Structure-based drug-development study against fibroblast growth factor receptor 2: molecular docking and Molecular dynamics simulation approaches.

Developing new therapeutic strategies to target specific molecular pathways has become a primary focus in modern drug discovery science. Fibroblast growth factor receptor 2 (FGFR2) is a critical signaling protein involved in various cellular processes and implicated in numerous diseases, including cancer. Existing FGFR2 inhibitors face limitations like drug resistance and specificity issues. In this study, we present an integrated structure-based bioinformatics analysis to explore the potential of FGFR2 inhibitors-like compounds from the PubChem database with the Tanimoto threshold of 80%. We conducted a structure-based virtual screening approach on a dataset comprising 2336 compounds sourced from the PubChem database. Primarily, the selection of promising compounds was based on several criteria, such as drug-likeness, binding affinities, docking scores, and selectivity. Further, we conducted all-atom molecular dynamics (MD) simulations for 200 ns, followed by an essential dynamics analysis. Finally, a promising FGFR2 inhibitor with PubChem CID:507883 (1-[7-(1H-benzimidazol-2-yl)-4-fluoro-1H-indol-3-yl]-2-(4-benzoylpiperazin-1-yl)ethane-1,2-dione) was screened out from the study. This compound indicates a higher potential for inhibiting FGFR2 than the control inhibitor, Zoligratinib. The identified compound, CID:507883 shows >80% structural similarity with Zoligratinib. ADMET analysis showed promising pharmacokinetic potential of the screened compound. Overall, the findings indicate that the compound CID:507883 may have promising potential to serve as a lead candidate against FGFR2 and could be further exploited in therapeutic development.

Role of socioeconomic factors and interkingdom crosstalk in the dental plaque microbiome in early childhood caries.

Early childhood caries (ECC) is influenced by microbial and host factors, including social, behavioral, and oral health. In this cross-sectional study, we analyze interkingdom dynamics in the dental plaque microbiome and its association with host variables. We use 16S rRNA and ITS1 amplicon sequencing on samples collected from preschool children and analyze questionnaire data to examine the social determinants of oral health. The results indicate a significant enrichment of Streptococcus mutans and Candida dubliniensis in ECC samples, in contrast to Neisseria oralis in caries-free children. Our interkingdom correlation analysis reveals that Candida dubliniensis is strongly correlated with both Neisseria bacilliformis and Prevotella veroralis in ECC. Additionally, ECC shows significant associations with host variables, including oral health status, age, place of residence, and mode of childbirth. This study provides empirical evidence associating the oral microbiome with socioeconomic and behavioral factors in relation to ECC, offering insights for developing targeted prevention strategies.

Adenylyl Cyclase Isoform 6 in the Pulmonary Artery Is Inhibited by Hypoxia via Cysteine Nitrosylation.

Persistent pulmonary hypertension of the newborn (PPHN) is a hypoxic disorder of pulmonary vascular relaxation, mediated in part by adenylyl cyclase (AC). Neonatal pulmonary arteries (PA) express mainly AC6 isoform, followed by AC3, 7 and 9. AC6 expression is upregulated in hypoxia. We reported AC enzyme inhibition due to S-nitrosylation in PPHN PA, and in PA myocytes exposed to hypoxia. We hypothesize that hypoxia promotes cysteine thiol nitrosylation of AC6, impairing cAMP production. HEK293T cells stably expressing AC isoforms (AC3, 5, 6, 7, 9), or cysteine-to-alanine mutants AC6_C1004A, AC6_C1145A or AC6_C447A were cultured in normoxia (21% O2) or hypoxia (10% O2) for 72 hours, or challenged with nitroso donor S-nitrosocysteine (CysNO). AC activity was determined by real-time live-cell cAMP measurement (cADDis assay) or terbium-norfloxacin AC catalytic assay, with or without challenge by allosteric agonist forskolin; protein S-nitrosylation detected by biotin switch method and quantified by affinity precipitation. Only AC6 catalytic activity is inhibited in hypoxia or by S-nitrosylating agent, in presence or absence of forskolin; impaired cAMP production in hypoxia correlates with increased cysteine nitrosylation of AC6. Selective AC6 inhibition in pulmonary artery myocytes extinguishes AC sensitivity to inhibition by hypoxia. Alanine substitution of C1004, but not of other cysteines, decreases S-nitrosylation of AC6. AC activity is diminished in AC6_C1004A compared to AC6 wild type. Substitution of C1004 also extinguishes the inhibition of AC6 by hypoxia. We conclude AC6 is uniquely S-nitrosylated in hypoxia, inhibiting its activity and cAMP generation. We speculate that S-nitrosylation at C1004 may inhibit AC6 interaction with Gαs, playing a role in PPHN pathophysiology.

A cross-cohort analysis of dental plaque microbiome in early childhood caries.

Early childhood caries (ECC) is a multifactorial disease with a microbiome playing a significant role in caries progression. Understanding changes at the microbiome level in ECC is required to develop diagnostic and preventive strategies. In our study, we combined data from small independent cohorts to compare microbiome composition using a unified pipeline and applied a batch correction to avoid the pitfalls of batch effects. Our meta-analysis identified common biomarker species between different studies. We identified the best machine learning method for the classification of ECC versus caries-free samples and compared the performance of this method using a leave-one-dataset-out approach. Our random forest model was found to be generalizable when used in combination with other studies. While our results highlight the potential microbial species involved in ECC and disease classification, we also mentioned the limitations that can serve as a guide for future researchers to design and use appropriate tools for such analyses.

Assessing forest fire dynamics and risk zones in Central Indian forests: a comparative study of the Khandwa and North Betul forest divisions of Madhya Pradesh.

Forest fires pose significant environmental and socioeconomic threats, particularly in regions such as Central India, where forest ecosystems are vital for biodiversity and local livelihoods. Understanding forest fire dynamics and identifying fire risk zones are crucial for effective mitigation. The current study explores the spatiotemporal dynamics of forest fires in the Khandwa and North Betul forest divisions in the Central Indian region over 22 years using Mann-Kendall and Sen's slope tests on MODIS (Moderate Resolution Imaging Spectroradiometer) fire point data. We found a nonsignificant increase in forest fires in both divisions. Khandwa showed a nonsignificant slope rise of more than three events per year, while North Betul revealed an increase of around one event per year. The lack of statistical significance suggests that upward trends of forest fire events may result from random fluctuations rather than consistent patterns. Spatial autocorrelation analysis revealed significant clustering of fire incidents in both regions. Khandwa confirmed moderate clustering (Moran's I = 0.043), whereas North Betul showed robust clustering (Moran's I = 0.096). Kernel density estimation further identified high-risk clusters in both divisions, necessitating zonal-wise targeted fire management strategies. Fire risk zonation was developed using the analytic hierarchy process (AHP), combining 10 environmental and socioeconomic factors. The AHP model, validated using MODIS fire data, showed reliable accuracy. The results revealed many of both divisions in the high- to very high-risk categories. Approximately, 45% of the area of the Khandwa and nearly 50% of the area of North Betul fall under high to very high fire risk zones. Khandwa's high-risk areas mainly lie in the northern and southeastern parts, while North Betul lies in the northwestern and north-eastern regions. The identified fire-prone areas indicate the pressing need for local or region-specific fire prevention and mitigation strategies. Thus, the findings of this study provide valuable insights into forest fire risk management and contribute to more focused research and methodological developments.

Integrative network pharmacology, molecular docking, and dynamic simulation analysis of a polyherbal formulation for potential therapeutic impact on prostate cancer.

Background: Prostate cancer (PCa) remains a significant health concern globally, prompting a continual search for novel therapeutic strategies. In this study, we employed a comprehensive approach combining network pharmacology, molecular docking and dynamic simulation to explore the potential impact of a polyherbal formulation on PCa. Methods: Utilizing comprehensive network pharmacology approaches, we elucidated the complex interactions between the bioactive compounds within the polyherbal formulation and key targets associated with PCa progression, highlighting their multitarget mechanisms through integrated protein‒protein interaction and KEGG pathway analyses. Molecular docking simulation studies were performed to predict the binding affinities and modes of interaction between the identified bioactive compounds and their respective protein targets. Results: Complex connections comprising 486 nodes and 845 edges were found by the compound-target network analysis. Significant interactions were observed, and the average node degree was 4.23. KEGG research revealed that PCa and the PI3K-Akt signalling pathway are implicated in modulating prostate cancer. The Quercetin docking investigations revealed that the binding energies for AR and PIK3R1 were -9 and -9.5 kcal/mol, respectively. Based on the results of the MD simulations, it appears that tiny molecules and proteins have formed stable complexes with low fluctuations. Conclusion: In conclusion, this comprehensive method emphasises the value of network pharmacology in conjunction with molecular docking and dynamic simulation in revealing the anti-PCa therapeutic potential of polyherbal formulations, opening up new possibilities for the creation of efficient anti-cancer medicines.

HIF1 activation safeguards cortical bone formation against impaired oxidative phosphorylation.

Energy metabolism, through pathways such as oxidative phosphorylation (OxPhos) and glycolysis, plays a pivotal role in cellular differentiation and function. Our study investigates the impact of OxPhos disruption in cortical bone development by deleting Mitochondrial Transcription Factor A (TFAM). TFAM controls OxPhos by regulating the transcription of mitochondrial genes. The cortical bone, constituting the long bones' rigid shell, is sheathed by the periosteum, a connective tissue layer populated with skeletal progenitors that spawn osteoblasts, the bone-forming cells. TFAM-deficient mice presented with thinner cortical bone, spontaneous midshaft fractures, and compromised periosteal cell bioenergetics, characterized by reduced ATP levels. Additionally, they exhibited an enlarged periosteal progenitor cell pool with impaired osteoblast differentiation. Increasing Hypoxia-Inducible Factor 1a (HIF1) activity within periosteal cells significantly mitigated the detrimental effects induced by TFAM deletion. HIF1 is known to promote glycolysis in all cell types. Our findings underscore the indispensability of OxPhos for the proper accrual of cortical bone mass and indicate a compensatory mechanism between OxPhos and glycolysis in periosteal cells. The study opens new avenues for understanding the relationship between energy metabolism and skeletal health and suggests that modulating bioenergetic pathways may provide a therapeutic avenue for conditions characterized by bone fragility.

A Systematic Review of the Impact of Benzimidazole-based Anthelmintics on Lung Cancer in Animal Models.

BACKGROUND: Emerging studies have reported the potential anticancer activity of FDA-approved benzimidazole-based anthelmintics against lung cancer. Therefore, the current systematic review aimed to explore the anticancer activity of benzimidazole-based anthelmintics in lung cancer animal models. METHOD: The databases including Pubmed, ScienceDirect, and Google Scholar were searched till April 2024 for the animal studies evaluating the anticancer activity of benzimidazole-based anthelmintics against lung cancer. The relevant data was extracted in the prepared format in Microsoft Excel. Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias (RoB) was used to assess the quality of included studies. The protocol for this study has been registered in PROSPERO (Registration number: CRD42022352141). RESULTS: Initially, we obtained 4150 articles, and finally eight articles were included in the current study. The information in the included studies was a bit diversified including different benzimidazole-based anthelmintics, dosage, route of administration, and duration of experiments. However, all studies reported that exposure to benzimidazole-based anthelmintics decreased tumor size and tumor volume in animal models of lung cancer. CONCLUSION: In conclusion, benzimidazole-based anthelmintics have the potential to treat lung cancer. However, more controlled and thorough preclinical studies are required to evaluate its efficacy, safety, and mechanism of anticancer activities.

Paediatric idiopathic intracranial hypertension: Epidemiology, clinical features and treatment outcomes in a tertiary care centre in Western Australia.

AIM: This retrospective study aims to analyse the epidemiology, clinical and neuroimaging features, treatment modalities, and outcomes of paediatric idiopathic intracranial hypertension (IIH) in a tertiary care centre in Australia. METHODS: Using the International Classification of Diseases Diagnostic Criteria for IIH, we identified and analysed a cohort of children diagnosed with IIH over a 5-year period (2017-2022). Data on patient demographics, symptomatology, examination findings, investigative results, treatments and outcomes were collected from medical records and electronic health records. RESULTS: A total of 45 cases were analysed. The pre-pubertal group saw a male predominance and the post-pubertal a female one. Increased body mass index was an associated comorbidity in majority of patients. Headaches (89%) and visual symptoms (56%) were the most common symptoms, with tinnitus also seen in 20% of patients. Papilledema was detected in 91% of the cases examined. The commonest neuroimaging features were optic nerve sheath distention (78%) and empty sella (49%). Acetazolamide was the primary treatment, with most patients responding well. Only a minority required surgical intervention. Long-term resolution of headaches was achieved in 89% of patients. CONCLUSIONS: The incidence of paediatric IIH in the West Australian population appears relatively high. It presents with subtle symptoms, emphasising the need for increased awareness among health-care providers. Younger children may represent a distinct subgroup with unique clinical features. Timely diagnosis and aggressive medical management lead to favourable outcomes. However, weight loss interventions showed limited effectiveness. This study underscores the importance of early recognition and management of paediatric IIH to optimise patient outcomes.

Assessing risk for severe domestic violence and related homicides perpetrated by partners and in-laws: adapted danger assessments for women in abusive relationships in India.

Despite domestic violence and related homicides perpetrated by partners and/or in-laws being a significant public health problem in India, there are no reliable and valid instruments to identify and intervene with women in domestic violence relationships. Continued domestic violence can escalate to severe, near-lethal, or lethal violence or homicide. The Danger Assessment (DA) is a risk assessment instrument designed to assess the likelihood of severe, near-lethal, or lethal violence in abusive relationships. However, the DA is not designed to determine the risk of future severe, near-lethal, or lethal violence by in-laws. In-law abuse plays a significant role in domestic violence-related homicides in India and other countries with similar cultural norms. This study addressed this gap by developing the Danger Assessment for in-laws (DA-L) to assess risk from in-laws, alongside the Danger Assessment for Women in India (DA-WI) to assess risk from partners. The study also examined the psychometric properties of the DA-L and DA-WI. Longitudinal data from 150 women in India were used to measure the reliability and validity of the two versions of the DA. The original DA items and additional risk items were examined using relative risk ratios for their relationship with severe violence at three-month follow-ups. Predictive validity was tested with the receiver operating characteristic curve. The study resulted in reliable and valid measures (11 items DA-L and 26-items DA-WI) of risk. The versions of the DA can be useful for practitioners in India and those working with Indian women in the US and other countries. The DAs can be used for identifying women in domestic violence relationships who are at risk for future severe domestic violence and guide the provision of tailored safety plans.

Structure-based screening of FDA-approved drugs identifies potential histone deacetylase 3 repurposed inhibitor: molecular docking and molecular dynamic simulation approaches.

Histone deacetylase 3 (HDAC3) is a member of the histone deacetylase family that has emerged as a crucial target in the quest for novel therapeutic interventions against various complex diseases, including cancer. The repositioning of FDA-approved drugs presents a promising avenue for the rapid discovery of potential HDAC3 inhibitors. In this study, we performed a structure-based virtual screening of FDA-approved drugs obtained from DrugBank. Candidate hits were selected based on their binding affinities and interactions with HDAC3. These promising hits were then subjected to a comprehensive assessment of their biological properties and drug profiles. Our investigation identified two FDA-approved drugs, Imatinib and Carpipramine, characterized by their exceptional affinity and specificity for the binding pocket of HDAC3. These molecules demonstrated a strong preference for HDAC3 binding site and formed interactions with functionally significant residues within the active site pocket. To gain deeper insights into the binding dynamics, structural stability, and interaction mechanisms, we performed molecular dynamics (MD) simulations spanning 300 nanoseconds (ns). The results of MD simulations indicated that Imatinib and Carpipramine stabilized the structure of HDAC3 and induced fewer conformational changes. Taken together, the findings from this study suggest that Imatinib and Carpipramine may offer significant therapeutic potential for treating complex diseases, especially cancer.

Synthesis and Neurobehavioral Evaluation of a Potent Multitargeted Inhibitor for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) poses a significant health challenge worldwide, affecting millions of individuals, and projected to increase further as the global population ages. Current pharmacological interventions primarily target acetylcholine deficiency and amyloid plaque formation, but offer limited efficacy and are often associated with adverse effects. Given the multifactorial nature of AD, there is a critical need for novel therapeutic approaches that simultaneously target multiple pathological pathways. Targeting key enzymes involved in AD pathophysiology, such as acetylcholinesterase, butyrylcholinesterase, beta-site APP cleaving enzyme 1 (BACE1), and gamma-secretase, is a potential strategy to mitigate disease progression. To this end, our research group has conducted comprehensive in silico screening to identify some lead compounds, including IQ6 (SSZ), capable of simultaneously inhibiting the enzymes mentioned above. Building upon this foundation, we synthesized SSZ, a novel multitargeted ligand/inhibitor to address various pathological mechanisms underlying AD. Chemically, SSZ exhibits pharmacological properties conducive to AD treatment, featuring pyrrolopyridine and N-cyclohexyl groups. Preclinical experimental evaluation of SSZ in AD rat model showed promising results, with notable improvements in behavioral and cognitive parameters. Specifically, SSZ treatment enhanced locomotor activity, ameliorated gait abnormalities, and improved cognitive function compared to untreated AD rats. Furthermore, brain morphological analysis demonstrated the neuroprotective effects of SSZ, attenuating Aß-induced neuronal damage and preserving brain morphology. Combined treatment of SSZ and conventional drugs (DON and MEM) showed synergistic effects, suggesting a potential therapeutic strategy for AD management. Overall, our study highlights the efficacy of multitargeted ligands like SSZ in combating AD by addressing the complex etiology of the disease. Further research is needed to elucidate the full therapeutic potential of SSZ and the exploration of similar compounds in clinical settings, offering hope for an effective AD treatment in the future.

SARS-CoV-2 inhibitory potential of fish oil-derived 2-pyrone compounds by acquiring linoleic acid binding site on the spike protein.

Traditional medicines have reportedly treated SARS-CoV-2 infection. Substantial evidence shows that fish oil supplements promote human immune function, suggesting they may lessen susceptibility to SARS-CoV-2 infection and suppress viral replication by inducing interferon. Fish oil was subjected to partition chromatography and separated into two compounds (EP01 and DH01). Isolated compounds were purified and characterized using UV, FTIR, NMR, and mass spectrometry to confirm their identity. Molecular docking was studied on the SARS CoV-2 variants of concern; SARS CoV-2 WT (PDB: 6VXX), SARS CoV-2 Alpha variant (PDB: 7LWS), SARS CoV-2 Delta variant (PDB: 7TOU), SARS CoV-2 Gamma variant (PDB: 7V78), SARS CoV-2 Kappa variant (PDB: 7VX9), and SARS CoV-2 Omicron variant (PDB: 7QO7) and TMPRSS2 (PDB: 7Y0E). Further selected protein-ligand complexes were subjected to 100 ns MD simulations to predict their biological potential in the SARS-CoV-2 treatment. In-vitro biological studies were carried out to support in-silico findings. Isolated compounds EP01 and DH01 were identified as 5-Tridecyltetrahydro-2H-pyran-2-one and 5-Heptadecyltetrahydro-2H-pyran-2-one, respectively. The compound EP01 significantly reduced (93.24 %) the viral RNA copy number with an IC50 of ~8.661 µM. EP01 proved to be a potent antiviral by in-vitro method against the SARS-CoV-2 clinical isolate, making it a promising antiviral candidate, with a single dose capable of preventing viral replication.

The anxiolytic effects of cannabinoids: A comprehensive review.

Cannabinoids, notably cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), have emerged as promising candidates for anxiety disorder treatment, supported by both preclinical and clinical evidence. CBD exhibits notable anxiolytic effects with a favourable safety profile, though concerns regarding mild side effects and drug interactions remain. Conversely, THC, the primary psychoactive compound, presents a range of side effects, underscoring the importance of careful dosage management and individualized treatment strategies. So far there are no FDA approved cannabinoid medications for anxiety. The review highlights challenges in cannabinoid research, including dosage variability, variable preclinical data, and limited long-term data. Despite these limitations, cannabinoids represent a promising avenue for anxiety management, with the potential for further optimization in formulation, dosing protocols, and consideration of interactions with conventional therapies. Addressing these challenges could pave the way for novel and personalized approaches to treating anxiety disorders using cannabinoid-based therapies.

Synergistic Interaction of Certain Essential Oils and Their Active Compounds with Fluconazole against Azole-resistant Strains of Cryptococcus neoformans.

OBJECTIVES: This study investigated the anti-cryptococcal potential of certain essential oils (EOs)/compounds alone and in combination with fluconazole. MATERIALS AND METHODS: We investigated the antifungal activity of oils of Cinnamomum verum, Cymbopogon citratus, Cymbopogon martini, and Syzygium aromaticum, and their major active ingredients cinnamaldehyde, citral, eugenol, and geraniol against clinical and standard strains of Cryptococcus neoformans (CN). Disc diffusion, broth microdilution, checkerboard methods, and transmission electron microscopy were employed to determine growth inhibition, synergistic interaction, and mechanism of action of test compounds. RESULTS: EOs/compounds showed pronounced antifungal efficacy against azole-resistant CN in the order of cinnamaldehyde > eugenol > S. aromaticum > C. verum > citral > C. citratus > geraniol ≥ C. martini, each exhibiting zone of inhibition >15 mm. These oils/compounds were highly cidal compared to fluconazole. Eugenol and cinnamaldehyde showed the strongest synergy with fluconazole against CN by lowering their MICs up to 32-fold. Transmission electron microscopy indicated damage of the fungal cell wall, cell membrane, and other endomembranous organelles. CONCLUSION: Test oils and their active compounds exhibited potential anti-cryptococcus activity against the azole-resistant strains of CN. Moreover, eugenol and cinnamaldehyde significantly potentiated the anti-cryptococcal activity of fluconazole. It is suggested that multiple sites of action from oils/compounds could turn static fluconazole into a cidal drug combination in combating cryptococcosis.

RésuméObjectifs: Cette étude a étudié le potentiel anti-cryptocoque de certaines huiles essentielles (HE)/composés seuls et en combinaison avec fluconazole. Matériels et méthodes: Nous avons étudié l'activité antifongique des huiles de Cinnamomum verum, Cymbopogon citratus, Cymbopogon martini et Syzygium spiceum , et leurs principaux ingrédients actifs, le cinnamaldéhyde, le citral, l'eugénol et le géraniol, contre les normes cliniques et standards. souches de Cryptococcus neoformans (CN). Diffusion sur disque, microdilution en bouillon, méthodes en damier et microscopie électronique à transmission ont été utilisés pour déterminer l'inhibition de la croissance, l'interaction synergique et le mécanisme d'action des composés testés. Résultats: HE/composés a montré une efficacité antifongique prononcée contre les CN résistantes aux azoles dans l'ordre suivant: cinnamaldéhyde > eugénol > S. spiceum > C. verum > citral > C. citratus > géraniol ≥ C. martini , chacun présentant une zone d'inhibition > 15 mm. Ces huiles/composés étaient hautement cides par rapport au fluconazole. L'eugénol et le cinnamaldéhyde ont montré la synergie la plus forte avec le fluconazole contre le CN en abaissant leurs CMI jusqu'à 32 fois. La microscopie électronique à transmission a indiqué des dommages à la paroi cellulaire fongique, à la membrane cellulaire et à d'autres organites endomembranaires. Conclusion: Les huiles testées et leurs composés actifs ont montré une activité anti-cryptocoque potentielle contre les souches de CN résistantes aux azoles. De plus, l'eugénol et le cinnamaldéhyde ont significativement potentialisé l'activité anticryptococcique du fluconazole. Il est suggéré que plusieurs Les sites d'action des huiles/composés pourraient transformer le fluconazole statique en une combinaison médicamenteuse cide pour lutter contre la cryptococcose.

Carbon Dots in Photodynamic Therapy: The Role of Dopant and Solvent on Optical and Photo-Responsive Properties.

Carbon dots (CDs) are novel carbon-based luminescent materials with wide-ranging applications in biosensing, bioimaging, drug transportation, optical devices, and beyond. Their advantageous attributes, including biocompatibility, biodegradability, antioxidant activity, photostability, small particle size (< 10 nm), and strong light absorption and excitation across a broad range of wavelengths, making them promising candidates in the field of photodynamic therapy (PDT) as photosensitizers (PSs). Further enhancements in functionality are imperative to enhance the effectiveness of CDs in PDT applications, notwithstanding their inherent benefits. Recently, doping agents and solvents have been demonstrated to improve CDs' optical properties, solubility, cytotoxicity, and organelle targeting efficiency. These improvements result from modifications to the CDs' carbon skeleton matrices, functional groups on the surface state, and chemical structures. This review discusses the modification of CDs with heteroatom dopants, dye dopants, and solvents to improve their physicochemical and optical properties for PDT applications. The correlations between the surface chemistry, functional groups, structure of the CDs and their optical characteristics toward quantum yield, redshift feature and reactive oxygen species generation, have also been discussed. Finally, the progressive trends for the use of CDs in PDT applications are also addressed in this review.

Digit-Serial DA-Based Fixed-Point RNNs: A Unified Approach for Enhancing Architectural Efficiency.

The next crucial step in artificial intelligence involves integrating neural network models into embedded and mobile systems. This requires designing compact and energy-efficient neural network models in silicon for optimized performance. This article introduces a unified approach for enhancing the architectural efficiency of long short-term memory (LSTM) recurrent neural networks (RNNs). Precisely, two new structures (I and II) based on the two's complement (TC) digit-serial distributed arithmetic (DSDA) technique are presented. The block-circulant matrix-vector multiplications (MVMs) and element-wise multiplications (EWMs) are formulated using TC DSDA. In addition, a fixed-point (FxP) training procedure for quantized LSTM RNNs is considered and validated for speech recognition tasks. Both structures leverage the circular rotation of weights and generate partial products with input digit slices. A new partial-product generator (PPG) and partial-product selector (PPS) designed to work with both unsigned and signed digits is introduced. In Structure I, a nonpipelined MVM is realized with a few PPGs and PPSs, followed by a shift-accumulate unit (SAU). Conversely, in Structure II, a suitably chosen depth-pipelined MVM is achieved with multiple PPGs and PPSs, followed by a shift-to-add tree (SAT). A critical path delay (CPD) analysis for both the proposed structures is also presented. Compared with previous works, post-synthesis results on 28 -nm fully depleted silicon-on-insulator (FDSOI) technology reveal that for a model size of 128 × 128 , Structures I and II provide 39.87% , 95.63% , and 30.95% , 91.18% more area and energy efficiencies, respectively.

Hydrolysable tannin improves growth performance and liver health of largemouth bass (Micropterus salmoides) fed high soybean meal diets.

This study provided evidence that the inclusion of hydrolysable tannin (HT) in high soybean meal (SBM) diets improved growth performance and glycolipid metabolism of largemouth bass (Micropterus salmoides). In vivo, various levels of HT were added to high SBM diets and fed to largemouth bass (initial weight: 6.00 ± 0.03 g) for 56 days. Results showed that a high level of SBM led to the reduction in growth performance, as evidenced by decreased weight gain rate and impaired hepatic function. Dietary supplementation with HT (1.0 g/kg) improved growth performance of largemouth bass, accompanied by the enhancements in hepatic antioxidant capacity and glycolipid metabolism. In vitro, HT facilitated glucose utilization in hepatocytes and positively influenced the modulation of crucial genes within the PI3K/Akt signaling pathway. Conversely, administration of LY294002 (a PI3K inhibitor) reversed the detrimental effects observed in hepatocytes exposed to high glucose levels. Overall, incorporating HT (1.0 g/kg) into the diet enhanced liver health and improved the absorption and utilization of SBM in largemouth bass, potentially achieved through modulation of the PI3K/Akt signaling pathway.

Artificial intelligence derived categorizations significantly improve HOMA IR/ß indicators: Combating diabetes through cross-interacting drugs.

Improvements in the homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of beta-cell function (HOMA-ß) significantly reduce the risk of disabling diabetic pathies. Nanoparticle (AuNP-AgNP)-metformin are concentration dependent cross-interacting drugs as they may have a synergistic as well as antagonistic effect(s) on HOMA indicators when administered concurrently. We have employed a blend of machine learning: Artificial Neural Network (ANN), and evolutionary optimization: multiobjective Genetic Algorithms (GA) to discover the optimum regime of the nanoparticle-metformin combination. We demonstrated how to successfully employ a tested and validated ANN to classify the exposed drug regimen into categories of interest based on gradient information. This study also prescribed standard categories of interest for the exposure of multiple diabetic drug regimen. The application of categorization greatly reduces the time and effort involved in reaching the optimum combination of multiple drug regimen based on the category of interest. Exposure of optimum AuNP, AgNP and Metformin to Diabetic rats significantly improved HOMA ß functionality (∼63 %), Insulin resistance (HOMA IR) of Diabetic animals was also reduced significantly (∼54 %). The methods explained in the study are versatile and are not limited to only diabetic drugs.

Fixed dose combination of aspirin and pantoprazole: Results of a multicenter, comparative, randomized, double-blind, double dummy, phase III study in Indian patients.

OBJECTIVE: To compare the efficacy and safety of a fixed-dose combination of aspirin and pantoprazole with that of aspirin alone for the prevention of gastro duodenal mucosal damage in patients taking aspirin for secondary prevention of cardiovascular disease or cerebrovascular disease. METHODS: This was a comparative, double-blind, double-dummy, randomized, multicenter, phase III study conducted in patients taking aspirin ≤150 mg daily for ≥3 to ≤6 months and expected to require daily aspirin therapy for at least 6 months for the secondary prevention of cardiovascular disease or cerebrovascular disease. RESULTS: A total of 240 patients were randomized to receive either a fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg or aspirin 150 mg alone in a 2:1 ratio. The proportion of non-responders (patients experiencing gastroduodenal events) was 9.7 % in the test group (fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg) compared to 19.7 % in the comparator group (aspirin 150 mg) at week 12, while the proportions were 11.0 % in the test group and 22.4 % in the comparator group at the end of 24 weeks of treatment (p-value was <0.05 at week 12 and 24). GI injuries were significantly less in test group as compared to comparator group. Both drugs were well tolerated by all patients. CONCLUSION: The fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg was found to be more efficacious and safer compared to aspirin 150 mg alone for the prevention of gastroduodenal mucosal damage in patients receiving aspirin.