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.

Computational and spectroscopic insight into the binding of citral with human transferrin: Targeting neurodegenerative diseases.

The involvement of neuroinflammation in the pathogenesis of neurodegenerative disorders (NDs) is very significant. Currently, only symptomatic treatments exist, and there are no drugs that modify the progression of Alzheimer's disease (AD) or other NDs. Consequently, there is increasing attention on addressing AD-related neuroinflammation using anti-inflammatory compounds and antioxidants. Currently, there is a growing exploration of dietary phytochemicals as potential therapeutic agents for treating inflammation. Citral, a monoterpene, is under increasing investigation due to its neuroprotective effects. The dysregulation of iron homeostasis is a crucial factor in supporting neuroinflammation, underscoring the significance of proper iron balance. Human transferrin (htf) is a major player involved in iron homeostasis. In this study, we examined binding and dynamics of htf-citral complex through diverse experimental methods. Molecular docking studies revealed that citral binds to crucial residues of htf, forming a stable complex. UV-visible spectroscopy demonstrated binding of citral with htf with good affinity, evident from binding constant of 1.48 × 105 M-1. Further, fluorescence spectroscopy entrenched a stable htf-citral complex formation; citral demonstrates an excellent binding affinity to htf with a binding constant of 106 M-1. Moreover, fluorescence binding assay at various temperatures deciphered htf-citral complex to be driven by both static and dynamic quenching. The analysis of enthalpy change (ΔH) and entropy change (ΔS) demonstrated that htf-citral complex formation was driven mainly by hydrophobic interactions.The current work gives a platform to develop innovative therapeutic strategies targeting neuroinflammation through citral, particularly iron homeostasis.

Antagonistic activity of two Bacillus strains against Fusarium oxysporum f. sp. capsici (FOC-1) causing Fusarium wilt and growth promotion activity of chili plant.

Fusarium oxysporum f. sp. capsici (Foc) poses a significant position in agriculture that has a negative impact on chili plant in terms of growth, fruit quality, and yield. Biological control is one of the promising strategies to control this pathogen in crops. Chili is considered as one of the most important crops in the Hyderabad region that is affected by Fusarium wilt disease. The pathogen was isolated from the infected samples in the region and was confirmed by morphological characteristics and PCR with a band of 488 bp. The bacterial strains were isolated from the rhizosphere soil of healthy plant and also confirmed by PCR with a band of 1,542 bp.The molecular characterization of the fungal and bacterial strain has shown 99.9% homology with the retrieved sequences of Fusarium oxysporum f. sp. capsici and Bacillus subtilis from NCBI. The 1-month-old Ghotki chili plants were inoculated with 1×105 cfu spore/ml-1 suspension and confirmed that the FOC-1 is responsible for chili Fusarium wilt disease. Subsequently, among the 33 screened Bacillus strains, only 11 showed antagonistic activity against F. oxysporum. Out of these, only two strains (AM13 and AM21) have shown maximum antagonistic activity against the pathogen by reducing the infection and promoting growth parameters of chili plants under both in vitro and greenhouse conditions. The study suggested that biological control is the most promising control strategy for the management of Fusarium wilt of chili in the field.

Screening of sugarcane germplasm against Sporisorium scitamineum and its effects on setts germination and tillering.

Sugarcane smut is the most damaging disease that is present almost across the globe, causing mild to severe yield losses depending upon the cultivar types, pathogen races and climatic conditions. Cultivation of smut-resistant cultivars is the most feasible and economical option to mitigate its damages. Previous investigations revealed that there is a scarcity of information on early detection and effective strategies to suppress etiological agents of smut disease due to the characteristics overlapping within species complexes. In this study, 104 sugarcane cultivars were screened by artificial inoculation with homogenate of all possible pathogen races of Sporisorium scitamineum during two consecutive growing seasons. The logistic smut growth pattern and the disease intrinsic rate were recorded by disease growth curve. Variable levels of disease incidence i.e., ranging from 0 to 54.10% were observed among these sugarcane cultivars. Besides, pathogen DNA in plant shoots of all the cultivars was successfully amplified by PCR method using smut-specific primers except 26 cultivars which showed an immune reaction in the field trial. Furthermore, the plant germination and tillering of susceptible sugarcane cultivars were greatly influenced by pathogen inoculation. In susceptible cultivars, S. scitamineum caused a significant reduction in setts germination, coupled with profuse tillering, resulting in fewer millable canes. Correlation analysis demonstrated that there was a positive relationship between reduction in setts germination and increase in the number of tillers. The present study would be helpful for the evaluation of smut resistance in a wide range of sugarcane germplasm, especially from the aspects of setts germination and tillers formation, and it also screened out several excellent germplasm for potential application in sugarcane breeding.

Unveiling the Molecular Interactions Between Human Transferrin and Limonene: Natural Compounds in Alzheimer's Disease Therapeutics.

Background: Neurodegeneration is a term describing an irreversible process of neuronal damage. In recent decades, research efforts have been directed towards deepening our knowledge of numerous neurodegenerative disorders, with a particular focus on conditions such as Alzheimer's disease (AD). Human transferrin (htf) is a key player in maintaining iron homeostasis within brain cells. Any disturbance in this equilibrium gives rise to the emergence of neurodegenerative diseases and associated pathologies, particularly AD. Limonene, a natural compound found in citrus fruits and various plants, has shown potential neuroprotective properties. Objective: In this study, our goal was to unravel the binding of limonene with htf, with the intention of comprehending the interaction mechanism of limonene with htf. Methods: Binding was scrutinized using fluorescence quenching and UV-Vis spectroscopic analyses. The binding mechanism of limonene was further investigated at the atomic level through molecular docking and extensive 200 ns molecular dynamic simulation (MD) studies. Results: Molecular docking uncovered that limonene interacted extensively with the deep cavity located within the htf binding pocket. MD results indicated that binding of limonene to htf did not induce substantial structural alterations, ultimately forming stable complex. The findings from fluorescence binding indicated a pronounced interaction between limonene and htf, limonene binds to htf with a binding constant (K) of 0.1×105 M-1. UV spectroscopy also advocated stable htf-limonene complex formation. Conclusions: The study deciphered the binding mechanism of limonene with htf, providing a platform to use limonene in AD therapeutics in context of iron homeostasis.

Comprehensive spectroscopic and computational insight into the binding of vanillin with human transferrin: targeting neuroinflammation in Alzheimer's disease therapeutics.

In present times, vanillin stands out as a promising therapeutic molecule that can be implicated in the treatment of neurodegenerative disorders (NDs), notably Alzheimer's disease (AD). This can be attributed to the highly potent scavenging activity of vanillin against reactive oxygen species (ROS). Oxidative stress leads to generation of ROS that serves a critical role in AD's pathological progression. It is apparent from various studies that diets rich in polyphenols prevent oxidative stress associated with AD development, implying the crucial role of vanillin in AD therapeutics. It is crucial to maintain iron balance to manage AD associated oxidative stress, unveiling the significance of human transferrin (hTf) that maintains iron homeostasis. Here, we have performed an integrated study of spectroscopic and computational approaches to get insight into the binding mechanism of vanillin with hTf. In the preliminary study, molecular docking deciphered that vanillin primarily occupies the hTf binding pocket, forming multiple interactions with its key residues. Moreover, the binding mechanism was evaluated at an atomistic level employing comprehensive molecular dynamic (MD) simulation. MD analysis demonstrated that binding of vanillin to hTf stabilizes its structure, without inducing any significant alterations in its native conformation. The docked complex was maintained throughout the simulations without changing its original conformation. Essential dynamics analysis further confirms that hTf achieved a stable conformation with vanillin. The outcomes were further supplemented by fluorescence spectroscopy which confirms the formation of stable hTf-vanillin complex. Taken together, the current study unveils the interaction mechanism of vanillin with hTf and providing a platform to use vanillin in AD therapeutics in the context of iron homeostasis.

3-Way hybrid analysis using clinical and magnetic resonance imaging for early diagnosis of Alzheimer's disease.

Alzheimer's is a progressive neurodegenerative disorder that leads to cognitive impairment and ultimately death. To select the most effective treatment options, it is crucial to diagnose and classify the disease early, as current treatments can only delay its progression. However, previous research on Alzheimer's disease (AD) has had limitations, such as inaccuracies and reliance on a small, unbalanced binary dataset. In this study, we aimed to evaluate the early stages of AD using three multiclass datasets: OASIS, EEG, and ADNI MRI. The research consisted of three phases: pre-processing, feature extraction, and classification using hybrid learning techniques. For the OASIS and ADNI MRI datasets, we computed the mean RGB value and used an averaging filter to enhance the images. We balanced and augmented the dataset to increase its size. In the case of the EEG dataset, we applied a band-pass filter for digital filtering to reduce noise and also balanced the dataset using random oversampling. To extract and classify features, we utilized a hybrid technique consisting of four algorithms: AlexNet-MLP, AlexNet-ETC, AlexNet-AdaBoost, and AlexNet-NB. The results showed that the AlexNet-ETC hybrid algorithm achieved the highest accuracy rate of 95.32% for the OASIS dataset. In the case of the EEG dataset, the AlexNet-MLP hybrid algorithm outperformed other approaches with the highest accuracy of 97.71%. For the ADNI MRI dataset, the AlexNet-MLP hybrid algorithm achieved an accuracy rate of 92.59%. Comparing these results with the current state of the art demonstrates the effectiveness of our findings.

Exploring the mechanism of interaction of glipizide with DNA: Combined in vitro and bioinformatics approach.

DNA, vital for biological processes, encodes hereditary data for protein synthesis, shaping cell structure and function. Since revealing its structure, DNA has become a target for various therapeutically vital molecules, spanning antidiabetic to anticancer drugs. These agents engage with DNA-associated proteins, DNA-RNA hybrids, or bind directly to the DNA helix, triggering diverse downstream effects. These interactions disrupt vital enzymes and proteins essential for maintaining cell structure and function. Analysing drug-DNA interactions has significantly advanced our understanding of drug mechanisms. Glipizide, an antidiabetic drug, is known to cause DNA damage in adipocytes. However, its extract mechanism of DNA interaction is unknown. This study delves into the interaction between glipizide and DNA utilizing various biophysical tools and computational technique to gain insights into the interaction mechanism. Analysis of UV-visible and fluorescence data reveals the formation of complex between DNA and glipizide. The binding affinity of glipizide to DNA was of moderate strength. Examination of thermodynamic parameters at different temperatures suggests that the binding was entropically spontaneous and energetically favourable. Various experiments such as thermal melting assays, viscosity measurement, and dye displacement assays confirmed the minor grove nature of binding of glipizide with DNA. Molecular dynamics studies confirmed the glipizide forms stable complex with DNA when simulated by mimicking the physiological conditions. The binding was mainly favoured by hydrogen bonds and glipizide slightly reduced nucleotide fluctuations of DNA. The study deciphers the mechanism of interaction of glipizide with DNA at molecular levels.

Splenic torsion mistaken for an ovarian cyst: a case report.

BACKGROUND: Wandering spleen (or ectopic spleen) refers to a hyper-mobile spleen resulting in its displacement from the normal anatomical position to usually in the lower abdominal or pelvic cavity. While ultrasound is often the first radiological modality used, Computed Tomography (CT) shows a clear picture and aides to reach a diagnosis. In circumstances where appropriate imaging modalities are not available, or the operator is inexperienced, diagnosis of wandering spleen can be missed. CASE PRESENTATION: A 22-nulligravida unmarried Sindhi female had presented to the Emergency Room (ER) with a 5-day history of intermittent severe lower abdominal pain. An ultrasound at a local practitioner had suggested an ovarian cyst. Ultrasound-pelvis and later CT scan at our facility reported an enlarged wandering spleen with torsion of its pedicle and infarction. Exploratory laparotomy with splenectomy was done. An enlarged wandering spleen was found with torsion of the splenic vein and thrombosed arterial supply from omentum wrapped over the mass. The patient developed thrombocytosis post-surgery but otherwise did well and was discharged after 2 days. CONCLUSION: Splenic torsion secondary to a wandering spleen can be challenging to diagnose, especially in resource limited settings where ultrasound might be the only modality available. Timely diagnosis and proper intervention are key to saving the life and the spleen.

Evaluation of the Binding Mechanism of Dietary Phytochemical, Ellagic Acid, with Human Transferrin: Spectroscopic, Calorimetric, and Computational Approaches Targeting Neurodegenerative Diseases.

Human transferrin (Htf) is vital in maintaining iron within the brain cells; any disruption results in the development of neurodegenerative diseases (NDs) and other related pathologies, especially Alzheimer's disease (AD). Ellagic acid (EA), a naturally occurring phenolic antioxidant, possesses neuroprotective potential and is present in a broad variety of fruits and vegetables. The current work explores the binding mechanism of dietary polyphenol, EA, with Htf by a combination of experimental and computational approaches. Molecular docking studies unveiled the binding of EA to Htf with good affinity. Molecular dynamic (MD) simulation further provided atomistic details of the binding process, demonstrating a stable Htf-EA complex formation without causing substantial alterations to the protein's conformation. Furthermore, fluorescence binding measurements indicated that EA forms a high-affinity interaction with Htf. Isothermal titration calorimetric measurements advocated the spontaneous nature of binding and also revealed the binding process to be exothermic. In conclusion, the study deciphered the binding mechanism of EA with Htf. The results demonstrated that EA binds with Htf with an excellent affinity spontaneously, thereby laying the groundwork for potential applications of EA in the realm of therapeutics for NDs in the context of iron homeostasis.

Survey dataset on mental health in tech professionals from open sourcing mental health surveys (2017-2021).

The dataset presented here was created by combining surveys conducted by Open Sourcing Mental Illness, a non-profit organization, from 2017 to 2021. The primary objective of the surveys was to assess the prevalence of mental health concerns among individuals employed in the technology sector and to gauge their attitudes toward mental health in the workplace. The dataset is filtered to include only those respondents with a primary tech role, and descriptive questions are removed, ensuring data consistency and validity of survey responses for effective analysis. The proposed dataset provides a valuable resource for researchers and practitioners to gain insights into the mental health concerns and attitudes of individuals employed in the technology sector, thus aiding the development of evidence-based interventions and policies to improve the well-being of employees.

Furosemide Derails Human Lysozyme Fibrillation by Interacting with Aggregation Hot Spots: A Biophysical Comprehension.

Kidney-associated human lysozyme amyloidosis leads to renal impairments;thus, patients are often prescribed furosemide. Based on this fact, the effect of furosemide on induced human lysozyme fibrillation, in vitro, is evaluated by spectroscopic, calorimetric, computational, and cellular-based assays/methods. Results show that furosemide increases the lag phase and decreases the apparent rate of aggregation of human lysozyme, thereby decelerating the nucleation phase and amyloid fibril formation, as confirmed by the decrease in the level of Thioflavin-T fluorescence. Fewer entities of hydrodynamic radii of ∼171 nm instead of amyloid fibrils (∼412 nm) are detected in human lysozyme in the presence of furosemide by dynamic light scattering. Moreover, furosemide decreases the extent of conversion of the α/ß structure of human lysozyme into a predominant ß-sheet. The isothermal titration calorimetry established that furosemide forms a complex with human lysozyme, which was also confirmed through fluorescence quenching and computational studies. Also, human lysozyme lytic activity is inhibited competitively by furosemide due to the involvement of amino acid residues of the active site in catalysis, as well as complex formation. Conclusively, furosemide interacts with Gln58, Ile59, Asn60, Ala108, and Trp109 of aggregation-prone regions 2 and 4 of human lysozyme, thereby masking its sites of aggregation and generating only lower-order entities that are less toxic to red blood cells than the fibrils. Thus, furosemide slows the progression of amyloid fibrillation in human lysozyme.

Investigating the binding interaction of quinoline yellow with bovine serum albumin and anti-amyloidogenic behavior of ferulic acid on QY-induced BSA fibrils.

Protein aggregation induces profound changes in the structure along with the conformation of the protein, and is responsible for the pathogenesis of a number of neurodegenerative conditions such as Huntington's, Creutzfeldt-Jacob, Type II diabetes mellitus, Alzheimer's, etc. Numerous multi-spectroscopic approaches and in-silico experiments were utilized to investigate BSA's biomolecular interaction and aggregation in the presence of quinoline yellow. The present research investigation evaluated the interaction of BSA with the food colorant (QY) at two different pH (7.4 and 2.0). The development of the BSA-QY complex was established with UV visible and fluorescence spectroscopy. The quenching of fluorescence upon the interaction of BSA with QY revealed the static nature of quenching mechanism. The Kb value obtained from our result is 4. 54 × 10-4 M-1. The results from the competitive site marker study infer that quinoline yellow is binding with the sub-domain IB of bovine serum albumin, specifically on site III. Three-dimensional fluorescence and synchronous fluorescence spectroscopy were applied for monitoring the alterations in the microenvironment of BSA upon the addition of quinoline yellow. The results from turbidity and RLS studies showed that higher concentrations of QY (80-400 µM) triggered bovine serum albumin (BSA) aggregation at pH 2.0. At pH 7.4, QY couldn't manage to trigger bovine serum albumin aggregation, perhaps because of the repulsion between negatively charged dye (QY) and anionic bovine serum albumin. The results from far-UV CD, Congo Red, and scanning electron microscopy implicate that the QY-induced aggregates exhibit amyloid fibril-like structures. Molecular docking results revealed that hydrophobic interactions, hydrogen bonding, and Pi-Sulfur interactions contribute to QY-induced aggregation of BSA. Further, the amyloid inhibitory potential of ferulic acid (FA), a phenolic acid on QY-induced aggregation of BSA, has also been assessed. The QY-induced amyloid fibrils are FA-soluble, as confirmed by turbidity, RLS, and far-UV CD studies. Far-UV CD results showed that FA retains α helix and inhibits cross ß sheet formation when the BSA samples were pre-incubated with increasing concentrations of FA (0-500 µM). Our findings conclude that QY dye successfully stimulates BSA aggregation, but ferulic acid inhibits QY-induced aggregation of BSA. Thus, FA can serve as a therapeutic agent and can help in the treatment of various amyloid-related conditions.

Biophysical insight into anti-amyloidogenic nature of novel ionic Co(II)(phen)(H2O)4]+[glycinate]- chemotherapeutic drug candidate against human lysozyme aggregation.

In the recent past, there has been an ever-increasing interest in the search for metal-based therapeutic drug candidates for protein misfolding disorders (PMDs) particularly neurodegenerative disorders such as Alzheimer's, Parkinson's, Prion's diseases, and amyotrophic lateral sclerosis. Also, different amyloidogenic variants of human lysozyme (HL) are involved in hereditary systemic amyloidosis. Metallo-therapeutic agents are extensively studied as antitumor agents, however, they are relatively unexplored for the treatment of non-neuropathic amyloidoses. In this work, inhibition potential of a novel ionic cobalt(II) therapeutic agent (CoTA) of the formulation [Co(phen)(H2O)4]+[glycinate]- is evaluated against HL fibrillation. Various biophysical techniques viz., dye-binding assays, dynamic light scattering (DLS), differential scanning calorimetry (DSC), electron microscopy, and molecular docking experiments validate the proposed mechanism of inhibition of HL fibrillation by CoTA. The experimental corroborative results of these studies reveal that CoTA can suppress and slow down HL fibrillation at physiological temperature and pH. DLS and 1-anilino-8-naphthalenesulfonate (ANS) assay show that reduced fibrillation in the presence of CoTA is marked by a significant decrease in the size and hydrophobicity of the aggregates. Fluorescence quenching and molecular docking results demonstrate that CoTA binds moderately to the aggregation-prone region of HL (Kb = 6.6 × 104 M-1), thereby, inhibiting HL fibrillation. In addition, far-UV CD and DSC show that binding of CoTA to HL does not cause any change in the stability of HL. More importantly, CoTA attenuates membrane damaging effects of HL aggregates against RBCs. This study identifies inorganic metal complexes as a therapeutic intervention for systemic amyloidosis.

Influence of industrial waste and mineral admixtures on durability and sustainability of high-performance concrete.

The present research explores the strength, durability, microstructure, embodied energy, and global warming potential investigations made toward cleaner production of high-performance concrete (HPC) using a new composition. For this, various mixes were considered by replacing cement with metakaolin (MK) and silica fumes (SF) while simultaneously altering fine aggregates with industrial waste, copper slag (CS) in 0%, 25%, 50%, 75%, and 100% at 0.23 w/b ratio. The observations on fresh properties show a decrease in the slump due to pozzolans MK and SF but get compensated by the inclusion of copper slag simultaneously. HPC mixes with 50% replacement of CS revealed the best outcomes in compressive and splitting tensile strengths. Upon testing the concrete mixes against resistance to sulfate exposure, chloride penetration, and water absorption, the durability performance results best for modified mixes having 50% CS substitution levels. Scanning electron microscopy and energy dispersive spectroscopy support a 25% substitution of CS, showing a thickset microstructure with an ample amount of C-S-H gel with negligible cracks and capillary channels resulting in having best-strengthening properties. Overall, decrement in embodied energies and global warming potential has resulted with a reduction in the usage of cement and river sand in modified concrete mixes, ultimately making the production sustainable as well as environment friendly.

Utilizing Siamese 4D-AlzNet and Transfer Learning to Identify Stages of Alzheimer's Disease.

Alzheimer's disease (AD) is the general form of dementia, leading to a progressive neurological disorder characterized by memory loss due to brain cell damage. Artificial Intelligence (AI) assists in the early identification and prediction of AD patients, determining future risks and benefits for radiologists and doctors to save time and cost. Since deep learning (DL) approaches work well with massive datasets and have recently become helpful for AD detection, there remains an area for improvement in automating detection performance. Present approaches somehow addressed the challenges of limited annotated data samples for binary classification. This contrasts with prior state-of-the-art techniques, which were constrained by their incapacity to capture abstract-level information. In this paper, we proposed a Siamese 4D-AlzNet model comprised of four parallel convolutional neural network (CNN) streams (Five CNN layer blocks) and customized transfer learning models (Frozen VGG-19, Frozen VGG-16, and customized AlexNet). Siamese 4D-AlzNet was vertically and horizontally stored, and the spatial features were passed to the final layer for classification. For experiments, T1-weighted MRI images comprised of four distinct subject classes, normal control (NC), mild cognitive impairment (MCI), late mild cognitive impairment (LMCI), and AD, have been employed. Our proposed models achieved outstanding accuracy, with a remarkable 95.05% accuracy distinguishing between normal and AD subjects. The performance across remaining binary class pairs consistently exceeded 90%. We thoroughly compared our model with the latest methods using the same dataset as our reference. Our proposed model improved NC-AD and MCI-AD classification accuracy by 2% 7%.

Natural compound plumbagin based inhibition of hIAPP revealed by Markov state models based on MD data along with experimental validations.

Human islet amyloid polypeptide (amylin or hIAPP) is a 37 residue hormone co-secreted with insulin from ß cells of the pancreas. In patients suffering from type-2 diabetes, amylin self-assembles into amyloid fibrils, ultimately leading to the death of the pancreatic cells. However, a research gap exists in preventing and treating such amyloidosis. Plumbagin, a natural compound, has previously been demonstrated to have inhibitory potential against insulin amyloidosis. Our investigation unveils collapsible regions within hIAPP that, upon collapse, facilitates hydrophobic and pi-pi interactions, ultimately leading to aggregation. Intriguingly plumbagin exhibits the ability to bind these specific collapsible regions, thereby impeding the aforementioned interactions that would otherwise drive hIAPP aggregation. We have used atomistic molecular dynamics approach to determine secondary structural changes. MSM shows metastable states forming native like hIAPP structure in presence of PGN. Our in silico results concur with in vitro results. The ThT assay revealed a striking 50% decrease in fluorescence intensity at a 1:1 ratio of hIAPP to Plumbagin. This finding suggests a significant inhibition of amyloid fibril formation by plumbagin, as ThT fluorescence directly correlates with the presence of these fibrils. Further TEM images revealed disappearance of hIAPP fibrils in plumbagin pre-treated hIAPP samples. Also, we have shown that plumbagin disrupts the intermolecular hydrogen bonding in hIAPP fibrils leading to an increase in the average beta strand spacing, thereby causing disaggregation of pre-formed fibrils demonstrating overall disruption of the aggregation machinery of hIAPP. Our work is the first to report a detailed atomistic simulation of 22 µs for hIAPP. Overall, our studies put plumbagin as a potential candidate for both preventive and therapeutic candidate for hIAPP amyloidosis.

Carbon-Supported Nanocomposite Synthesis, Characterization, and Application as an Efficient Adsorbent for Ciprofloxacin and Amoxicillin.

The existence of antibiotics in the environment has recently raised serious concerns about their possible hazards to human health and the water ecosystem. In the current study, an activated carbon-supported nanocomposite, AC-CoFe2O3, was synthesized by a coprecipitation method, characterized, and then applied to adsorb different drugs from water. The synthesized composites were characterized by using energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller plots, and scanning electron microscopy. The adsorption of both Ciprofloxacin (Cipro) and Amoxicillin (Amoxi) antibiotics on the composite followed the pseudo-second-order kinetic model (R2 = 0.9981 and 0.9974 mg g-1 min-1, respectively). Langmuir isotherm was the best-fit model showing 312.17 and 217.76 mg g-1 adsorption capacities for Ciprofloxacin and Amoxicillin, respectively, at 333 K. The negative Gibbs free energy (ΔG°) specified the spontaneity of the method. The positive change in the enthalpy (ΔH) indicated that the adsorption process was assisted by higher temperatures. The different optimized parameters were pH, contact time, adsorbent weight, concentration, and temperature. The maximum adsorption of Cipro was found to be 98.41% at pH 12, while for Amoxi, it was 89.09% at pH 2 at 333 K. The drugs were then successfully determined from natural water samples at optimized conditions using these nanocomposites.

Advancements in gene therapy approaches for atrial fibrillation: Targeted delivery, mechanistic insights and future prospects.

Atrial fibrillation (AF) remains a complex and challenging arrhythmia to treat, necessitating innovative therapeutic strategies. This review explores the evolving landscape of gene therapy for AF, focusing on targeted delivery methods, mechanistic insights, and future prospects. Direct myocardial injection, reversible electroporation, and gene painting techniques are discussed as effective means of delivering therapeutic genes, emphasizing their potential to modulate both structural and electrical aspects of the AF substrate. The importance of identifying precise targets for gene therapy, particularly in the context of AF-associated genetic, structural, and electrical abnormalities, is highlighted. Current studies employing animal models, such as mice and large animals, provide valuable insights into the efficacy and limitations of gene therapy approaches. The significance of imaging methods for detecting atrial fibrosis and guiding targeted gene delivery is underscored. Activation mapping techniques offer a nuanced understanding of AF-specific mechanisms, enabling tailored gene therapy interventions. Future prospects include the integration of advanced imaging, activation mapping, and percutaneous catheter-based techniques to refine transendocardial gene delivery, with potential applications in both ventricular and atrial contexts. As gene therapy for AF progresses, bridging the translational gap between preclinical models and clinical applications is imperative for the successful implementation of these promising approaches.

Antibacterial, antioxidant, and anticancer potential of green fabricated silver nanoparticles made from Viburnum grandiflorum leaf extract.

BACKGROUND: Recently, researchers are focusing on creating new tools to combat the antibiotic resistant bacteria and malignancy issues, which pose significant threats to humanity. Biosynthesized silver nanoparticles (AgNPs) are thought to be a potential solution to these issues. The biosynthesis method, known for its environmentally friendly and cost-effective characteristics, can produce small-sized AgNPs with antimicrobial and anticancer properties. In this study, AgNPs were bio-fabricated from the distilled water and methanolic extracts of Viburnum grandiflorum leaves. Physio-chemical characterization of the bio-fabricated AgNPs was conducted using UV-visible spectroscopy, scanning electron microscopy, energy dispersive X-ray, and X-ray diffraction analysis. RESULTS: AgNPs produced from the methanol extract were smaller in size (12.28 nm) compared to those from the aqueous extract (17.77 nm). The bioengineered AgNPs exhibited a circular shape with a crystalline nature. These biosynthesized AgNPs demonstrated excellent bactericidal activity against both gram-negative (Pseudomonas aeruginosa) and gram-positive (Staphylococcus aureus) bacteria. Highest antibacterial activity was observed with the methanol extract against P. aeruginosa (14.66 ± 0.74 mm). AgNPs from the methanol extract also displayed the highest antioxidant activity, with an IC50 value of 188.00 ± 2.67 µg/mL against 2,2-diphenyl-1-picrylhydrazyl (DPPH). Furthermore, AgNPs exhibited notable cytotoxic activity against Rhabdomyosarcoma cell line (RD cell) of human muscle cancer cell. The IC50 values calculated from the MTT assay were 26.28 ± 1.58 and 21.49 ± 1.44 µg/mL for AgNPs synthesized from aqueous and methanol extracts, respectively. CONCLUSION: The methanol extract of V. grandiflorum leaves demonstrates significant potential for synthesizing AgNPs with effective antibacterial, antioxidant, and anticancer actions, making them applicable in various biomedical applications.