Unveiling G protein-coupled inwardly-rectifying potassium channel 4 (GIRK4) inverse agonists: A novel simulation-driven approach leveraging cellular ion flow coupled with chemometrics and protein conformational dynamics.

GIRK channels are crucial in regulating cardiac excitability and present promising therapeutic targets. Notably, the genetic absence of GIRK4 prevents atrial fibrillation (AF) in knockout mice, yet research on specific GIRK4 modulators is limited. Addressing the challenges posed by GIRK4's intrinsic constitutive activity, we hypothesize that a GIRK inverse agonist unlike the traditional antagonist can actively downregulate the channel activity alongside reduction of the aberrant basal signaling which can translate to enhanced therapeutic efficacy.

Chemometric modeling, inverse docking, and molecular simulations-driven design for multilayered prioritization of novel leishmanicidal agents based on a 2-aminobenzimidazole scaffold.

Leishmaniasis, a major neglected tropical disease (NTD), affects millions of people globally. Current treatments are plagued by infection relapse, high toxicity, and lengthy regimens. A contemporary study investigated the 2-aminobenzimidazole scaffold for leishmanicidal activity but it was found to be associated with poor exposure and lack of efficacy in vivo.

Elevated Contact Stresses Compromise Activity-Mediated Cartilage Rehydration but not Lubrication.

Purpose: Understanding how obesity-a key risk factor for osteoarthritis-effects articular cartilage function is critical to understand OA pathoetiology. Cartilage, a biphasic material, supports vanishingly low friction coefficients in vivo, but is tribomechanically compromised by load-induced interstitial pressure/lubrication loss. To maintain tribomechanical function, cartilage must recover fluid lost to habitual/average contact stresses, a problem obesity likely exacerbates.

Artificial intelligence to predict inhibitors of drug-metabolizing enzymes and transporters for safer drug design.

Introduction: Drug-metabolizing enzymes (DMEs) and transporters (DTs) play integral roles in drug metabolism and drug-drug interactions (DDIs) which directly impact drug efficacy and safety. It is well-established that inhibition of DMEs and DTs often leads to adverse drug reactions (ADRs) and therapeutic failure. As such, early prediction of such inhibitors is vital in drug development.

Ligand-based cheminformatics and free energy-inspired molecular simulations for prioritizing and optimizing G-protein coupled receptor kinase-6 (GRK6) inhibitors in multiple myeloma treatment.

Multiple myeloma (MM) is the second most frequently diagnosed hematological malignancy, presenting limited treatment options with no curative potential and significant drug resistance. Recent studies involving genetic knockdown established the crucial role of GRK6 in upholding the viability of MM cells, emphasizing the need to identify potential inhibitors. Computational exploration of GRK6 inhibitors has not been attempted previously.

Ecotoxicological risk assessment of active pharmaceutical ingredients (APIs) against different aquatic species leveraging intelligent consensus prediction and i-QSTTR modeling.

The increasing presence of active pharmaceutical ingredients (APIs) in aquatic ecosystems, driven by widespread human use, poses significant risks, including acute and chronic toxicity to aquatic species. However, the scarcity of experimental toxicity data on APIs and related compounds due to the high costs, time requirements, and ethical concerns associated with animal testing hinders comprehensive risk assessment. In response, we developed quantitative structure-toxicity relationship (QSTR) and interspecies quantitative structure toxicity-toxicity relationship (i-QSTTR) models for three key aquatic species: zebrafish, water fleas, and green algae, using NOEC as an endpoint, following OECD guidelines.

Structural basis of CDNF interaction with the UPR regulator GRP78.

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that is a disease-modifying drug candidate for Parkinson's disease. CDNF has pleiotropic protective effects on stressed cells, but its mechanism of action remains incompletely understood. Here, we use state-of-the-art advanced structural techniques to resolve the structural basis of CDNF interaction with GRP78, the master regulator of the unfolded protein response (UPR) pathway.

Demographic Characteristics and Treatment Outcomes of Advanced Renal Cell Carcinoma With Clear Cell Histology: A Single-Center Experience From India.

Background Treatment of metastatic renal cell cancer (mRCC) has revolutionized with the introduction of anti-VEGF tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). There is limited data in the literature on the outcomes of Indian patients treated with TKI. Here, we report the outcome of mRCC treated with first-line TKI in a resource-poor setting.

Unveiling G-protein coupled receptor kinase-5 inhibitors for chronic degenerative diseases: Multilayered prioritization employing explainable machine learning-driven multi-class QSAR, ligand-based pharmacophore and free energy-inspired molecular simulation.

GRK5 holds a pivotal role in cellular signaling pathways, with its overexpression in cardiomyocytes, neuronal cells, and tumor cells strongly associated with various chronic degenerative diseases, which highlights the urgent need for potential inhibitors. In this study, multiclass classification-based QSAR models were developed using diverse machine learning algorithms. These models were built from curated compounds with experimentally derived GRK5 inhibitory activity.

First report on chemometrics-driven multilayered lead prioritization in addressing oxysterol-mediated overexpression of G protein-coupled receptor 183.

Contemporary research has convincingly demonstrated that upregulation of G protein-coupled receptor 183 (GPR183), orchestrated by its endogenous agonist, 7α,25-dihydroxyxcholesterol (7α,25-OHC), leads to the development of cancer, diabetes, multiple sclerosis, infectious, and inflammatory diseases. A recent study unveiled the cryo-EM structure of 7α,25-OHC bound GPR183 complex, presenting an untapped opportunity for computational exploration of potential GPR183 inhibitors, which served as our inspiration for the current work. A predictive and validated two-dimensional QSAR model using genetic algorithm (GA) and multiple linear regression (MLR) on experimental GPR183 inhibition data was developed.

Conference report: Introducing oncology to undergraduate medical and allied health sciences students: reflections from 2nd cancer TMC Oncology Congress 2023 at Kolkata, India.

Despite the high cancer burden in low-middle-income-countries, medical students often have inadequate exposure to oncology. This may contribute to reduced interest in pursuing training in the field. The second ecancer TMC Oncology Congress at Kolkata on 30th September and 1st October 2023 was planned primarily to introduce undergraduate medical and allied health science students to oncology.

HER-096 is a CDNF-derived brain-penetrating peptidomimetic that protects dopaminergic neurons in a mouse synucleinopathy model of Parkinson's disease.

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotropic factor that modulates unfolded protein response (UPR) pathway signaling and alleviates endoplasmic reticulum (ER) stress providing cytoprotective effects in different models of neurodegenerative disorders. Here, we developed a brain-penetrating peptidomimetic compound based on human CDNF. This compound called HER-096 shows similar potency and mechanism of action as CDNF, and promotes dopamine neuron survival, reduces α-synuclein aggregation and modulates UPR signaling in in vitro models.

Cell therapy biomanufacturing: integrating biomaterial and flow-based membrane technologies for production of engineered T-cells.

Adoptive T-cell therapies (ATCTs) are increasingly important for the treatment of cancer, where patient immune cells are engineered to target and eradicate diseased cells. The biomanufacturing of ATCTs involves a series of time-intensive, lab-scale steps, including isolation, activation, genetic modification, and expansion of a patient's T-cells prior to achieving a final product. Innovative modular technologies are needed to produce cell therapies at improved scale and enhanced efficacy.

Facilitators and barriers of preventive behaviors against COVID-19 during Ramadan: A phenomenology of Indonesian adults.

Introduction: Intercity mobility restriction, physical distancing, and mask-wearing are preventive behaviors to reduce the transmission of COVID-19. However, strong cultural and religious traditions become particular challenges in Indonesia. This study uses the Behavior Change Wheel to explore barriers and facilitators for intercity mobility restriction, physical distancing, and mask-wearing during Ramadan.

Cerebral Venous Sinus Thrombosis Following Scrub Typhus Infection: A Case Report and a Review of the Literature.

Neurological manifestations of scrub typhus, a re-emerging infectious disease of tropic/subtropics caused by infection, have been ever-evolving. Several central nervous system infections have been acknowledged for the development of cerebral venous sinus thrombosis (CVT). Nevertheless, CVT has been a rarely described addendum to the ever-evolving "neuro-scrub" spectrum.

Understanding the post-2010 increase in food bank use in England: new quasi-experimental analysis of the role of welfare policy.

Background: The number of food banks (charitable outlets of emergency food parcels) and the volume of food distributed by them increased multi-fold in the United Kingdom (UK) since 2010. The overwhelming majority of users of food banks are severely food insecure. Since food insecurity implies a nutritionally inadequate diet, and poor dietary intake has been linked to a number of diseases and chronic conditions, the rise in the number of people using food banks is a phenomenon of significant importance for public health.

The DNA polymerase of bacteriophage YerA41 replicates its T-modified DNA in a primer-independent manner.

Yersinia phage YerA41 is morphologically similar to jumbo bacteriophages. The isolated genomic material of YerA41 could not be digested by restriction enzymes, and used as a template by conventional DNA polymerases. Nucleoside analysis of the YerA41 genomic material, carried out to find out whether this was due to modified nucleotides, revealed the presence of a ca 1 kDa substitution of thymidine with apparent oligosaccharide character.

Outcomes of HIDAC 18 g Versus IDAC 9 g in Consolidation Therapy of Acute Myeloid Leukemia: A Retrospective Study.

Background: Cytarabine based therapy has been the standard consolidation regimen for AML (acute myeloid leukemia) for decades. However, the optimal dose, regimen and schedule is not known. HIDAC (high dose cytarabine at 18 g/m) has been the conventional standard, however, recent studies have shown that intermediate doses of cytarabine (IDAC) have equal efficacy and lesser toxicities.

xViTCOS: Explainable Vision Transformer Based COVID-19 Screening Using Radiography.

Since its outbreak, the rapid spread of COrona VIrus Disease 2019 (COVID-19) across the globe has pushed the health care system in many countries to the verge of collapse. Therefore, it is imperative to correctly identify COVID-19 positive patients and isolate them as soon as possible to contain the spread of the disease and reduce the ongoing burden on the healthcare system. The primary COVID-19 screening test, RT-PCR although accurate and reliable, has a long turn-around time.

Membrane interaction and disulphide-bridge formation in the unconventional secretion of Tau.

Misfolded, pathological tau protein propagates from cell to cell causing neuronal degeneration in Alzheimer's disease and other tauopathies. The molecular mechanisms of this process have remained elusive. Unconventional secretion of tau takes place via several different routes, including direct penetration through the plasma membrane.

Psychosocial counseling of patients planned for hematopoietic stem-cell transplantation for malignant conditions-practical challenges and solutions from India.

Hematopoietic stem-cell transplantation (HSCT) is a life-saving procedure often performed to cure relapsed and difficult-to-treat malignancies. Only a handful of centers in India were initially involved in the delivery of these services. However, in the last decade, more than 100 centers in the private and public domain have started offering transplant services in the country.

Automatic detection of sleep apnea events based on inter-band energy ratio obtained from multi-band EEG signal.

Sleep apnea is a potentially serious sleep disorder characterised by abnormal pauses in breathing. Electroencephalogram (EEG) signal analysis plays an important role for detecting sleep apnea events. In this research work, a method is proposed on the basis of inter-band energy ratio features obtained from multi-band EEG signals for subject-specific classification of sleep apnea and non-apnea events.

Sleep Apnea Detection Based on Rician Modeling of Feature Variation in Multiband EEG Signal.

Sleep apnea, a serious sleep disorder affecting a large population, causes disruptions in breathing during sleep. In this paper, an automatic apnea detection scheme is proposed using single lead electroencephalography (EEG) signal to discriminate apnea patients and healthy subjects as well as to deal with the difficult task of classifying apnea and nonapnea events of an apnea patient. A unique multiband subframe based feature extraction scheme is developed to capture the feature variation pattern within a frame of EEG data, which is shown to exhibit significantly different characteristics in apnea and nonapnea frames.

Intracameral Use of Nepafenac: Safety and Efficacy Study.

Purpose: To test the intracameral safety of nepafenac and its efficacy in inhibiting prostaglandin synthesis during phacoemulsification surgery.

Methods: The safety evaluation was conducted in normal eyes of rabbits, 0.1ml of 0.