Classification of Lung Diseases Using an Attention-Based Modified DenseNet Model.

Lung diseases represent a significant global health threat, impacting both well-being and mortality rates. Diagnostic procedures such as Computed Tomography (CT) scans and X-ray imaging play a pivotal role in identifying these conditions. X-rays, due to their easy accessibility and affordability, serve as a convenient and cost-effective option for diagnosing lung diseases. Our proposed method utilized the Contrast-Limited Adaptive Histogram Equalization (CLAHE) enhancement technique on X-ray images to highlight the key feature maps related to lung diseases using DenseNet201. We have augmented the existing Densenet201 model with a hybrid pooling and channel attention mechanism. The experimental results demonstrate the superiority of our model over well-known pre-trained models, such as VGG16, VGG19, InceptionV3, Xception, ResNet50, ResNet152, ResNet50V2, ResNet152V2, MobileNetV2, DenseNet121, DenseNet169, and DenseNet201. Our model achieves impressive accuracy, precision, recall, and F1-scores of 95.34%, 97%, 96%, and 96%, respectively. We also provide visual insights into our model's decision-making process using Gradient-weighted Class Activation Mapping (Grad-CAM) to identify normal, pneumothorax, and atelectasis cases. The experimental results of our model in terms of heatmap may help radiologists improve their diagnostic abilities and labelling processes.

The more the merrier: optimizing monomer concentration for supersaturation controlled synthesis of stable ultra-small CsPbBr3 nanocrystals for blue emission.

Synthesis of strongly quantum confined and emissive CsPbBr3 perovskite nanocrystals with sizes <4 nm has proven challenging owing to fast nucleation and rapid growth. In this work, ultra-small blue-emitting (∼461 nm) CsPbBr3 nanocrystals with an average particle size of 3.2 nm are synthesized via a high-temperature (170 °C) colloidal approach by controlling the supersaturation reaction conditions. Our approach yielded stable nanocrystals with uniform size, shape, and excellent color purity, making them promising for blue light emitting diode (LED) applications.

Effect of Surface Chemistry on Hemolysis, Thrombogenicity, and Toxicity of Carbon Nanotube Doped Thermally Sprayed Hydroxyapatite Implants.

Assessing blood compatibility is crucial before in vivo procedures and is considered more reliable than many in vitro tests. This study examines the physiochemical properties and blood compatibility of bioactive powders ((0.5-2 wt % carbon nanotube (CNT)/alumina)-20 wt %)) produced through a heterocoagulation colloidal technique followed by ball milling with hydroxyapatite (HAp). The 1 wt % CNT composite demonstrated a surface charge ∼5 times higher than HAp at pH 7.4, with a value of -11 mV compared to -2 mV. This increase in electrostatic charge is desirable for achieving hemocompatibility, as evidenced by a range of blood compatibility assessments, including hemolysis, blood clotting, platelet adhesion, platelet activation, and coagulation assays (prothrombin time (PT) and activated partial thrombin time (aPTT)). The 1 wt % CNT composite exhibited hemolysis ranging from 2 to 7%, indicating its hemocompatibility. In the blood clot investigation, the absorbance values for 1-2 wt % CNT samples were 0.927 ± 0.038 and 1.184 ± 0.128, respectively, indicating their nonthrombogenicity. Additionally, the percentage of platelet adhered on the 1 wt % CNT sample (∼5.67%) showed a ∼2.5-fold decrement compared to the clinically used negative control, polypropylene (∼13.73%). The PT and aPTT experiments showed no difference in the coagulation time for CNT samples even at higher concentrations, unlike HAC2 (80 mg). In conclusion, the 1 wt % CNT sample was nontoxic to human blood, making it more hemocompatible, nonhemolytic, and nonthrombogenic than other samples. This reliable study reduces the need for additional in vitro and in vivo studies before clinical trials, saving time and cost.

Efficacy of Transarterial Chemoembolization Combined With Camrelizumab in the Treatment of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Hepatocellular carcinoma (HCC) is the most common primary cancer of liver tissue and is often caused by chronic liver diseases. The Barcelona Clinic Liver Cancer (BCLC) staging system is commonly used to determine the stage and prognosis of HCC. Transarterial chemoembolization (TACE) is the recommended first-line therapy for intermediate-stage HCC (patients who have asymptomatic, multi-nodular hepatocellular carcinoma). Over the past 10 years, the combination of TACE with immune checkpoint inhibitors, such as Camrelizumab, has shown promising results in treating HCC. We conducted a systematic review and meta-analysis following PRISMA guidelines. A comprehensive search of PubMed, MEDLINE, Elsevier, Scopus, ATC abstracts, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases was performed to identify relevant studies on the effectiveness of TACE combined with Camrelizumab in the treatment of HCC. Study selection, data extraction, and quality assurance were conducted by independent investigators. From 1023 identified citations, six studies were included in the final analysis. The combined results of these studies showed a complete response rate of 7.35%, a partial response rate of 37.10%, stable disease in 28.76% of patients, an objective response rate of 46.13%, a disease control rate of 77.19%, and progression-free survival of 6.2 months. The combination of TACE and Camrelizumab appears to be a safe and effective treatment option for patients with advanced, recurrent, and unresectable HCC. However, the included studies had limitations such as retrospective design and small sample sizes. Further research is needed to validate and expand on these findings.

Matching-adjusted indirect comparison of PFS and OS comparing ribociclib plus letrozole versus palbociclib plus letrozole as first-line treatment of HR+/HER2- advanced breast cancer.

Background: Current standard-of-care first-line treatment of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) is cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + endocrine therapy. In the MONALEESA-2 trial, first-line ribociclib + letrozole demonstrated statistically significant overall survival (OS) benefit versus placebo + letrozole in postmenopausal patients with HR+/HER2- ABC. In the PALOMA-2 trial, first-line palbociclib + letrozole did not show OS benefit versus placebo + letrozole in a similar patient population. Understanding OS outcomes in the respective trials is critical for treatment decisions; however, there are no head-to-head clinical trial data comparing ribociclib and palbociclib. Objectives: To conduct a matching-adjusted indirect comparison (MAIC) to compare progression-free survival (PFS) and OS of first-line ribociclib + letrozole versus palbociclib + letrozole in postmenopausal patients with HR+/HER2- ABC. Design: Letrozole-anchored MAIC using individual patient data from MONALEESA-2 and published summary data from PALOMA-2. Methods: Using individual data, patients from MONALEESA-2 who matched inclusion criteria from PALOMA-2 were selected, and weighting was conducted to ensure baseline characteristics were similar to those in published aggregated data from PALOMA-2. The Bucher method was used to generate corresponding hazard ratios (HRs). Results: The final effective sample size compared n = 150 (ribociclib) and n = 112 (placebo) MONALEESA-2 patients with n = 444 (palbociclib) and n = 222 (placebo) PALOMA-2 patients. After matching and weighting, patient characteristics were well balanced. MAIC analysis showed a numerical PFS benefit [HR, 0.80; 95% confidence interval (CI), 0.58-1.11; p = 0.187] and significant OS benefit (HR, 0.68; 95% CI, 0.48-0.96; p = 0.031) with ribociclib + letrozole versus palbociclib + letrozole. Conclusion: Results of this cross-trial MAIC analysis showed a numerical PFS benefit and significantly greater OS benefit with first-line ribociclib + letrozole versus palbociclib + letrozole. These results support letrozole + ribociclib as the preferred first-line CDK4/6i for postmenopausal patients with HR+/HER2- ABC. Trial registration: NCT01958021; https://www.clinicaltrials.gov/study/NCT01958021 (MONALEESA-2) and NCT01740427; https://clinicaltrials.gov/study/NCT01740427 (PALOMA-2).

Dual-target drugs against Leishmania donovani for potential novel therapeutics.

Antioxidant defense mechanisms are important for a parasite to overcome oxidative stress and survive within host macrophage cells. Mitochondrial iron superoxide dismutase A (FeSODA) and trypanothione reductase (TR) are critical enzymes in the antioxidant defense mechanism of Leishmania donovani. FeSODA is responsible for neutralizing reactive oxygen species in mitochondria, while TR is responsible for reducing trypanothione, the molecules that help the parasite fight oxidative stress in Leishmania. In this study, we used multitarget ligands to inhibit both the FeSODA and TR enzymes. We combined structure-based drug design using virtual screening approach to find inhibitors against both the targets. The ZINC15 database of biogenic compounds was utilized to extract drugs-like molecules against leishmaniasis. The compounds were screened by standard precision (SP) and extra precision (XP) docking methods. Two compounds, ZINC000008876351 and ZINC000253403245, were selected based on molecular docking based on the binding affinity for both the targets. The screened molecules ZINC000008876351 and ZINC000253403245 showed strong hydrogen bonding with the target proteins according to the Molecular mechanics with generalised Born and surface area solvation (MM-GBSA) techniques. These two compounds were also experimentally investigated on promastigotes stage of L. donovani. Under in vitro condition, the compounds show inhibitory effects on L. donovani promastigotes with IC50 values of 24.82 ± 0.61 µM for ZINC000008876351 and 7.52 ± 0.17 µM for ZINC000253403245. Thus, the screened compounds seem to have good potential as therapeutic candidates for leishmaniasis.

Deciphering shared attributes of plant long non-coding RNAs through a comparative computational approach.

Over the past decade, long non-coding RNA (lncRNA), which lacks protein-coding potential, has emerged as an essential regulator of the genome. The present study examined 13,599 lncRNAs in Arabidopsis thaliana, 11,565 in Oryza sativa, and 32,397 in Zea mays for their characteristic features and explored the associated genomic and epigenomic features. We found lncRNAs were distributed throughout the chromosomes and the Helitron family of transposable elements (TEs) enriched, while the terminal inverted repeat depleted in lncRNA transcribing regions. Our analyses determined that lncRNA transcribing regions show rare or weak signals for most epigenetic marks except for H3K9me2 and cytosine methylation in all three plant species. LncRNAs showed preferential localization in the nucleus and cytoplasm; however, the distribution ratio in the cytoplasm and nucleus varies among the studied plant species. We identified several conserved endogenous target mimic sites in the lncRNAs among the studied plants. We found 233, 301, and 273 unique miRNAs, potentially targeting the lncRNAs of A. thaliana, O. sativa, and Z. mays, respectively. Our study has revealed that miRNAs, which interact with lncRNAs, target genes that are involved in a diverse array of biological and molecular processes. The miRNA-targeted lncRNAs displayed a strong affinity for several transcription factors, including ERF and BBR-BPC, mutually present in all three plants, advocating their conserved functions. Overall, the present study showed that plant lncRNAs exhibit conserved genomic and epigenomic characteristics and potentially govern the growth and development of plants.

Mild sleep restriction increases endothelial oxidative stress in female persons.

Sleep restriction is associated with increased cardiovascular risk, which is more pronounced in female than male persons. We reported recently first causal evidence that mild, prolonged sleep restriction mimicking "real-life" conditions impairs endothelial function, a key step in the development and progression of cardiovascular disease, in healthy female persons. However, the underlying mechanisms are unclear. In model organisms, sleep restriction increases oxidative stress and upregulates antioxidant response via induction of the antioxidant regulator nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Here, we assessed directly endothelial cell oxidative stress and antioxidant responses in healthy female persons (n = 35) after 6 weeks of mild sleep restriction (1.5 h less than habitual sleep) using randomized crossover design. Sleep restriction markedly increased endothelial oxidative stress without upregulating antioxidant response. Using RNA-seq and a predicted protein-protein interaction database, we identified reduced expression of endothelial Defective in Cullin Neddylation-1 Domain Containing 3 (DCUN1D3), a protein that licenses Nrf2 antioxidant responses, as a mediator of impaired endothelial antioxidant response in sleep restriction. Thus, sleep restriction impairs clearance of endothelial oxidative stress that over time increases cardiovascular risk.Trial Registration: NCT02835261 .

Repurposing the in-house generated Alzheimer's disease targeting molecules through computational and preliminary in-vitro studies for the management of SARS-coronavirus-2.

Covid-19 was declared a world pandemic. Recent studies demonstrated that Covid-19 impairs CNS activity by crossing the blood-brain barrier and ensuing cognitive impairment. In this study, we have utilized Covid-19 main protease (Mpro) as a biological target to repurpose our previously reported multifunctional compounds targeting Alzheimer's disease. Molecular docking, spatial orientation, molecular dynamics simulation, MM-GBSA energy calculation, and DFT studies were carried out with these molecules. Among all the compounds, F27, F44, and F56 exhibited higher binding energy (- 8.03, - 8.65, and - 8.68 kcal/mol, respectively) over the co-crystal ligand O6K (- 7.00 kcal/mol). In MD simulation, compounds F27, F44, and F56 could make a stable complex with Mpro target throughout the simulation. The compounds were synthesized following reported methods and subjected for cytotoxicity, and assessment of their capability to cross the blood-brain barrier in PAMPA assay, and antioxidant property evaluation through DPPH assay. The compounds F27, F44, and F56 exhibited cytocompatibility with the SiHA cell line and also displayed significant antioxidant properties with IC50 = 45.80 ± 0.27 µM, 44.42 ± 0.30 µM, and 42.74 ± 0.23 µM respectively. In the PAMPA assays, the permeability coefficient (Pe) value of F27, F44, and F56 lies in the acceptable range (Pe > 4). The results of the computational and preliminary in-vitro studies strongly corroborate the potential of F27, F44, and F56 as a lead for further optimization in treating the CNS complications associated with Covid-19.

Novel chemical scaffold as potential drug against Leishmania donovani: Integrated computational and experimental approaches.

In this study, we have screened a large number of Food and Drug Administration-approved compounds for novel anti-leishmanial molecules targeting the citrate synthase enzyme of the parasite. Based on their docking and molecular dynamic simulation statistics, five compounds were selected. These compounds followed Lipinski's rule of five. Additionally, in vitro, antileishmanial and cytotoxicity studies were performed. The three compounds, Abemaciclib, Bazedoxifene, and Vorapaxar, had shown effective anti-leishmanial activities with IC50 values of 0.92 ± 0.02, 0.65 ± 0.09, and 6.1 ± 0.91 against Leishmania donovani promastigote and with EC50 values of 1.52 ± 0.37, 2.11 ± 0.38, 10.4 ± 1.27 against intramacrophagic amastigote without significantly harming macrophage cells. Among them, from in silico and antileishmanial activities studies, Abemaciclib had been selected based on their less binding energy, good antileishmanial activities, and also a significant difference in their binding energy with human citrate synthase for cell death mechanistic studies using flow cytometry and a DNA fragmentation assay. The action of this compound resulted in an increased reactive oxygen species production, depolarization of mitochondrial membrane potential, DNA damage, and an increase in the sub-G1 cell population. These properties are the hallmarks of apoptosis which were further confirmed by apoptotic assay. Based on the above result, this anticancer compound Abemaciclib could be employed as a potential treatment option for leishmaniasis after further confirmation.

Periodic orbits in deterministic discrete-time evolutionary game dynamics: An information-theoretic perspective.

Even though the existence of nonconvergent evolution of the states of populations in ecological and evolutionary contexts is an undeniable fact, insightful game-theoretic interpretations of such outcomes are scarce in the literature of evolutionary game theory. As a proof-of-concept, we tap into the information-theoretic concept of relative entropy in order to construct a game-theoretic interpretation for periodic orbits in a wide class of deterministic discrete-time evolutionary game dynamics, primarily investigating the two-player two-strategy case. Effectively, we present a consistent generalization of the evolutionarily stable strategy-the cornerstone of the evolutionary game theory-and aptly term the generalized concept "information stable orbit." The information stable orbit captures the essence of the evolutionarily stable strategy in that it compares the total payoff obtained against an evolving mutant with the total payoff that the mutant gets while playing against itself. Furthermore, we discuss the connection of the information stable orbit with the dynamical stability of the corresponding periodic orbit.

Structure-based drug designing against Leishmania donovani using docking and molecular dynamics simulation studies: exploring glutathione synthetase as a drug target.

In the pursuit of developing novel anti-leishmanial agents, we conducted an extensive computational study to screen inhibitors from the FDA-approved ZINC database against Leishmania donovani glutathione synthetase. The three-dimensional structure of Leishmania donovani glutathione synthetase was constructed by homology modeling, using the crystallographic structure of Trypanosoma brucei glutathione synthetase as a template. Subsequently, molecular docking studies were carried out for a large number of compounds using AutoDock Vina. Among the screened compounds, we selected the top five with strong binding affinity to Leishmania donovani glutathione synthetase but having a very low affinity to its human homolog. Further investigations on protein-ligand complexes were done by conducting molecular dynamics (MD) simulation and MM/PBSA analysis. The results revealed that Olysio (Simeprevir) exhibited the lowest binding energy (-89.21 kcal/mol), followed by Telithromycin (-45.34 kcal/mol). These findings showed that these compounds have the potential to act as inhibitors of glutathione synthetase. Hence, our study provides valuable insights for the development of a novel therapeutic strategy against Leishmania donovani by targeting the glutathione synthetase enzyme.Communicated by Ramaswamy H. Sarma.

Proteomics profiling and in silico analysis of peptides identified during Fusarium oxysporum infection in castor (Ricinus communis).

Castor is industrially important non-edible oil seeds crop severely affected by soil borne pathogen Fusarium oxysporum f. sp. ricini which causes heavy economic losses among the castor growing states in India and worldwide. The development of Fusarium wilt resistant varieties in castor is also challenging because the genes identified for resistance are recessive in nature. Unlike transcriptomics and genomics, proteomics is always a method of choice for quick identification of novel proteins expressed during biological events. Therefore, comparative proteomic approach was employed for identification of proteins released in resistant genotype during Fusarium infection. Protein was extracted from inoculated 48-1 resistant and JI-35 susceptible genotype and subjected to 2D-gel electrophoresis coupled with RPLC-MS/MS. This analysis resulted in 18 unique peptides in resistant genotype and 8 unique peptides in susceptible genotype were identified through MASCOT search database. The real time expression study showed that 5 genes namely CCR 1, Germin like protein 5-1, RPP8, Laccase 4 and Chitinase like 6 was found highly up-regulated during Fusarium oxysporum infection. Furthermore, end point PCR analysis of c-DNA showed amplification of three genes namely Chitinase 6 like, RPP8 and ß-glucanase exclusively in resistant genotype indicating that these genes may be involved in resistance phenomenon in castor. Up-regulation of CCR-1 and Laccase 4 involved in lignin biosynthesis provides mechanical strength and may help to prevent the entry of fungal mycelia and protein Germin like 5-1 helps to neutralized ROS by SOD activity. The clear role of these genes can be further confirmed through functional genomics for castor improvement and also for development of transgenic in different crops for wilt resistance.

Stability estimation through multivariate approach among solasodine-rich lines of Solanum khasianum (C.B. Clarke): an important industrial plant.

Solanum khasianum is a medicinally important plant that is a source of steroidal alkaloids 'solasodine.' It has various industrial applications, including oral contraceptives and other pharmaceutical uses. The present study was based on 186 germplasm of S. khasianum, which were analyzed for the stability of economically important traits like solasodine content and fruit yield. The collected germplasm was planted during Kharif 2018, 2019, and 2020 in RCBD with three replications at the experimental farm of CSIR-NEIST, Jorhat, Assam, India. A multivariate approach for stability analysis was applied to identify stable germplasm of S. khasianum for economically important traits. The germplasm was analyzed for additive main effects and multiplicative interaction (AMMI), GGE biplot, multi-trait stability index, and Shukla's variance which were evaluated for three environments. The AMMI ANOVA revealed significant GE interaction for all the studied traits. The stable and high-yielding germplasm was identified from the AMMI biplot, GGE biplot, Shukla's variance value, and MTSI plot analysis. Lines no. 90, 85, 70, 107, and 62 were identified as highly stable fruit yielders while, lines no. 1, 146, and 68 were identified as stable high solasodine lines. However, considering both traits, i.e., high fruit yield and solasodine content, MTSI analysis was performed which showed that lines 1, 85, 70,155, 71, 114, 65, 86, 62, 116, 32, and 182 could be used in a breeding program. Thus, this identified germplasm can be considered for further varietal development and could be used in a breeding program. The findings of the present study would be beneficial for the S. khasianum breeding program.

Applications of extended surfaces for improvement in the performance of solar air heaters-a detailed systematic review.

The objective of this research article is to present a comprehensive review of the work carried out to improve the thermal as well exergetic performance of the conventional smooth absorber plate solar air heater (SAH) duct by the use of the various configurations and arrangements of extended surfaces (fins) for the forced convection. In the SAH duct, these extended surfaces are attached along the air-flow path on the top absorber, on the bottom plate, or on the both plate surfaces. It enhances the performance of the conventional SAH by increasing the surface area and makes flow turbulent by their presence. Several experimental, theoretical, and simulation works, which have been performed by the researchers by utilizing the extended surfaces to improve the thermal efficiency based on first law of thermodynamics, exergy, and entropy generation analysis on the basis of the second law of thermodynamics for SAH ducts, have been included in the present article. Subsequently, an effort has been made to calculate the Nusselt number and friction factor by using the correlations reported by the researchers for comparing the performance of different configurations of fin SAHs. This comprehensive review article will be useful for the investigators and researchers who are working in the area of extended surface SAHs.

Drug Encapsulated Lipid-Polymeric Nanohybrid as a Chemo-therapeutic Platform of Cancer.

The focus of this research is to design a bioengineered drug delivery vehicle that is efficient in anti-cancer drug delivery in a controlled manner. The experimental work focuses on constructing a methotrexate-loaded nano lipid polymer system (MTX-NLPHS) that can transport methotrexate (MTX) in MCF-7 cell lines in a controlled manner through endocytosis via phosphatidylcholine. In this experiment, MTX is embedded with polylactic-co-glycolic acid (PLGA) in phosphatidylcholine, which acts as a liposomal framework for regulated drug delivery. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and dynamic light scattering (DLS) were utilized to characterize the developed nanohybrid system. The particle size and encapsulation efficiency of the MTX-NLPHS were found to be 198 ± 8.44 nm and 86.48 ± 0.31 %, respectively, which is suitable for biological applications. The polydispersity index (PDI) and zeta potential of the final system were found to be 0.134 ± 0.048 and -28 ± 3.50 mV, respectively. The lower value of PDI showed the homogenous nature of the particle size, whereas higher negative zeta potential prevented the system from agglomeration. An in vitro release kinetics was conducted to see the release pattern of the system, which took 250 h for 100% drug release This kind of system may carry the drug for a long time in the circulatory system and prevent the drug discharge. Other cell culture assays such as 3-(4, 5-dimethyl thiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) and reactive oxygen species (ROS) monitoring were used to see the effect of inducers on the cellular system. MTT assay showed cell toxicity of MTX-NLPHS reduced at the lower concentration of the MTX, however, toxicity increased at the higher concentration of the MTX as compared to free MTX. ROS monitoring c revealed more scavenging of ROS using MTX-NLPHS as compared to free MTX. Confocal microscopy suggested the MTX-NLPHS induced more nuclear elongation with cell shrinkage comparatively.

Integrated computational and experimental approach for novel anti-leishmanial molecules by targeting Dephospho-coenzyme A kinase.

Coenzyme A acts as a necessary cofactor for many enzymes and is a part of many biochemical processes. One of the critical enzymes involved in Coenzyme A synthesis is Dephospho-coenzyme A-kinase (DPCK). In this study, we have used integrated computational and experimental approaches for promising inhibitors of DPCK using the natural products available in the ZINC database for anti-leishmanial drug development. The top hit compounds chosen after molecular docking were Veratramine, Azulene, Hupehenine, and Hederagenin. The free binding energy of Veratramine, Azulene, Hupehenine, and Hederagenin was estimated. Besides the favourable binding point, the ligands also showed good hydrogen bonding and other interactions with key residues of the enzyme's active site. The natural compounds were also experimentally investigated for their effect on the L. donovani promastigotes and murine macrophage (J774A.1). A good antileishmanial activity by the compounds on the promastigotes was observed as estimated by the MTT assay. The in-vitro experiments revealed that Hupehenine (IC50 = 7.34 ± 0.37 µM) and Veratramine (IC50 = 12.46 ± 2.28 µM) exhibited better inhibition than Hederagenin (IC50 = 23.36 ± 0.54 µM) and Azulene (IC50 = 24.42 ± 3.28 µM). This work has identified novel anti-leishmanial molecules possibly acting through the inhibition of DPCK.

Targeting two potential sites of SARS-CoV-2 main protease through computational drug repurposing.

Before the rise of SARS-CoV-2, emergence of different coronaviruses such as SARS-CoV and MERS-CoV has been reported that indicates possibility of the future novel pathogen from the coronavirus family at a pandemic level. In this context, explicit studies on identifying inhibitors focused on the coronavirus life cycle, are immensely important. The main protease is critical for the life cycle of coronaviruses. Majority of the work done on the inhibitor studies on the catalytically active dimeric SARS-CoV-2 main protease (Mpro), primarily focussed on the catalytic site of a single protomer, with a few targeting the dimeric site. In this study, we have exploited the FDA-approved drugs, for a computational drug repurposing study against the Mpro. A virtual screening approach was employed with docking and molecular dynamics (MD) methods. Out of 1576, FDA-approved compounds, our study suggests three compounds: netupitant, paliperidone and vilazodone as possible inhibitors with a potential to inhibit both sites (monomeric and dimeric) of the Mpro. These compounds were found to be stable during the MD simulations and their post simulation binding energies were also correlated for both the targeted sites, suggesting equal binding capacity. This unique efficiency of the reported compounds might support further experimental studies on developing inhibitors against SARS-CoV-2 main protease.Communicated by Ramaswamy H. Sarma.

Krebs cycle enzymes for targeted therapeutics and immunotherapy for anti-leishmanial drug development using: Pathways, potential targets, and future perspectives.

Leishmaniasis is a parasitic and neglected tropical disease which majorly impacts poor and developing nations. One of the significant factors that impacts the severity of the pathological condition includes the socioeconomic background of the affected region. The rise of drug-resistant Leishmania is a serious concern for the effectiveness of the present treatment. As a result, the drug options need to be relooked immediately. Leishmania employs Krebs cycle intermediates for its needs after infection for establishing various defense mechanisms to escape the host immune responses. Nevertheless, a variety of immunological reactions are also seen during infection, which clear the parasites. One of the more promising strategies in this regard would involve combining targeted therapy and immunotherapy. The targeted treatments work by obstructing vital pathways that are required for Leishmania to grow and survive. The mechanism of action of immunotherapy is the control of the host immune response, which entails the blockage of molecular pathways essential for the growth and maintenance of the parasite. The Krebs cycle intermediates have important biochemical roles. Additionally, in macrophages and dendritic cells, they play roles as signalling molecules for controlling inflammatory responses. The review brings together the available literature about the importance of Krebs cycle metabolites as potential treatment targets for leishmaniasis.

Gene Alterations Induced by Glutamine (Q) Encoding CAG Repeats Associated with Neurodegeneration.

Several studies have been reported linking the role of polyglutamine (polyQ) disease-associated proteins with altered gene regulation induced by an unstable trinucleotide (CAG) repeat. Owing to their dynamic nature of expansion, these DNA repeats form secondary structures interfering with the normal cellular mechanisms like replication and transcription and, thereby, have become the underlying cause of numerous neurodegenerative disorders involving mental retardation and/or muscular or neuronal degeneration. Despite the widespread expression of the disease-causing protein, specific subsets of neurons are susceptible to specific patterns of inheritance and clinical symptoms. Although this cell-type selectivity is still elusive and less understood, it has been found that aberrant transcriptional regulation is one of the primary causes of polyQ diseases where the functions of histone-modifying complexes are disrupted. Besides, epigenetic modifications play a critical role in the pathogenesis of these diseases. In this chapter, we will be delving into how these polyQ repeats induce the self-assembly and aggregation of altered carrier proteins based on gene alterations, causing neuronal toxicity and cellular deaths. Besides, genomic instability in CAG repeats due to altered chromatin-related enzymes will be highlighted, along with epigenetic changes present in many polyQ disorders. Understanding the underlying molecular mechanisms in the root cause of these disorders will culminate in identifying therapeutic approaches for the treatment of these neurodegenerative disorders.