Bioinspired Diiron Complex with Proton Shuttling and Redox-Active Ligand for Electrocatalytic Hydrogen Evolution.

A µ-oxo diiron complex, featuring the pyridine-2,6-dicarboxamide-based thiazoline-derived redox-active ligand, H2L (H2L = N2,N6-bis(4,5-dihydrothiazol-2-yl)pyridine-2,6-dicarboxamide), was synthesized and thoroughly characterized. [FeIII-(µ-O)-FeIII] showed electrocatalytic hydrogen evolution reaction activity in the presence of different organic acids of varying pKa values in dimethylformamide. Through electrochemical analysis, we found that [FeIII-(µ-O)-FeIII] is a precatalyst that undergoes concerted two-electron reduction to generate an active catalyst. Fourier transform infrared spectrum of reduced species and density functional theory (DFT) investigation indicate that the active catalyst contains a bridged hydroxo unit which serves as a local proton source for the Fe(III) hydride intermediate to release H2. We propose that in this active catalyst, the thiazolinium moiety acts as a proton-transferring group. Additionally, under sufficiently strong acidic conditions, bridged oxygen gets protonated before two-electron reduction. In the presence of exogenous acids of varying strengths, it displays electro-assisted catalytic response at a distinct applied potential. Stepwise electron-transfer and protonation reactions on the metal center and the ligand were studied through DFT to understand the thermodynamically favorable pathways. An ECEC or EECC mechanism is proposed depending on the acid strength and applied potential.

Exploring the role of trifarotene against RAR-α: an investigation of expression pattern and clinicopathological significance of RAR-α in breast cancer.

Introduction: The members retinoic acid receptors (RARs) (α, ß, and γ) and retinoid X receptors (RXRs) (α, ß, and γ) belong to the retinoid receptor family. They regulate the biological action of classical retinoids through nuclear retinoid receptors, a transcription factor that is regulated by ligands. Through the binding of particular retinoic acid-responsive elements (RAREs) located in target gene promoters, RARs and members of the RXRs form heterodimers. By binding to its nuclear receptors and triggering the transcription of the target genes downstream, retinoic acid (RA) mediates the expression of certain genes. Retinoids so mainly control gene expression to carry out their biological actions. RARs are essential for many biological processes, such as development, immunity, reproduction, organogenesis, and homeostasis. Apart from their physiological functions, RARs are also linked to pathologies and tumors due to mutations, protein fusions, changes in expression levels, or abnormal post-translational changes that lead to aberrant functions and homeostasis breakdown. The oncogenic development of animal tissues or cultured cells is linked to altered expression of retinoid receptors. The RAR-α is over-expressed in several malignancies. Increased invasion and migration in several cancer forms, including HNSC carcinoma, pediatric low-grade gliomas, lung adenocarcinoma, and breast cancer, have been linked to its upregulated expression. Numerous approved therapeutic regimens targeting RAR-α have been developed, improving patient survival rates. Objective: This study's main objective was to identify novel RAR-α-targeting drugs and evaluate the expression patterns of RAR-α in breast cancer patients. Methodology: In-silico investigation using a variety of bioinformatics tools like UALCAN, TISCH, TIMER 2.0, ENRICHR, and others were employed to examine the expression of RAR-α. Further we evaluated in-silico inhibition of RAR-α with trifarotene and also tested the cytotoxicity of trifarotene in breast cancer cells. Results: Our research indicates that RAR-α is upregulated in several malignancies including Breast Cancer. It regulates granulocyte differentiation and has an association with the retinoic acid receptor signaling pathway and cellular response to estrogen stimulus. Furthermore, trifarotene was found as a potential synthetic compound that targets RAR-α through in silico and in-vitro study. Discussion: Overall, this research indicates that elevated expression of RAR-α enhances the onset of breast cancer. Using trifarotene medication to target RAR-α will significantly boost the response of breast cancer individuals to treatment and delay the development of resistance to drugs.

Efficacy of wet cupping in the pain management of cervical spondylosis - A randomized, controlled, open -label, parallel-group clinical trial.

BACKGROUND AND OBJECTIVE: Cervical spondylosis is a chronic degenerative process of the cervical spine characterized by pain in neck, degenerative changes in intervertebral disc and osteophyte formation. Cervical spondylosis is translated as Waja' ur Raqaba, a type of joint pain. The present study was aimed to evaluate the effect of wet cupping in the pain management of cervical spondylosis. METHODS: This Open, randomized, controlled, clinical study was conducted on 44 patients. Subjects in the test group (n = 22) received a series of three-staged wet cupping treatment, performed on 0, 7th and 14th day. Subjects in the control group (n = 22) received 12 sittings of Transcutaneous Electrical Nerve Stimulation (TENS): 6 sittings per week for two weeks. The objective findings of treatment were assessed with the help of VAS, Neck Disability Index (NDI) and Cervical range of motion. RESULTS: Intra group comparison in test group from baseline to 21st day were found highly significant (p < 0.001) in terms of VAS, NDI, Flexion, Extension and Left rotation score. While in Right rotation, Left rotation and Left lateral flexion score were found moderately significant (p < 0.01). Statistically significant difference was observed between two groups at 21st day in VAS scale, NDI, and Cervical range of motion score (p < 0.001). INTERPRETATION AND CONCLUSION: Hijama Bish Shart was found better in the management of pain due to cervical spondylosis than TENS. It can be concluded that Hijama Bish Shart may a better option for the pain management of cervical spondylosis. CLINICAL TRIAL REGISTRATION: The trial was registered on clinical trial registry website (www.ctri.nic.in) bearing a CTRI Number, CTRI/2020/03/024,249.

Recent advances in AIEgen-based chemosensors for small molecule detection, with a focus on ion sensing.

Since the aggregation-based emission (AIE) phenomenon emerged in 2001, numerous chemical designs have been built around the AIE concept, displaying its utility for diverse applications, including optics, electronics, energy, and biosciences. The present review critically evaluates the broad applicability of AIEgen-based chemical models towards sensing small analytes and the structural design strategies adjusting the mode of action reported since the last decade. Various AIEgen models have been discussed, providing qualitative and quantitative estimation of cationic metal ions and anionic species, as well as biomolecular, cellular, and organelle-specific probes. A systematic overview of the reported structural design and the underlying working mode will pave the way for designing and developing the next generation of AIEgens for specific applications.

ToTE: A global database on trees of the treeline ecotone.

Globally, treelines form a transition zone between tree-dominated forest downslope and treeless alpine vegetation upslope. Treelines represent the highest boundary of "tree" life form in high-elevation mountains and at high latitudes. Recently, treelines have been shifting upslope in response to climate warming, so it has become important to understand global tree diversity and treeline distributions. However, to the best of our knowledge, no global database on tree flora of treelines exists, which limits our capacity to undertake macroecological analyses. Here, for the first time, we present a global data set on the trees of the treeline ecotone, supported by an online ToTE database. We synthesized the database from 1202 studies published over the last 60 years (1962 to 2022) following the Preferred Reporting Items in Systematic Reviews and Meta-Analysis (PRISMA) protocol. We classified the tree species in the database into three categories: treeline tree (TL) species, near to treeline (NTL) tree species, and tree species with an upper montane range limit (TUMR). The ToTE Version-1 presents a total of 208 tree taxa, including 189 species, five subspecies, and 14 varieties, belonging to 54 genera and 26 families distributed across 34 mountain regions worldwide that either grow exactly at the treeline or have a range limit below the treeline. Of the total taxa, 155, 14, and 39 belong to TL, NTL, and TUMR, respectively. Genera such as Abies, Picea, Pinus, Larix, and Juniperus are more represented in the treeline tree category. On the other hand, Acer, Prunus, Populus, and Quercus have more representatives in the near to treeline category, whereas Erica, Nothofagus, and Polylepis contribute more tree species with an upper montane range limit. Furthermore, families such as Rosaceae and Pinaceae include trees that occur both at the treeline and with an upper montane range limit, whereas Sapindaceae includes trees that occur exclusively near to treeline. Our database also includes information on the global distribution patterns of treeline tree species richness across mountains and biomes. The mountains with the highest number of tree species are the Andes (39) followed by the Himalaya (37). Close to 67% of tree species show restricted distributions in different mountains, with the highest endemism in the Andes and the Himalaya. In terms of tree species distribution, Pinus sylvestris was widespread, with a distribution across nine mountain regions, followed by Picea glauca and Fagus sylvatica, both distributed across five mountain regions. In terms of species' distribution across biomes, the temperate biome harbors the highest treeline tree species richness (152 species), which may reflect the fact that the majority of studies are available from the temperate regions of the world. The remaining 56 species are distributed within five other biomes, with the least in dry tropical and subarctic (four species each). Furthermore, currently 40 treeline tree species fall under different International Union for Conservation of Nature threat categories. We anticipate that our database will help advance research on macroecological, biogeographic, evolutionary, climate-change, and conservation aspects of the treeline on a global scale. The data are released under a Creative Commons Attribution 4.0 international license. Please cite this data paper when the data are reused.

Advancements in the development of fluorescent chemosensors based on CN bond isomerization/modulation mechanistic approaches.

The CN bond isomerization/modulation as a fluorescence signalling mechanism was explored by studying the photophysical properties of conformationally restricted molecules. From the beginning, the CN bond isomerization method has attracted the attention of researchers owing to its simplicity, high selectivity, and sensitivity in fluorescence evaluation. Continuous developments in the field of sensing using CN bond-containing compounds have been achieved via the customization of the isomerization process around the CN bond in numerous ways, and the results were obtained in the form of specific discrete photophysical changes. CN isomerization causes significant fluorescence enhancement in response to detected metal cations and other reactive species (Cys, Hys, ClO-, etc.) straightforwardly and effectively. This review sheds light on the process of CN bond isomerization/modulation as a signalling mechanism depending on fluorescence changes via conformational restriction. In addition, CN bond isomerization-based fluorescent sensors have yet to be well reviewed, although several fluorescent sensors based on this signalling mechanism have been reported. Therefore, CN-based fluorescent sensors are summarized in this review.

Exploring HMMR as a therapeutic frontier in breast cancer treatment, its interaction with various cell cycle genes, and targeting its overexpression through specific inhibitors.

Among women, breast carcinoma is one of the most complex cancers, with one of the highest death rates worldwide. There have been significant improvements in treatment methods, but its early detection still remains an issue to be resolved. This study explores the multifaceted function of hyaluronan-mediated motility receptor (HMMR) in breast cancer progression. HMMR's association with key cell cycle regulators (AURKA, TPX2, and CDK1) underscores its pivotal role in cancer initiation and advancement. HMMR's involvement in microtubule assembly and cellular interactions, both extracellularly and intracellularly, provides critical insights into its contribution to cancer cell processes. Elevated HMMR expression triggered by inflammatory signals correlates with unfavorable prognosis in breast cancer and various other malignancies. Therefore, recognizing HMMR as a promising therapeutic target, the study validates the overexpression of HMMR in breast cancer and various pan cancers and its correlation with certain proteins such as AURKA, TPX2, and CDK1 through online databases. Furthermore, the pathways associated with HMMR were explored using pathway enrichment analysis, such as Gene Ontology, offering a foundation for the development of effective strategies in breast cancer treatment. The study further highlights compounds capable of inhibiting certain pathways, which, in turn, would inhibit the upregulation of HMMR in breast cancer. The results were further validated via MD simulations in addition to molecular docking to explore protein-protein/ligand interaction. Consequently, these findings imply that HMMR could play a pivotal role as a crucial oncogenic regulator, highlighting its potential as a promising target for the therapeutic intervention of breast carcinoma.

Molecular Prediction and Correlation of the Structure and Function of Universal Stress Protein A (UspA) from Salmonella Typhimurium.

Salmonella Typhimurium (ST) is a zoonotic pathogen that can cause gastroenteritis in humans when they consume contaminated food or water. When exposed to various stressors, both from living organisms (biotic) and the environment (abiotic), Salmonella Typhimurium produces Universal Stress Proteins (USPs). These proteins are gaining recognition for their crucial role in bacterial stress resistance and the ability to enter a prolonged state of growth arrest. Additionally, USPs exhibit diverse structures due to the fusion of the USP domain with different catalytic motifs, enabling them to participate in various reactions and cellular activities during stressful conditions. In this particular study, researchers cloned and analyzed the uspA gene obtained from poultry-derived strains of Salmonella Typhimurium. The gene comprises 435 base pairs, encoding a USP family protein consisting of 144 amino acids. Phylogenetic analysis demonstrated a close relationship between the uspA genes of Salmonella Typhimurium and those found in other bacterial species. We used molecular dynamics simulations and 3D structure prediction to ensure that the USPA protein was stable. Furthermore, we also carried out motif search and network analysis of protein-protein interactions. The findings from this study offer valuable insights for the development of inhibitors targeted against Salmonella Typhimurium.

Barriers to healthcare utilization among married women in Afghanistan: the role of asset ownership and women's autonomy.

Women face multiple socio-economic, cultural, contextual, and perceived barriers in health service utilization. Moreover, poor autonomy and financial constraints act as crucial factors to their healthcare accessibility. Therefore, the objective of the present study is to study the association between health care utilization barriers and women empowerment, including asset ownership among currently married women in Afghanistan. Data of 28,661 currently married women from Afghanistan demographic health survey (2015) was used to carry out this study. Barriers to access healthcare were computed based on problems related to permission, money, distance, and companionship, whereas women empowerment and asset ownership were computed as potential covariates along with other socio-economic risk factors. Bivariate and logistic analysis was carried out to study the association and odds of explanatory variables. Our results confirm the significant and strong association between the barriers to access healthcare and various explanatory variables. Women having any decision-making autonomy are less likely to face any odds [(AOR = 0.56, p < 0.001), CI: 0.51-0.61] among the currently married women than those who don't have any decision-making authority. Similarly, women who justify their beating for some specific reasons face the greater difficulty of accessing health care [(AOR = 1.76, p < 0.001), CI: 1.61-1.93]. In terms of asset ownership, women having any asset ownership (land or household) are less likely to face any barriers in health services utilization given the lower odds [(AOR = 0.91, p < 0.001), CI: 0.90-0.98]. Accessing maternal health is a crucial policy challenge in Afghanistan. A substantial proportion of women face barriers related to approval, money, distance, and companionship while accessing the health services utilization in Afghanistan. Similarly, women empowerment and asset ownership are significantly associated with health service accessibility. This paper therefore suggests for some policy interventions to strengthen the healthcare needs of women and ensure healthcare accessibility by scaling down these potential barriers like poor autonomy, asset ownership and domestic violence.

Metronomic chemotherapy and drug repurposing: A paradigm shift in oncology.

Cancer represents a significant global health and economic burden due to its high mortality rates. While effective in some instances, traditional chemotherapy often falls short of entirely eradicating various types of cancer. It can cause severe side effects due to harm to healthy cells. Two therapeutic approaches have risen to the forefront to address these limitations: metronomic chemotherapy (MCT) and drug repurposing. Metronomic chemotherapy is an innovative approach that breaks from traditional models. It involves the administration of chemotherapeutic regimens at lower doses, without long drug-free intervals that have previously been a hallmark of such treatments. This method offers a significant reduction in side effects and improved disease management. Simultaneously, drug repurposing has gained considerable attraction in cancer treatment. This approach involves utilizing existing drugs, initially developed for other therapeutic purposes, as potential cancer treatments. The application of known drugs in a new context accelerates the timeline from laboratory to patient due to pre-existing safety and dosage data. The intersection of these two strategies gives rise to a novel therapeutic approach named 'Metronomics.' This approach encapsulates the benefits of both MCT and drug repurposing, leading to reduced toxicity, potential for oral administration, improved patient quality of life, accelerated clinical implementation, and enhanced affordability. Numerous clinical studies have endorsed the efficacy of metronomic chemotherapy with tolerable side effects, underlining the potential of Metronomics in better cancer management, particularly in low- and middle-income countries. This review underscores the benefits and applications of metronomic chemotherapy and drug repurposing, specifically in the context of breast cancer, showcasing the promising results of pre-clinical and clinical studies. However, we acknowledge the necessity of additional clinical investigations to definitively establish the role of metronomic chemotherapy in conjunction with other treatments in comprehensive cancer management.

Harnessing the power of gold: advancements in anticancer gold complexes and their functionalized nanoparticles.

Cancer poses a formidable challenge, necessitating improved treatment strategies. Metal-based drugs and nanotechnology offer new hope in this battle. Versatile gold complexes and functionalized gold nanoparticles exhibit unique properties like biologically inert behaviour, outstanding light absorption, and heat-conversion abilities. These nanoparticles can be finely tuned for drug delivery, enabling precise and targeted cancer therapy. Their exceptional drug-loading capacity and low toxicity, stemming from excellent stability, biocompatibility, and customizable shapes, make them a promising option for enhancing cancer treatment outcomes and improving diagnostic imaging. Leveraging these attributes, researchers can design more effective and targeted cancer therapeutics. The potential of functionalized gold nanoparticles to advance cancer treatment and diagnostics holds a promising avenue for further exploration and development in the fight against cancer. This review article delves into the finely tuned attributes of functionalized gold nanoparticles, unveiling their potential for application in drug delivery for precise and targeted cancer therapy.

Network pharmacology and experimental validation for deciphering the action mechanism of Fritillaria cirrhosa D. Don constituents in suppressing breast carcinoma.

Fritillaria cirrhosa D. Don is a well-known medicinal plant of Kashmir Himalaya. Traditionally, it has been used to treat several diseases, including cancer. However, the molecular mechanism behind anticancer activity remains unclear. Therefore, in the present study, we have performed high performance-liquid chromatography-mass spectrometry (HR-LC/MS), network pharmacology, molecular docking and molecular dynamic (MD) simulation methods were used to explore the underlying molecular mechanism of F. cirrhosa for the treatment of breast cancer (BC). The targets of F. cirrhosa for treating BC were predicted using databases like SwissTargetPrediction, Gene Cards and OMIM. Protein-protein interaction analysis and network construction were performed using the Search Tool for the Retrieval of Interacting Genes/Proteins programme, and analysis of Gene Ontology term enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment was done using the Cytoscape programme. In addition, molecular docking was used to investigate intermolecular interactions between the compounds and the proteins using the Autodock tool. MD simulations studies were also used to explore the stability of the representative AKT1 gene peiminine and Imperialine-3-ß-glucoside. In addition, experimental treatment of F. cirrhosa was also verified. HR-LC/MS detected the presence of several secondary metabolites. Afterward, molecular docking was used to verify the effective activity of the active ingredients against the prospective targets. Additionally, Peiminine and Imperialine-3-ß-glucoside showed the highest binding energy score against AKT-1 (-12.99 kcal/mol and -12.08 kcal/mol). AKT1 with Peiminine and Imperialine-3-ß-glucoside was further explored for MD simulations. During the MD simulation study at 100 nanoseconds, a stable complex formation of AKT1 + Peiminine and Imperialine-3-ß-glucoside was observed. The binding free energy calculations using MM/GBSA showed significant binding of the ligand with protein (ΔG: -79.83 ± 3.0 kcal/mol) between AKT1 + Peiminine was observed. The principal component analysis exhibited a stable converged structure by achieving global motion. Lastly, F. cirrhosa extracts also exhibited momentous anticancer activity through in vitro studies. Therefore, present study revealed the molecular mechanism of F. cirrhosa constituents for the effective treatment of BC by deactivating various multiple gene targets, multiple pathways particularly the PI3K-Akt signaling pathway. These findings emphasized the momentous anti-BC activity of F. cirrhosa constituents.Communicated by Ramaswamy H. Sarma.

Fritillaria cirrhosa D. Don is well-known, the medicinal plant in the Kashmir Himalaya. Traditionally, it has been used to treat various diseases, including cancer.Many secondary metabolites were identified in F. cirrhosa using high performance-liquid chromatography-mass spectrometry technique, and these bioactive components and potential breast cancer (BC) therapy targets were validated using network pharmacology, molecular docking and MD simulation studies.The bioactive components such as Peimine, Imperialine 3-glucoside and other vital phytocompounds of F. cirrhosa have been demonstrated to interact with AKT1 efficiently, indicating their relevance in inhibiting AKT1 and other protein targets in BC.This study overall showed the anticancer activity of F. cirrhosa extracts by integrating network pharmacology, docking analysis and in vitro experiments.

Impacts of hydrometeorological factors on discharge simulation in the North West Himalayas: a SUFI-2 algorithm-driven investigation using the SWAT model.

The Soil and Water Assessment Tool (SWAT) is a computational hydrological model extensively utilised for developing sustainable strategies and viable approaches for prudent management of water resources. The central emphasis of this study is on the utilisation of SWAT model along with SWAT-CUP (SWAT calibration toolbox) to simulate streamflow in the upper Jhelum basin, the North West Himalayas, for a period of 20 years from 2000 to 2019. The global sensitivity analysis algorithm, Sequential Uncertainty Fitting 2 (SUFI-2) of SWAT-CUP, is used for sensitivity and uncertainty analysis. The optimised parameter set estimated by SUFI-2 constitutes 11 parameters that are found to be sensitive with soil conservation service (SCS) curve number (CN) being the most influential parameter followed by snowmelt base temperature. Autocorrelation analysis using the autocorrelation function was conducted on the temperature and precipitation time series data, followed by a pre-whitening procedure to remove any autocorrelation effects. Subsequently, the modified Mann-Kendall (MMK) test was applied to examine trends in the annual temperature and precipitation data. The results indicated statistically significant positive trends in both datasets on an annual scale. The results for the calibration period (2003-2014) for monthly simulation displayed good model performance at three gauging stations, Rambiara, Sangam and Ram Munshi Bagh with R2 values of 0.83, 0.847, 0.829, P factor values of 0.73, 0.76, 0.75 and R factor values of 0.61, 0.58, 0.63, respectively. The validation results for monthly simulation for the 2015-2019 period showed good model agreement with R2 values of 0.817, 0.853, and 0.836, P factor values of 0.76, 0.8, and 0.75 and R factor values of 0.62, 0.53, and 0.65, respectively. The study concludes that the SWAT hydrological model can perform satisfactorily in high mountainous catchments and can be employed to analyse the impact of land use-land cover changes and the effect of climate variation on streamflow dynamics.

Targeting breast cancer stem cells through retinoids: A new hope for treatment.

Breast cancer is a complex and diverse disease accounting for nearly 30% of all cancers diagnosed in females. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. With over half a million deaths annually, it is imperative to explore new therapeutic approaches to combat the disease. Within a breast tumor, a small sub-population of heterogeneous cells, with a unique ability of self-renew and differentiation and responsible for tumor formation, initiation, and recurrence are referred to as breast cancer stem cells (BCSCs). These BCSCs have been identified as one of the main contributors to chemoresistance in breast cancer, making them an attractive target for developing novel therapeutic strategies. These cells exhibit surface biomarkers such as CD44+, CD24-/LOW, ALDH, CD133, and CD49f phenotypes. Higher expression of CD44+ and ALDH activity has been associated with the formation of tumors in various cancers. Moreover, the abnormal regulation of signaling pathways, including Hedgehog, Notch, ß-catenin, JAK/STAT, and P13K/AKT/mTOR, leads to the formation of cancer stem cells, resulting in the development of tumors. The growing drug resistance in BC is a significant challenge, highlighting the need for new therapeutic strategies to combat this dreadful disease. Retinoids, a large group of synthetic derivatives of vitamin A, have been studied as chemopreventive agents in clinical trials and have been shown to regulate various crucial biological functions including vision, development, inflammation, and metabolism. On a cellular level, the retinoid activity has been well characterized and translated and is known to induce differentiation and apoptosis, which play important roles in the outcome of the transformation of tissues into malignant. Retinoids have been investigated extensively for their use in the treatment and prevention of cancer due to their high receptor-binding affinity to directly modulate gene expression programs. Therefore, in this study, we aim to summarize the current understanding of BCSCs, their biomarkers, and the associated signaling pathways. Retinoids, such as Adapalene, a third-generation retinoid, have shown promising anti-cancer potential and may serve as therapeutic agents to target BCSCs.

Effect of quercetin on steroidogenesis and folliculogenesis in ovary of mice with experimentally-induced polycystic ovarian syndrome.

Introduction: Polycystic Ovary syndrome (PCOS) affects the health of many women around theworld. Apart from fundamental metabolic problems connected to PCOS, focus of our study is on the role of quercetin on genes relevant to steroidogenesis and folliculogenesis. Methods: Eighteen mature parkes strain mice (4-5 weeks old) weighing18-21 g were randomly divided into three groups of six each as follows: Group I serves as the control and was given water and a regular chow diet ad lib for 66 days; group II was given oral gavage administration of letrozole (LETZ) (6 mg/kgbw) for 21 days to induce PCOS and was left untreated for 45 days; For three weeks, Group III received oral gavage dose of LETZ (6 mg/kg), after which it received Quercetin (QUER) (125 mg/kg bw orally daily) for 45 days. Results: In our study we observed that mice with PCOS had irregular estrous cycle with increased LH/FSH ratio, decreased estrogen level and decline in expression of Kitl, Bmp1, Cyp11a1, Cyp19a1, Ar, lhr, Fshr and Esr1 in ovary. Moreover, we observed increase in the expression of CYP17a1, as well as increase in cholesterol, triglycerides, testosterone, vascular endothelial growth factor VEGF and insulin levels. All these changes were reversed after the administration of quercetin in PCOS mice. Discussion: Quercetin treatment reversed the molecular, functional and morphological abnormalities brought on due to letrozole in pathological and physiological setting, particularly the issues of reproduction connected to PCOS. Quercetin doesn't act locally only but it acts systematically as it works on Pituitary (LH/FSH)- Ovary (gonad hormones) axis. the Side effects of Quercetin have to be targeted in future researches. Quercetin may act as a promising candidate for medical management of human PCOS.

Network pharmacology combined with molecular docking and in vitro verification reveals the therapeutic potential of Delphinium roylei munz constituents on breast carcinoma.

Delphinium roylei Munz is an indigenous medicinal plant to India where its activity against cancer has not been previously investigated, and its specific interactions of bioactive compounds with vulnerable breast cancer drug targets remain largely unknown. Therefore, in the current study, we aimed to evaluate the anti-breast cancer activity of different extracts of D. roylei against breast cancer and deciphering the molecular mechanism by Network Pharmacology combined with Molecular Docking and in vitro verification. The experimental plant was extracted with various organic solvents according to their polarity index. Phytocompounds were identified by High resolution-liquid chromatography-mass spectrometry (HR-LC/MS) technique, and SwissADME programme evaluated their physicochemical properties. Next, target(s) associated with the obtained bioactives or breast cancer-related targets were retrieved by public databases, and the Venn diagram selected the overlapping targets. The networks between overlapping targets and bioactive were visualized, constructed, and analyzed by STRING programme and Cytoscape software. Finally, we implemented a molecular docking test (MDT) using AutoDock Vina to explore key target(s) and compound(s). HR-LC/MS detected hundreds of phytocompounds, and few were accepted by Lipinski's rules after virtual screening and therefore classified as drug-like compounds (DLCs). A total of 464 potential target genes were attained for the nine quantitative phytocompounds and using Gene Cards, OMIM and DisGeNET platforms, 12063 disease targets linked to breast cancer were retrieved. With Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment, a total of 20 signalling pathways were manifested, and a hub signalling pathway (PI3K-Akt signalling pathway), a key target (Akt1), and a key compound (8-Hydroxycoumarin) were selected among the 20 signalling pathways via molecular docking studies. The molecular docking investigation revealed that among the nine phytoconstituents, 8-hydroxycoumarin showed the best binding energy (-9.2 kcal/mol) with the Akt1 breast cancer target. 8-hydroxycoumarin followed all the ADME property prediction using SwissADME, and 100 nanoseconds (ns) MD simulations of 8-hydroxycoumarin complexes with Akt1 were found to be stable. Furthermore, D. roylei extracts also showed significant antioxidant and anticancer activity through in vitro studies. Our findings indicated for the first time that D. roylei extracts could be used in the treatment of BC.

Integrons in the development of antimicrobial resistance: critical review and perspectives.

Antibiotic resistance development and pathogen cross-dissemination are both considered essential risks to human health on a worldwide scale. Antimicrobial resistance genes (AMRs) are acquired, expressed, disseminated, and traded mainly through integrons, the key players capable of transferring genes from bacterial chromosomes to plasmids and their integration by integrase to the target pathogenic host. Moreover, integrons play a central role in disseminating and assembling genes connected with antibiotic resistance in pathogenic and commensal bacterial species. They exhibit a large and concealed diversity in the natural environment, raising concerns about their potential for comprehensive application in bacterial adaptation. They should be viewed as a dangerous pool of resistance determinants from the "One Health approach." Among the three documented classes of integrons reported viz., class-1, 2, and 3, class 1 has been found frequently associated with AMRs in humans and is a critical genetic element to serve as a target for therapeutics to AMRs through gene silencing or combinatorial therapies. The direct method of screening gene cassettes linked to pathogenesis and resistance harbored by integrons is a novel way to assess human health. In the last decade, they have witnessed surveying the integron-associated gene cassettes associated with increased drug tolerance and rising pathogenicity of human pathogenic microbes. Consequently, we aimed to unravel the structure and functions of integrons and their integration mechanism by understanding horizontal gene transfer from one trophic group to another. Many updates for the gene cassettes harbored by integrons related to resistance and pathogenicity are extensively explored. Additionally, an updated account of the assessment of AMRs and prevailing antibiotic resistance by integrons in humans is grossly detailed-lastly, the estimation of AMR dissemination by employing integrons as potential biomarkers are also highlighted. The current review on integrons will pave the way to clinical understanding for devising a roadmap solution to AMR and pathogenicity. Graphical AbstractThe graphical abstract displays how integron-aided AMRs to humans: Transposons capture integron gene cassettes to yield high mobility integrons that target res sites of plasmids. These plasmids, in turn, promote the mobility of acquired integrons into diverse bacterial species. The acquisitions of resistant genes are transferred to humans through horizontal gene transfer.

Complete Second Branchial Cleft Fistulas: A Clinicosurgical Experience.

A complete second branchial fistula is very rare and has an internal opening at the tonsillar fossa and an external opening at the lower third of the sternocleidomastoid (SCM). Patients commonly present with persistent or intermittent mucoid or mucopurulent discharge from an external opening. The diagnosis is most often clinical and radiological investigations are rarely needed. Treatment of choice is complete surgical excision. The aim of this article is to aware young ENT surgeons of the various clinical and intraoperative surgical findings that can be encountered while dealing with these cases. This observational study was done for a period of 10 years. A total of 20 cases of fistula were included which intraoperatively had a complete track from tonsillar fossa to neck. Excision of the tract was carried out via combined transcervical and transoral approach under general anaesthesia using two incisions in stepladder pattern. Each patient was seen after one year of surgery to assess for any recurrence. Different findings of patients including age/sex at surgery, initial presentation, family history, laterality of the fistula tract, Intraoperative surgical findings, complications, and recurrences. were noted. Of the 20 patients, 13 (65%) were females and 7 (35%) were Females. Most common complaint was fistulous opening with intermittent discharge(15patients; 75%).Branchial cleft fistulae more commonly affected the right neck (14 patients, 78%) among unilateral cases and 2 patients (10%) had bilateral fistulae. No patient had associated congenital anomaly/syndrome, family history or and visible opening in tonsillar area. Glossopharyngeal nerve was identified in 12 cases and track was seen passing lateral to it except in one case. The internal opening of track was seen over posterior tonsillar pillar in 15 cases (75%) while in 5 patient the track was seen entering tonsillar tissue or bed. Tonsillectomy was done in 5 cases while not done in 15 cases where track was seen entering posterior pillar. All patients were seen at one year follow up. No recurrence was seen at one year of follow up. Complete second branchial cleft fistulae are rare. They are usually right sided and unilateral. The track passes between carotid bifurcation and invariably passes lateral to both glossopharyngeal and hypoglossal nerves. Track usually ends at the posterior tonsillar pillar. Tonsillectomy is not routinely indicated. Recurrences are not typically seen.

Implications of the Pore Size of Graphitic Carbon Nitride Monolayers on the Selectivity of Dual-Boron Atom Catalysts for the Reduction of N2 to Urea and Ammonia: A Computational Investigation.

The formation of urea by electrocatalytic means remains a great challenge due to the lack of a suitable catalyst that is capable of not only activating inert N2 and CO2 molecules but also circumventing the complexity associated with subsequent reaction steps leading to urea formation. Herein, by means of comprehensive density functional theory simulations, we investigate the catalytic activity of highly stable transition-metal-free dual-boron atom-doped graphitic carbon-nitride monolayers with different pore sizes toward urea production under ambient conditions. As per the results, dual boron atoms impregnated in g-C2N and g-C6N6 monolayers with large pore diameters can successfully activate the N2 molecule and lead to the spontaneous formation of the *NCO*N intermediate, which is the most crucial step for urea formation via direct coupling of N2 and CO2. Interestingly, the B2@g-C2N and B2@g-C6N6 favor urea production with low limiting potentials of -1.11 and -1.18 V compared to very high limiting potentials of -1.71 and -1.88 V, respectively, for ammonia synthesis, leading to an almost 100% Faradaic efficiency for urea formation over ammonia. The dual-boron doping in g-C3N4 with a smaller pore size depicts comparatively weaker N2 adsorption than g-C2N and g-C6N6 counterparts. Further, B2@g-C3N4 prefers ammonia formation at a very low limiting potential of -0.40 V compared to a very high limiting potential of -2.11 V for urea formation. Thus, our findings clearly highlight the critical role played by the pore size of carbon-nitride monolayers in tuning the reactivity and catalytic activity of dual-boron atom catalysts toward urea formation in a selective manner, thereby providing valuable guidance in exploring other highly efficient urea catalysts.

Optimizing the NRR activity of single and double boron atom catalysts using a suitable support: a first principles investigation.

Designing cost effective transition-metal free electrocatalysts for nitrogen fixation under ambient conditions is highly appealing from an industrial point of view. Using density functional theory calculations in combination with the computational hydrogen electrode model, we investigate the N2 activation and reduction activity of ten different model catalysts obtained by supporting single and double boron atoms on five different substrates (viz. GaN, graphene, graphyne, MoS2 and g-C3N4). Our results demonstrate that the single/double boron atom catalysts bind favourably on these substrates, leading to a considerable change in the electronic structure of these materials. The N2 binding and activation results reveal that the substrate plays an important role by promoting the charge transfer from the single/double boron atom catalysts to the antibonding orbitals of *N2 to form strong B-N bonds and subsequently activate the inert NN bond. Double boron atom catalysts supported on graphene, MoS2 and g-C3N4 reveal very high binding energies of -2.38, -2.11 and -1.71 eV respectively, whereas single boron atom catalysts supported on graphene and g-C3N4 monolayers bind N2 with very high binding energies of -1.45 and -2.38 eV, respectively. The N2 binding on these catalysts is further explained by means of orbital projected density of states plots which reflect greater overlap between the N2 and B states for the catalysts, which bind N2 strongly. The simulated reaction pathways reveal that the single and double boron atom catalysts supported on g-C3N4 exhibit excellent catalytic activity with very low limiting potentials of -0.67 and -0.36 V, respectively, while simultaneously suppressing the HER. Thus, the current work provides important insights to advance the design of transition-metal free catalysts for electrochemical nitrogen fixation from an electronic structure point of view.