.

The research investigates the virulence factors of Pseudomonas aeruginosa (P. aeruginosa), a pathogen known for its ability to cause human infections by releasing various exoenzymes and virulence factors. Particularly relevant in ocular infections, where tissue degeneration can occur, even after bacterial growth has ceased due to the potential role of secreted proteins/enzymes. Clinical isolates of P. aeruginosa, both ocular (146) and non-ocular (54), were examined to determine the frequency and mechanism of virulence factors. Phenotypic characterization revealed the production of alginate, biofilm, phospholipase C, and alkaline protease, while genotypic testing using internal uniplex PCR identified the presence of Exo U, S, T, Y, and LasB genes. Results showed a significant prevalence of Exo U and Y genes in ocular isolates, a finding unique to Indian studies. Additionally, the study noted that ocular isolates often contained all four secretomes, suggesting a potential link between these factors and ocular infections. These findings contribute to understanding the pathogenesis of P. aeruginosa infections, particularly in ocular contexts, and highlights the importance of comprehensive virulence factor analysis in clinical settings., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues. A Tet-On doxycycline-inducible CAIX expressing cell line was established to mimic various CAIX densities, providing coverage from CAIX-high skrc-59 tumor cells to CAIX-low MMNK-1 cholangiocytes. Assessing the killing of CAR-T cells, we demonstrated that low-affinity/high-avidity fine-tuned G9 CAR-T has a wider therapeutic window compared to high-affinity/high-avidity G250 that was used in the first anti-CAIX CAR-T clinical trial but displayed serious OTOT effects. To assess the therapeutic effect of G9 on patient samples, we generated ccRCC patient derived organotypic tumor spheroid (PDOTS) ex vivo cultures and demonstrated that G9 CAR-T cells exhibited superior efficacy, migration and cytokine release in these miniature tumors. Moreover, in an RCC orthotopic mouse model, G9 CAR-T cells showed enhanced tumor control compared to G250. In summary, G9 has successfully mitigated OTOT side effects and in doing so has made CAIX a druggable immunotherapeutic target., (© 2024. The Author(s).)

Molecular Property Diagnostic Suite (MPDS) was conceived and developed as an open-source disease-specific web portal based on Galaxy. MPDS COVID-19 was developed for COVID-19 as a one-stop solution for drug discovery research. Galaxy platforms enable the creation of customized workflows connecting various modules in the web server. The architecture of MPDS COVID-19 effectively employs Galaxy v22.04 features, which are ported on CentOS 7.8 and Python 3.7. MPDS COVID-19 provides significant updates and the addition of several new tools updated after six years. Tools developed by our group in Perl/Python and open-source tools are collated and integrated into MPDS COVID-19 using XML scripts. Our MPDS suite aims to facilitate transparent and open innovation. This approach significantly helps bring inclusiveness in the community while promoting free access and participation in software development., Availability & Implementation: The MPDS COVID-19 portal can be accessed at https://mpds.neist.res.in:8085/., Competing Interests: The authors declare that they have no competing interests., (© The Author(s) 2024.)

This study aimed to investigate the characterization of zinc oxide nanoparticles (ZnONPs) produced from Cucurbita pepo L. (pumpkin seeds) and their selective cytotoxic effectiveness on human colon cancer cells (HCT 116) and African Green Monkey Kidney, Vero cells. The study also investigated the antioxidant activity of ZnONPs. The study also examined ZnONPs' antioxidant properties. This was motivated by the limited research on the comparative cytotoxic effects of ZnO NPs on normal and HCT116 cells. The ZnO NPs were characterized using Fourier-transform infrared spectroscopy (FTIR), Thermogravimetric Analysis (TGA), Transmission Electron Microscope/Selected Area Electron Diffraction (TEM/SAED), and Scanning Electron Microscope-Energy Dispersive X-ray (SEM-EDX) for determination of chemical fingerprinting, heat stability, size, and morphology of the elements, respectively. Based on the results, ZnO NPs from pumpkins were found to be less than 5 μm and agglomerates in nature. Furthermore, the ZnO NPs fingerprinting and SEM-EDX element analysis were similar to previous literature, suggesting the sample was proven as ZnO NPs. The ZnO NPs also stable at a temperature of 380°C indicating that the green material is quite robust at 60-400°C. The cell viability of Vero cells and HCT 116 cell line were measured at two different time points (24 and 48 h) to assess the cytotoxicity effects of ZnO NP on these cells using AlamarBlue assay. Cytotoxic results have shown that ZnO NPs did not inhibit Vero cells but were slightly toxic to cancer cells, with a dose-response curve IC50 = ~409.7 μg/mL. This green synthesis of ZnO NPs was found to be non-toxic to normal cells but has a slight cytotoxicity effect on HCT 116 cells. A theoretical study used molecular docking to investigate nanoparticle interaction with cyclin-dependent kinase 2 (CDK2), exploring its mechanism in inhibiting CDK2's role in cancer. Further study should be carried out to determine suitable concentrations for cytotoxicity studies. Additionally, DPPH has a significant antioxidant capacity, with an IC50 of 142.857 μg/mL. RESEARCH HIGHLIGHTS: Pumpkin seed extracts facilitated a rapid, high-yielding, and environmentally friendly synthesis of ZnO nanoparticles. Spectrophotometric analysis was used to investigate the optical properties, scalability, size, shape, dispersity, and stability of ZnO NPs. The cytotoxicity of ZnO NPs on Vero and HCT 116 cells was assessed, showing no inhibition of Vero cells and cytotoxicity of cancer cells. The DPPH assay was also used to investigate the antioxidant potential of biogenic nanoparticles. A molecular docking study was performed to investigate the interaction of ZnO NPs with CDK2 and to explore the mechanism by which they inhibit CDK2's role in cancer., (© 2023 Wiley Periodicals LLC.)

The robust structural nature of human serum albumin (HSA) is responsible for its multifarious functional property. The site specific glycation of HSA due to hyperglycaemia (excess glucose) causes structural changes which have an impact on the functioning of the protein. This work investigates the effects of glucose-mediated glycation in the altered inter-domain motion, distorted binding site conformation and modified hydration patterns, Trp214 orientation, and secondary structure transition using simulation approach. Here we have observed an increase of turns in the helices of glycated HSA, which modulates the open-close conformation of Sudlow I & II. The secondary structure changes of glycated HSA indicate plausible reduction in the alpha helical content in the helices which participates in ligand binding. It also affects geometrical features of drug binding sites (Sudlow I and II) such as volume and hydration. We found that glycation disturbs domain specific mobility patterns of HSA, a substantial feature for albumin drug binding ability which is also correlated with changes in the local environment of Trp214.Communicated by Ramaswamy H. Sarma.

Treatment for renal cell carcinoma (RCC) has improved dramatically over the last decade, shifting from high-dose cytokine therapy in combination with surgical resection of tumors to targeted therapy, immunotherapy, and combination therapies. However, curative treatment, particularly for advanced-stage disease, remains rare. Cell therapy as a "living drug" has achieved hematological malignancy cures with a high response rate, and significant research efforts have been made to facilitate its translation to solid tumors. Herein, we overview the cellular therapies for RCC focusing on allogeneic hematopoietic stem cell transplantation, T cell receptor gene-modified T cells, chimeric antigen receptor (CAR) T cells, CAR natural killer (NK) cells, lymphokine-activated killer (LAK) cells, γδ T cells, and dendritic cell vaccination. We have also included perspectives for using other recent approaches, such as CAR macrophages, dendritic cell-cytokine induced killer cells and regulatory CAR-T cells to shed light on preclinical development of cell therapy and advancing cell therapy into clinic to achieve cures for RCC., (© 2024. The Author(s).)

Cellular genome is considered a dynamic blueprint of a cell since it encodes genetic information that gets temporally altered due to various endogenous and exogenous insults. Largely, the extent of genomic dynamicity is controlled by the trade-off between DNA repair processes and the genotoxic potential of the causative agent (genotoxins or potential carcinogens). A subset of genotoxins form DNA adducts by covalently binding to the cellular DNA, triggering structural or functional changes that lead to significant alterations in cellular processes via genetic (e. g., mutations) or non-genetic (e. g., epigenome) routes. Identification, quantification, and characterization of DNA adducts are indispensable for their comprehensive understanding and could expedite the ongoing efforts in predicting carcinogenicity and their mode of action. In this review, we elaborate on using Artificial Intelligence (AI)-based modeling in adducts biology and present multiple computational strategies to gain advancements in decoding DNA adducts. The proposed AI-based strategies encompass predictive modeling for adduct formation via metabolic activation, novel adducts' identification, prediction of biochemical routes for adduct formation, adducts' half-life predictions within biological ecosystems, and, establishing methods to predict the link between adducts chemistry and its location within the genomic DNA. In summary, we discuss some futuristic AI-based approaches in DNA adduct biology., (© 2023 Wiley-VCH GmbH.)

Background: In the 21st century, nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder. The prevalence of NAFLD within the general population in India ranges from 9 to 53%. The gold standard for assessing the severity of liver fibrosis is liver biopsy. However, due to various difficulties involved with liver biopsy, it is imperative to identify different non-invasive tools that can replace liver biopsy., Methodology: A prospective observational study of 130 patients meeting the inclusion criteria for NAFLD was done for a period of 18 months. We aimed to compare the performance characteristics of different noninvasive scores [fibrosis-4 (FIB-4) score, nonalcoholic fatty liver disease fibrosis score (NFS), and aspartate aminotransferase to platelet ratio index (APRI)] in predicting advanced fibrosis as assessed by FibroScan., Results: In the study, 76.9% of patients were male. Advanced fibrosis was seen in 12.3% of the patients. Majority of the patients with advanced fibrosis had metabolic syndrome. Based on the area under the receiver operating characteristic curve (AUROC), the new cut-off for ruling out advanced fibrosis for FIB-4, NFS, and APRI were 1.18, -0.9, and 0.65, respectively, and APRI had the best AUROC (0.768)., Conclusion: Abnormal glycemic status and metabolic syndrome were risk factors for advanced fibrosis. The newly derived cut-offs for the FIB-4 score, NFS score, and APRI score had a better Negative predictive value compared to the original cut-offs., How to Cite This Article: Bhayani PD, Parameswaran SA, Palaniswamy KR, et al. Is Aspartate Aminotransferase to Platelet Ratio Index a Better Noninvasive Score for Predicting Advanced Fibrosis in Nonalcoholic Fatty Liver Disease Patients? Euroasian J Hepato-Gastroenterol 2024;14(1):35-39., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2024; The Author(s).)

There is a rising noncommunicable disease (NCD) burden in low- and middle-income countries. Sub-Saharan Africa (SSA) bears a higher burden than the global average with South Africa (SA) enduring the highest regional burden. SA among other southern African countries also bears a high prevalence of HIV and other chronic communicable diseases. Having a perspective on common chronic diseases in the ever-increasing numbers of adult cancer patients in SA will inform our understanding of approaches to better manage them. This commentary reviews regional and national studies and data of low- and middle-income countries and particularly SA on the chronic infectious and NCD multimorbidity burden among adult cancer patients. It also reflects on the considerable health system challenges of managing discordant multimorbidity among adult cancer patients within the SA Public Health System. Despite the critical need to better manage the growing MM burden in general and particularly the high prevalence of discordant multimorbidity among cancer patients, there is a dearth of research into MM management generally and in LMICs particularly.

The design of novel fibril imaging molecules for medical diagnosis requires the simultaneous optimization of fibril-specific optical properties and binding specificity toward amyloid fibrils. Because of the possibility to monitor internal organs and deep tissues, the two-photon probes that can absorb in the infrared (IR) and near-IR (NIR) region with a significant two-photon absorption cross section are of immense interest. To contribute to this exploration of chemical compounds suitable for two-photon fibril imaging, we have computationally studied the one- and two-photon properties of a donor-acceptor-substituted DANIR-2c probe, which was used for in vivo detection of β-amyloid deposits using fluorescence spectroscopy. In particular, a multiscale computational approach was employed involving molecular docking, molecular dynamics, hybrid QM/MM molecular dynamics, and coupled-cluster/MM to study the binding of the studied probe to amyloid fibril and its one- and two-photon absorption properties in the fibrillar environment. Multiple binding sites are available for this probe in amyloid fibril, and the one corresponding to the largest binding affinity exhibits also the largest and experimentally meaningful two-photon absorption cross section, thus demonstrating the potential of the studied probe in two-photon microscopy.

Purpose: Women living with HIV (WLWH) and breast cancer (BC) have worse overall survival than HIV-negative women with BC, and poor adherence to prescribed tamoxifen is known to contribute to poor survival. We therefore investigated the association of HIV infection with adherence to adjuvant tamoxifen among women with localized hormone receptor (HR)-positive breast cancer in South Africa., Methods: Among 4,097 women diagnosed with breast cancer at six hospitals in the prospective South African Breast Cancer and HIV Outcomes (SABCHO) cohort study between July 2015 and December 2020, we focused on black women with stages I-III HR-positive breast cancer who were prescribed 20 mg of adjuvant tamoxifen daily. We collected venous blood once from each participant during a routine clinic visit, and analyzed concentrations of tamoxifen and its metabolites using a triple quadruple mass spectrometer. We defined non-adherence as a tamoxifen level < 60 ng/mL after 3 months of daily tamoxifen use. We compared tamoxifen-related side effects, and concurrent medication use among women with and without HIV and developed multivariable logistic regression models of tamoxifen non-adherence., Results: Among 369 subjects, 78 (21.1%) were WLWH and 291 (78.9%) were HIV-negative. After a median (interquartile range) time of 13.0 (6.2-25.2) months since tamoxifen initiation, the tamoxifen serum concentration ranged between 1.54 and 943.0 ng/mL and 208 (56.4%) women were non-adherent to tamoxifen. Women < 40 years of age were more likely to be non-adherent than women > 60 years (73.4% vs 52.6%, odds ratio (OR) = 2.49, 95% confidence interval (CI) = 1.26-4.94); likewise, WLWH (70.5% vs 52.6%, OR = 2.16, 95% CI = 1.26-3.70) than HIV-negative women. In an adjusted model WLWH had twice the odds of non-adherence to tamoxifen, compared to HIV-negative women (OR = 2.40, 95% CI = 1.11-5.20)., Conclusion: High rates of non-adherence to adjuvant tamoxifen may limit the overall survival of black South African women with HR-positive breast cancer, especially among WLWH., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hypersensitivity reactions are characterized by inappropriate response of the immune system to an inciting antigen, which results in damage to various body tissues. Respiratory system can be involved as a part of hypersensitivity reaction by a myriad of conditions ranging from infective pathologies like tuberculosis to non-infective processes such as asthma, graft- versus host disease, sarcoidosis and vasculitic disorders. Recognition of specific imaging features in appropriate clinical setting helps in diagnosing these conditions. We present a review of mechanism of different types of hypersensitivity reactions; and imaging features of various such pathological conditions affecting the respiratory system., (Copyright © 2022 Elsevier Inc. All rights reserved.)

New variants of SARS-CoV-2 are being reported worldwide. The World Health Organization has reported Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Omicron (B.1.1.529) as the variants of concern. There are speculations that the variants might evade the host immune responses induced by currently available vaccines and develop resistance to drugs under consideration. The first step of viral infection in COVID-19 occurs through the interaction of the spike protein's receptor-binding domain (RBD) with the peptidase domain of the human ACE-2 (hACE-2) receptor. This study aims to get a molecular-level understanding of the mechanism behind the increased infection rate in the alpha variant. We have computationally studied the spike protein interaction in both the wild-type and B.1.1.7 variant with the hACE-2 receptor using molecular dynamics and MM-GBSA based binding free energy calculations. The binding free energy difference shows that the mutant variant of the spike protein has increased binding affinity for the hACE-2 receptor ( i.e. ΔG(N501Y,A570D) is in the range -7.2 to -7.6 kcal mol -1 ) and the results were validated using Density functional theory. We demonstrate that with the use of state-of-the-art computational approaches, we can, in advance, predict the virulent nature of variants of SARS-CoV-2 and alert the world healthcare system.

A typical drug discovery project involves identifying active compounds with significant binding potential for selected disease-specific targets. Experimental high-throughput screening (HTS) is a traditional approach to drug discovery, but is expensive and time-consuming when dealing with huge chemical libraries with billions of compounds. The search space can be narrowed down with the use of reliable computational screening approaches. In this review, we focus on various machine-learning (ML) and deep-learning (DL)-based scoring functions developed for solving classification and ranking problems in drug discovery. We highlight studies in which ML and DL models were successfully deployed to identify lead compounds for which the experimental validations are available from bioassay studies., 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 © 2022. Published by Elsevier Ltd.)

The current global health emergency in the form of the Coronavirus 2019 (COVID-19) pandemic has highlighted the need for fast, accurate, and efficient drug discovery pipelines. Traditional drug discovery projects relying on in vitro high-throughput screening (HTS) involve large investments and sophisticated experimental set-ups, affordable only to big biopharmaceutical companies. In this scenario, application of efficient state-of-the-art computational methods and modern artificial intelligence (AI)-based algorithms for rapid screening of repurposable chemical space [approved drugs and natural products (NPs) with proven pharmacokinetic profiles] to identify the initial leads is a powerful option to save resources and time. Structure-based drug repurposing is a popular in silico repurposing approach. In this review, we discuss traditional and modern AI-based computational methods and tools applied at various stages for structure-based drug discovery (SBDD) pipelines. Additionally, we highlight the role of generative models in generating molecules with scaffolds from repurposable chemical space., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

With the promising advantages of the near-infrared region (NIR) emissive markers for serum albumin becoming very prominent recently, we devised CyG-NHS as the cyanine derived longest NIR-I emissive optical marker possessing albumin selective recognition ability in diverse biological milieu. Multiscale modeling involving molecular docking, molecular dynamics, and implicit solvent binding free energy calculations have been employed to gain insights into the unique binding ability of the developed probe at domain-I of albumin, in contrast to the good number of domain IIA or IIIA binding probes available in the literature reports. The binding free energy was found to be -31.8 kcal mol -1 majorly predominated by hydrophobic interactions. Besides, the conformational dynamics of CyG-NHS in an aqueous medium and the albumin microenvironment have been comprehensively studied and discussed. The potentiality of this optical platform to monitor the intracellular albumin levels in human hepatoma (HepG2) cells in different pathophysiological states has been demonstrated here. Also, the competency of the phenformin drug in restoring the albumin levels in chronic hyperinsulinemic and hypercholesterolemic in vitro models has been established through the visualization approach. Altogether, the findings of this study throw light on the significance of the development of a suitable optical marker for the visualization of critical bioevents related to albumin.

We present fluorogenic cationic organo chalcogens that are highly selective to RNA. We have demonstrated that the conformational dynamics and subsequently the optical properties of these dyes can be controlled to facilitate efficient bioimaging. We report the application of organoselenium and organosulfur-based cell-permeable red-emissive probes bearing a favorable cyclic sidearm for selective and high contrast imaging of cell nucleoli. The probes exhibit high quantum yield upon interacting with RNA in an aqueous solution. An in-depth multiscale simulation study reveals that the prominent rotational freezing of the electron-donating sidearm of the probes in the microenvironment of RNA helps in attaining more planar conformation when compared to DNA. It exerts a greater extent of intramolecular charge transfer and hence leads to enhanced fluorescence emission. A systematic structure-interaction relationship study highlighted the impact of heavy-chalcogens toward the improved emissive properties of the probes., (© 2022 Wiley-VCH GmbH.)

Stereoselectivity is important in many pharmacological processes but its impact on drug membrane transport is scarcely understood. Recent studies showed strong stereoselective effects in the cellular uptake of fenoterol by the organic cation transporters OCT1 and OCT2. To provide possible molecular explanations, homology models were developed and the putative interactions between fenoterol enantiomers and key residues explored in silico through computational docking, molecular dynamics simulations, and binding free energy calculations as well as in vitro by site-directed mutagenesis and cellular uptake assays. Our results suggest that the observed 1.9-fold higher maximum transport velocity (v max ) for (R,R)- over (S,S)-fenoterol in OCT1 is because the enantiomers bind to two distinct binding sites. Mutating PHE355 and ILE442, predicted to interact with (R,R)-fenoterol, reduced the v max ratio to 1.5 and 1.3, respectively, and to 1.2 in combination. Mutating THR272, predicted to interact with (S,S)-fenoterol, slightly increased stereoselectivity (v max ratio of 2.2), while F244A resulted in a 35-fold increase in v max and a lower affinity (29-fold higher K m ) for (S,S)-fenoterol. Both enantiomers of salbutamol, for which almost no stereoselectivity was observed, were predicted to occupy the same binding pocket as (R,R)-fenoterol. Unlike for OCT1, both fenoterol enantiomers bind in the same region in OCT2 but in different conformations. Mutating THR246, predicted to interact with (S,S)-fenoterol in OCT2, led to an 11-fold decreased v max . Altogether, our mutagenesis results correlate relatively well with our computational predictions and thereby provide an experimentally-corroborated hypothesis for the strong and contrasting enantiopreference in fenoterol uptake by OCT1 and OCT2., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achieve more potent and more selective inhibitors. In this work, four subseries of C5-NH 2 modified oseltamivir derivatives were designed and synthesized to explore every region inside the 150-cavity. Among them, compound 23d was exceptionally potent against the whole panel of Group-1 NAs with IC 50 values ranging from 0.26 to 0.73 nM, being 15-53 times better than oseltamivir carboxylate (OSC) and 7-11 times better than zanamivir. In cellular assays, 23d showed more potent or equipotent antiviral activities against corresponding virus strains compared to OSC with no cytotoxicity. Furthermore, 23d exhibited high metabolic stability in human liver microsomes (HLM) and low inhibitory effect on main cytochrome P450 enzymes. Notably, 23d displayed favorable druggability in vivo and potent antiviral efficacy in the embryonated egg model and mice model. Overall, 23d appears to be a promising candidate for the treatment of influenza virus infection.

Alzheimer's disease is characterized by the accumulation of amyloid beta (Aβ) and Tau aggregates in the brain, which induces various pathological events resulting in neurodegeneration. There have been continuous efforts to develop modulators of the Aβ and Tau aggregation process to halt or modify disease progression. A few small-molecule-based inhibitors that target both Aβ and Tau pathology have been reported. Here, we report the screening of a targeted library of small molecules to modulate Aβ and Tau aggregation together with their in vitro, in silico and cellular studies. In vitro ThT fluorescence assay, dot blot assay, gel electrophoresis and transmission electron microscopy (TEM) results have shown that thiophene-based lead molecules effectively modulate Aβ aggregation and inhibit Tau aggregation. In silico studies performed by employing molecular docking, molecular dynamics and binding-free energy calculations have helped in understanding the mechanism of interaction of the lead thiophene compounds with Aβ and Tau fibril targets. In cellulo studies revealed that the lead candidate is biocompatible and effectively ameliorates neuronal cells from Aβ and Tau-mediated amyloid toxicity., (© 2021 Wiley-VCH GmbH.)

Background and Aim: Though rodenticidal hepatotoxicity is reported from India, there is no systematic study to assess its magnitude. This study aimed to assess exposure to rodenticide as a risk factor for acute hepatotoxicity in Tamil Nadu, India., Methods: We retrospectively analyzed acute hepatotoxicity caused by ingestion of hepatotoxin or potentially hepatotoxic drug overdose across 15 hospitals in 6 districts of Tamil Nadu from 1 January 2019 to 30 June 2019. Study exclusion criteria were idiosyncratic drug-induced liver injury and chronic liver diseases., Results: Of the 702 patients, 685 gave history of consuming rodenticide; hepatotoxicity in the other patients resulted from paracetamol overdose (n=10) and due to other drugs (n=7); 97% patients had a suicidal intent. Of 671 patients with complete data, ratio of number of patients with hepatotoxicity due to rodenticide to paracetamol overdose was 450:6 (i.e. 75:1). The 451 rodenticidal hepatotoxicity patients (255 males, 75% were 15-34 years old) underwent conservative management (n=396), plasma exchange (n=54) and plasma exchange followed by liver transplant (n=1); 159 patients (35%) had poor outcome (131 died, 28 discharged in moribund state). Based on our observations, we estimate a case burden of 1584 rodenticidal hepatotoxicity patients (95% CI: 265-6119) with poor outcome in 554 patients in Tamil Nadu from January 2019 to June 2019. Population attributable risk for rodenticide as cause of hepatotoxicity was 22.7%., Conclusion: Rodenticide ingestion was an important cause of acute hepatotoxicity in Tamil Nadu. Most patients were young and one-third had poor outcome. Public health interventions are needed to address this., (© 2021. Indian Society of Gastroenterology.)

Tauopathies are a subclass of neurodegenerative diseases characterized by an accumulation of microtubule binding tau fibrils in brain regions. Diseases such as Alzheimer's (AD), chronic traumatic encephalopathy (CTE), Pick's disease (PiD), and corticobasal degeneration (CBD) belong to this subclass. Development of tracers which can visualize and discriminate between different tauopathies is of clinical importance in the diagnosis of various tauopathies. Currently, several tau tracers are available for in vivo imaging using a positron emission tomography (PET) technique. Among these tracers, PBB3 is reported to bind to various types of tau fibrils with comparable binding affinities. In contrast, tau tracer AV-1451 is reported to bind to specific types of tau fibrils (in particular to AD-associated and CTE) with higher binding affinity and only show nonspecific or weaker binding toward tau fibrils dominant with 3R isoforms (associated with PiD). The tau fibrils associated with different tauopathies can adopt different microstructures with different binding site microenvironments. By using detailed studies of the binding profiles of tau tracers for different types of tau fibrils, it may be possible to design tracers with high selectivity toward a specific tauopathy. The microstructures for the tau fibrils from patients with AD, PiD, and CTE have recently been demonstrated by cryogenic electron microscopy (cryo-EM) measurements allowing structure-based in silico simulations. In the present study, we have performed a multiscale computational study involving molecular docking, molecular dynamics, free energy calculations, and QM fragmentation calculations to understand the binding profiles of tau tracer AV-1451 and its potential use for diagnosis of AD, CTE, and PiD tauopathies. Our computational study reveals that different affinity binding sites exist for AV-1451 in the tau fibrils associated with different tauopathies. The binding affinity of this tracer toward different tau fibrils goes in this order: PiD > AD > CTE. The interaction energies for different tau fibril-tracer complexes using the QM fragmentation scheme also showed the same trend. However, by carrying out molecular dynamics simulations for the AD-derived tau fibrils in organic solvents, we found additional high affinity binding sites for AV-1451. The AV-1451 binding profile in these cryptic sites correctly explains the preferential binding of this tracer toward the AD fibrils when compared with the PiD fibrils. This study clearly demonstrates having a cryo-EM structure is still not sufficient for the structure-based tracer discovery for certain targets, as they may have "potential but hidden" high affinity binding sites, and we need additional strategies to identify them.

The discovery of small molecules that exhibit turn-on far-red or near-infrared (NIR) fluorescence upon DNA binding and understanding how they bind DNA are important for imaging and bioanalytical applications. Here we report the DNA-bound structure and the DNA binding mechanism of quinone cyanine dithiazole (QCy-DT), a recently reported AT-specific turn-on NIR fluorescent probe for double-stranded DNA. The nuclear magnetic resonance (NMR)-derived structure showed minor groove binding but no specific ligand-DNA interactions, consistent with an endothermic and entropy-driven binding mechanism deduced from isothermal titration calorimetry. Minor groove binding is typically fast because it minimally perturbs the DNA structure. However, QCy-DT exhibited unusually slow DNA binding. The cyanine-based probe is capable of cis - trans isomerization due to overlapping methine bridges, with 16 possible slowly interconverting cis / trans isomers. Using NMR, density functional theory, and free energy calculations, we show that the DNA-free and DNA-bound environments of QCy-DT prefer distinctly different isomers, indicating that the origin of the slow kinetics is a cis - trans isomerization and that the minor groove preferentially selects an otherwise unstable cis / trans isomer of QCy-DT. Flux analysis showed the conformational selection pathway to be the dominating DNA binding mechanism at low DNA concentrations, which switches to the induced fit pathway at high DNA concentrations. This report of cis / trans isomerization of a ligand, upon binding the DNA minor groove, expands the prevailing understanding of unique discriminatory powers of the minor groove and has an important bearing on using polymethine cyanine dyes to probe the kinetics of molecular interactions.

Background: Minimally invasive parathyroid surgery is the standard of care in patients with Primary Hyperparathyroidism (PHPT) which requires accurate preoperative localization. Of all the available imaging modalities, 4DCT is considered the best modality for localization, however it entails the risk of ionizing radiation. To circumvent this 4DMRI was evaluated for parathyroid lesion localization., Purpose: To evaluate and compare the accuracy of 4DCT and 4DMRI in the localization of parathyroid Lesions., Materials and Methods: In this ethically approved observational diagnostic study, 135 patients (age range: 10-75 years, male: female ratio - 1:2.1) with clinically and biochemically suspected PHPT were recruited. Of these, 56 patients underwent both 4DCT and 4DMRI. Six patients with positive imaging who didn't undergo surgery were excluded. A total of 50 patients with 61 proven parathyroid lesions were included for analysis. 48 patients had surgical and histopathological findings for the confirmation of imaging findings., Results: Both 4DCT and 4DMRI correctly detected 59/61 lesions in 48 patients. There was one false positive and two true negatives. In addition, 2 (3.22 %) lesions which were not detected by 4DCT and 4DMRI were found on surgery. The sensitivity of both 4DCT and 4DMRI was 96.7 %; specificity was 66.6 % and accuracy was 95.2 %., Conclusion: 4DMRI and 4DCT had similar accuracy for the detection of parathyroid lesions. However, 4DMRI has the advantage of lack of exposure to ionizing radiation, which can be beneficial in younger patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

RNA interference (RNAi) is an innate cellular mechanism triggered by a double-stranded RNA (dsRNA) molecule causing selective inhibition of gene expression. Here, we demonstrated the RNAi technology for gene silencing in sugarcane for biofuel production. This chapter describes an efficient model system that established to target the caffeic acid O-methyltransferase (COMT) gene and the RNAi construct is designed and delivered through Agrobacterium mediated stable sugarcane transformation. Also, the approach for an analysis of resulting putative transgenic plants for a targeted RNAi mediated gene silencing is described.

Three types of chemical entities, namely, small organic molecules (organics), peptides, and biologics, are mainly used as drug candidates for the treatment of various diseases. Even though the peptide drugs are known since 1920 in association with the clinical use of insulin, only a limited number of peptides are currently used for therapeutics due to various disadvantages associated with them such as limited serum and blood stability, oral bioavailability, and permeability. Since, through chemical modifications and structure tuning, many of these limitations can be overcome, peptide-based drugs are gaining attention in pharmaceutical research. As of today, there are more than 60 peptide-based drugs approved by FDA, and over 150 peptides are in the advanced clinical studies. In this book chapter, the peptide-based lead compounds and drugs available for treating various viral diseases and their advantages and disadvantages when compared to small molecules drugs are discussed., (© 2021. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.)

Monoamine oxidase B (MAO-B) is a potential biomarker for Parkinson's disease (PD), a neurodegenerative disease associated with the loss of motor activities in human subjects. The disease state is associated with dopamine deprival, and so the inhibitors of MAO-B can serve as therapeutic drugs for PD. Since the expression level of MAO-B directly correlates to the disease progress, the distribution and population of this enzyme can be employed to monitor disease development. One of the approaches available for estimating the population is two-photon imaging. The ligands used for two-photon imaging should have high binding affinity and binding specificity toward MAO-B along with significant two-photon absorption cross sections when they are bound to the target. In this article, we study using a multiscale modeling approach, the binding affinity and spectroscopic properties (one- and two-photon absorption) of three (Flu1, Flu2, Flu3) of the currently available probes for monitoring the MAO-B level. We report that the binding affinity of the probes can be explained using the molecular size and binding cavity volume. The experimentally determined one-photon absorption spectrum is well reproduced by the employed QM/MM approaches, and the most accurate spectral shifts, on passing from one probe to another, are obtained at the coupled-cluster (CC2) level of theory. An important conclusion from this study is also the demonstration that intrinsic molecular two-photon absorption strengths (δ 2PA ) increase in the order δ 2PA (Flu1) > δ 2PA (Flu2) > δ 2PA (Flu3). This is in contrast with experimental data, which predict similar values of two-photon absorption cross sections for Flu1 and Flu3. We demontrate, based on the results of electronic-structure calculations for Flu1 that this discrepancy cannot be explained by an explicit account for neighboring residues (which could lead to charge transfer between a probe and neighboring aromatic amino acids thus boosting δ 2PA ). In summary, we show that the employed multiscale approach not only can optimize two-photon absorption properties and verify binding affinity, but it can also help in detailed analyses of experimental data.

The selective recognition and imaging of oncogene specific G-quadruplex (GQ) structures holds great promise in the development of diagnostic therapy (theranostics) for cancer and has been challenging due to their structural dynamics and diversity. We report selective recognition of GQ by a small molecule through unique hybrid loop stacking and groove binding mode with turn on far-red fluorescence response and anticancer activity demonstrating the potential implications for GQ-targeted cancer theranostics. Methods: Biophysical investigation reveal the turn on far-red emission property of TGP18 for selective recognition of GQ. In cellulo studies including DNA damage and oxidative stress evaluation guided us to perform in vitro (3D spheroid) and in vivo (xenograft mice model) anti-cancer activity, and tumor tissue imaging to assess the theranostic potential of TGP18. Results: Neocuproine-based far-red turn on fluorescence probe TGP18 shows GQ-to-duplex selectivity and specifically recognizes BCL-2 GQ with high affinity through a unique hybrid binding mode involving loop-stacking and groove interactions. Our study reveals that the selective recognition originating from the distinct loop structure of GQ that alters the overall probe interaction and binding affinity. TGP18 binding to anti-apoptotic BCL-2 GQ ablates the pro-survival function and elicit anti-cancer activity by inducing apoptosis in cancer cells. We deciphered that inhibition of BCL-2 transcription synergized with signaling cascade of nucleolar stress, DNA damage and oxidative stress in triggering apoptosis signaling pathway. Conclusion: Intervention of GQ mediated lethality by TGP18 has translated into anti-cancer activity in both in vitro 3D spheroid culture and in vivo xenograft models of lung and breast cancer with superior efficacy for the former. In vivo therapeutic efficacy supplemented with tumor 3D spheroid and tissue imaging potential define the role of TGP18 in GQ-targeted cancer theranostics., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Previous efforts in our lab have led to the development of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) thiophene[3,2- d ]pyrimidine compound 1 ( K-5a2 ) with promising activity against wild-type and mutant HIV-1 strains. In this work, a series of novel diarylpyrimidines derivatives carrying a structurally diverse motif at the right wing of the lead K-5a2 was designed and synthesized as potential anti-HIV-1 agents. The results demonstrated that 8a yielded exceptionally potent activity against HIV-1 wild-type (50% effective concentration (EC 50 ) = 3.30 nM) and mutant strain RES056 (EC 50 = 22.6 nM) in MT-4 cells; in the reverse transcriptase inhibitory assay, 8a (half maximal inhibitory concentration (IC 50 ) = 0.028 μM) was remarkably superior to that of K-5a2 (IC 50 = 0.300 μM) and comparable to that of etravirine (ETR; IC 50 = 0.011 μM). Notably, 8a exhibited better druggability than that of K-5a2 , including significantly reduced CYP enzymatic inhibitory activity (IC 50 > 50 μM), lower human ether-à-go-go related gene (hERG) inhibition (IC 50 > 30 μM), and improved metabolic stability (short half-life, T 1/2 = 77.5 min) in vitro .

Background There has been growing support for digital Cognitive Behavioral Therapy (dCBT-I) as a scalable intervention that both reduces insomnia and prevents depression. However, the mechanisms by which dCBT-I reduces and prevents depression is less clear. Methods This was a randomized controlled trial with two parallel arms: dCBT-I (N=358), or online sleep education as the control condition (N=300). Outcome variables were measured at pre-treatment, post-treatment, and one-year follow-up, and included the Insomnia Severity Index (ISI), the Quick Inventory of Depressive Symptomatology (QIDS-SR 16 ), and the Perseverative Thinking Questionnaire (PTQ). The analyses tested change in PTQ scores as a mediator for post-treatment insomnia, post-treatment depression, and incident depression at one-year follow-up. Results Reductions in rumination (PTQ) were significantly larger in the dCBT-I condition compared to control. Results also showed that reductions in rumination significantly mediated the improvement in post-treatment insomnia severity (proportional effect = 11%) and post-treatment depression severity (proportional effect = 19%) associated with the dCBT-I condition. Finally, reductions in rumination also significantly mediated the prevention of clinically significant depression via dCBT-I (proportional effect = 42%). Limitations Depression was measured with a validated self-report instrument instead of clinical interviews. Durability of results beyond one-year follow-up should also be tested in future research. Conclusions Results provide evidence that rumination is an important mechanism in how dCBT-I reduces and prevents depression., Competing Interests: Declaration of Competing Interest Dr. Drake reports receiving nonfinancial support from Big Health Ltd (provision of Sleepio for use in clinical trials). All other authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Plant nuclear factor ( NF-Y ) is a transcription activating factor, consisting of three subunits, and plays a key regulatory role in many stress-responsive mechanisms including drought and salinity stresses. NF-Ys function both as complex and individual subunits. Considering the importance of sugarcane as a commercial crop with high socio-economic importance and the crop being affected mostly by water deficit stress and salinity stress causing significant yield loss, nuclear transcriptional factor NF-YB2 was focused in this study. Plant nuclear factor subunit B2 from Erianthus arundinaceus ( EaNF-YB2 ), a wild relative of sugarcane which is known for its drought and salinity stress tolerance, and commercial Saccharum hybrid Co 86032 ( ShNF-YB2 ) was isolated and characterized . Both EaNF-YB2 and ShNF-YB2 genes are 543 bp long that encodes for a polypeptide of 180 amino acid residues. Comparison of EaNF-YB2 and ShNF-YB2 gene sequences revealed nucleotide substitutions at nine positions corresponding to three synonymous and six nonsynonymous amino acid substitutions that resulted in variations in physiochemical properties. However, multiple sequence alignment (MSA) of NF-YB2 proteins showed conservation of functionally important amino acid residues. In silico analysis revealed NF-YB2 to be a hydrophilic and intracellular protein, and EaNF-YB2 is thermally more stable than that of ShNF-YB2. Phylogenetic analysis suggested the lower rate of evolution of NF-YB2 . Subcellular localization in sugarcane callus revealed NF-YB2 localization at nucleus that further evidenced it to be a transcription activation factor. Comparative RT-qPCR experiments showed a significantly higher level of NF-YB2 expression in E. arundinaceus when compared to that in the commercial Saccharum hybrid Co 86032 under drought and salinity stresses. Hence, EaNF-YB2 could be an ideal candidate gene, and its overexpression in sugarcane through genetic engineering approach might enhance tolerance to drought and salinity stresses., Competing Interests: Conflict of interestThe authors have declared that no competing interests exist., (© King Abdulaziz City for Science and Technology 2020.)

Several multidrug-resistant organisms have emerged, which increases the threat to public health around the world and a limited number of therapeutics were available to counteract these issues. Thus, researchers are trying to find out novel antimicrobials to overcome multidrug-resistant issues. The present study aimed to isolate antibacterial principles against the clinical isolates of multidrug-resistant (MDR) Staphylococcus aureus from the ethyl acetate extract of Gycosmis pentaphylla . The isolation and structural characterization of bioactive compounds were carried out using various chromatographic techniques (TLC, column, HPLC, and LC-MS) and spectral studies such as FT-IR, CHNS analysis, 1 H-NMR, and 13 C-NMR. The antimicrobial potential of isolated compounds was assessed according to the standard methods. The isolated compounds were identified as arborine and skimmianine, which exhibited a significant antibacterial effect with the lowest MIC and MBC values against MDR S. aureus and in vitro kinetic and protein leakage assays supported the antimicrobial activity. Significant morphological changes such as uneven cell surfaces and morphology, cell shrinkage, and cell membrane damages were observed in the MDR S. aureus upon the treatment of arborine and skimmianine. The present investigation concludes that the isolated arborine and skimmianine compounds from G. pentaphylla harbor a strong antibacterial activity against MDR S. aureus and may be used as alternative natural drugs in the treatment of MDR S. aureus ., (Copyright © 2020 Murugan, Srinivasan, Murugan, Kim and Natarajan.)

Assembly and co-assemblies of peptide amphiphiles through specific noncovalent forces expand the space of molecular architectonics-driven construction of diverse nanoarchitectures with potential biological applications. In this work, cyclic dipeptide amphiphiles (CDPAs) of cyclo(Gly-Asp) with varying lengths of alkyl chains ( C8 - C18 ) were synthesized, and their molecular organization was studied. The noncovalent interactions of the components, CDP and alkyl chain, drive the molecular self-assembly of CDPAs into well-defined and diverse nanoarchitectures such as nanotubes, nanospheres, nano/microsheets, and flowers. The co-assembly of CDPAs with biological molecules such as nucleosides was studied to ascertain their utility as potential drug delivery vehicles. Mechanical properties of these nanoarchitectures in nanoindentation study established them as robust in nature. A temperature-dependent NMR study confirmed the formation of stable co-assembly of CDPAs, primarily driven by the intermolecular hydrogen bonding interactions. Computational modeling of oligomers of CDPAs and their co-assembly with nucleosides/nucleotides reveal the molecular level interactions and driving force behind such assemblies. CDPAs exhibit good biocompatibility and cytocompatibility, as revealed by the cellular studies which substantiated their suitability for drug delivery applications. The co-assembly of CDPA with an anticancer drug 5-bromo-2'-deoxyuridine (BrdU) was studied as a drug delivery platform and cytotoxicity was successfully assessed in HeLa cells. Computational modeling of the oligomers of CDPAs and their co-assembly with the drug molecule was performed to understand the molecular level interactions and driving force behind the assemblies. Our findings reveal the design strategy to construct diverse structural architectures using CDP as the modular building unit and specific molecular interactions driven co-assembly for potential application as drug delivery carrier.

Multiple lines of evidence indicate that amyloid beta (Aβ) peptide is responsible for the pathological devastation caused in Alzheimer's disease (AD). Aβ aggregation species predominantly contribute to multifaceted toxicity observed in neuronal cells including generation of reactive oxygen species (ROS), mitochondrial dysfunction, interfering with synaptic signaling, and activation of premature apoptosis. Herein, we report a natural product berberine-derived (Ber-D) multifunctional inhibitor to ameliorate in cellulo multifaceted toxicity of AD. The structural attributes of polyphenolic Ber-D have contributed to its efficient Cu chelation and arresting the redox cycle to prevent the generation of ROS and rescue biomacromolecules from oxidative damage. Ber-D inhibits metal-dependent and -independent Aβ aggregation, which is supported by in silico studies. Ber-D treatment averts mitochondrial dysfunction and corresponding neuronal toxicity contributing to premature apoptosis. These key multifunctional attributes make Ber-D a potential therapeutic candidate to ameliorate multifaceted Aβ toxicity in AD., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abnormal deposition of hyperphosphorylated tau as neurofibrillary tangles (NFTs) is an important pathological hallmark of Alzheimer's disease (AD) and of other neurodegenerative disorders. A noninvasive positron emission tomography (PET) tracer that quantifies neurofibrillary tangles in vivo can enhance the clinical diagnosis of AD and can also be used to evaluate the efficacy of therapeutics aimed at reducing the abnormal aggregation of the tau fibril in the brain. In this paper, we study the binding profile of fibrillar tau aggregates with a PET tracer PI2620, which is a new second generation tau PET tracer that is presently experimentally and clinically studied. The target structure for the tau fibril is based on cryo-electron microscopy (cryo-EM) structure. A multiscale simulation workflow including molecular docking, molecular dynamics simulation, metadynamics simulation, and free energy calculations was implemented. We find that PI2620 can bind to eight surface binding sites, three core binding sites, and one entry site. The binding at the core sites and entry site is found to be much more favorable than that on the surface sites due to stronger hydrophobic interactions and less solvent exposure. Furthermore, the entry site which is formed by the terminal β-sheets of the fibril is found to have the highest binding affinity to PI2620. Importantly, the binding capacity at the entry site can be much higher than that at other core sites, due to its easy accessibility. Therefore, the entry site is believed to be the major binding site for PI2620. A previous computational study on tracers with tau fibrils reports a maximum of four binding sites. Through use of methods that allow us to locate "cryptic binding sites", we report here additional core sites available for binding and we address the limitation of using the cryo-EM structure alone for structure-based tracer design. Our results could be helpful for elucidating the binding mechanism of imaging tracers with the fibrillar form of tau, a knowledge that in turn can be used to guide the development of compounds with higher affinity and selectivity for tau using structure-based design strategies.

Understanding blood glucose levels in our body can be a key part in identifying and diagnosing prediabetes. Herein, nickel oxide (NiO) decorated molybdenum disulfide (MoS 2 ) nanosheets have been synthesized via a hydrothermal process to develop a non-enzymatic sensor for the detection of glucose. The surface morphology of the NiO/MoS 2 nanocomposite was comprehensively investigated by field-emission scanning electron microscopy (FE-SEM), high-resolution transmission electron microscopy (HR-TEM), powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS) and Brunauer-Emmett-Teller (BET) analysis. The electro-catalytic activity of the as-prepared NiO/MoS 2 nanocomposite towards glucose oxidation was investigated by cyclic voltammetry, electrochemical impedance spectroscopy (EIS) and amperometry in 0.1 M NaOH. The NiO/MoS 2 nanocomposite-based sensor showed outstanding electrocatalytic activity for the direct electro-oxidation of glucose due to it having more catalytic active sites, good conductivity, excellent electron transport and high specific surface area. Meanwhile, the NiO/MoS 2 modified glassy carbon electrode (GCE) showed a linear range of glucose detection from 0.01 to 10 mM by amperometry at 0.55 V. The effect of other common interferent molecules on the electrode response was also tested using alanine, l-cysteine, fructose, hydrogen peroxide, lactose, uric acid, dopamine and ascorbic acid. These molecules did not interfere in the detection of glucose. Moreover, this NiO/MoS 2 /GCE sensor offered rapid response (2 s) and a wide linear range with a detection limit of 1.62 μM for glucose. The reproducibility, repeatability and stability of the sensor were also evaluated. The real application of the sensor was tested in a blood serum sample in the absence and presence of spiked glucose and its recovery values (96.1 to 99.8%) indicated that this method can be successfully applied to detect glucose in real samples., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: In India, there is no feedback regarding 34% of tuberculosis (TB) patients diagnosed and referred from medical colleges for treatment to peripheral health institutions (PHIs)., Objectives: The aim of this study is to measure the effectiveness of the new intervention package, developed based on qualitative study in reducing pretreatment loss to follow-up (PTLFU) of all TB patients diagnosed and referred for treatment from medical colleges to PHIs., Materials and Methods: An intervention was developed based on the findings of in depth-interviews conducted among different stakeholders such as TB patients who did/did not report, service providers working in four medical colleges in Pondicherry. Intervention consisting of phone calls, home visits, etc., was implemented for a period of 6 months. The baseline and endline proportion of TB patients for whom feedback received was determined from the available records (Revised National TB Control Program State Task Force Quarterly reports)., Results: Patient's ignorance, lack of faith in healthcare system, side effects and social stigma, unpleasant experience in hospitals, poor accessibility to directly observed treatment, short-course centers, drugs shortage, poor coordination between program and hospital staff were the risk factors for PTLFU. At baseline, the proportions of feedback received about TB patients referred for treatment from medical colleges to PHIs was 46%. After the initiation of interventions, it increased to 61% and 66% in the first and second quarters of 2017, respectively., Conclusion: Risk factors for PTLFU were multi-factorial related to both patient and health system. Simple, feasible interventions such as phone calls and home visits to TB patients were effective in reducing PTLFU., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Indian Journal of Community Medicine.)