Objective: To investigate the network pharmacology of furosemide in horses and identify potential off-target interactions that could influence cardiac electrophysiology and arrhythmogenic risk. Procedures: Human protein targets of furosemide were predicted using SwissTargetPrediction and mapped to equine orthologs through gene name matching and UniProt verification. Molecular docking against all equine targets was performed using AutoDock Vina integrated with PrankWeb. High-affinity targets (affinity <125 µM) were subjected to protein-protein interaction network and molecular function enrichment analyses in STRING. Network enrichment analyses were performed for all targets of furosemide, its metabolites (furosemide glucuronide and saluamine), and targets shared between the parent drug and metabolites. Results: Nineteen high-affinity targets of furosemide were identified, including SLC5A2, CDK9, AURKA, MAP2K1, and multiple carbonic anhydrase isoforms. Network analysis highlighted clusters related to ion transport, kinase signalling, and zinc-dependent enzymatic activity. Carbonic anhydrase and zinc-binding functions were prominent in broader network and enrichment analyses, suggesting potential off-target effects of furosemide in cardiopulmonary tissues. Conclusions: Furosemide interacts with multiple equine proteins beyond its canonical renal target, including carbonic anhydrases and zinc-dependent enzymes. These interactions may influence cardiac acid-base homeostasis and electrophysiological stability, providing a plausible mechanism for arrhythmogenic risk and SCD in racehorses. Further in vitro and in vivo studies are warranted to validate these findings and guide safer therapeutic use in high-performance equines.

Two-dimensional transition metal dichalcogenides (TMDCs) have been extensively investigated due to their tunable properties. In this work, density functional theory (DFT) is employed to investigate the adsorption behavior and sensing characteristics of HCN on pristine and doped MoS2 monolayers (X-MoS2, where X = P, N, Si, Al, B, Cl). The structural, electronic, and optical characteristics of all systems are examined to study the sensing properties of various doped MoS2 monolayers. In particular, the Al-MoS2 system demonstrates the strongest adsorption characterized by chemisorption, while the remaining systems show interactions of physisorption type. Recovery time and changes in electronic and optical properties reveal that Si-MoS2 possesses an ultrafast response of the order of microseconds, while Al-MoS2 exhibits a significantly longer recovery time, making it unsuitable for reusable sensors. P-MoS2, Si-MoS2, and Al-MoS2 monolayers show pronounced changes in their properties after HCN adsorption. To explore tunability in adsorption strength and recovery behavior, systems with two and three dopant atoms are further studied for P, Si, and Al doping. The results indicate that double doping enhances adsorption strength, whereas triple symmetric doping weakens it. Based on adsorption energy, recovery time, and electronic response, 2P-MoS2 and 3Al-MoS2 are identified as promising candidates for electrochemical and chemiresistive sensing of HCN. Additionally, the observed optical response in the ultraviolet region highlights their potential in UV-range optical sensor design.

Polymeric heart valves have emerged as promising class of next-generation prostheses, offering combined advantages of mechanical durability and biological compatibility. However, long-term success of such valves depends critically on selection of suitable polymeric materials that can endure repetitive mechanical stresses while maintaining excellent hemocompatibility. In this context, ultra-high-molecular-weight polyethylene (UHMWPE) has gained attention due to its excellent wear resistance, high toughness, low friction coefficient, chemical stability and biocompatibility. The present study investigates the suitability and compatibility of UHMWPE for heart valve applications, emphasizing its thermal, dynamic mechanical, hemocompatibility and antithrombogenic characteristics. Thermal analyses confirmed the high thermal stability and semi-crystalline (similar to 41%) nature of UHMWPE well beyond physiological temperatures, while dynamic mechanical analysis at body temperature (37 degrees C) revealed a predominantly elastic response with low energy dissipation under frequency and strain-controlled loading. Hemolysis testing demonstrated a hemolytic ratio of 1.5%, confirming UHMWPE's non-hemolytic behavior. Blood smear formation analysis revealed no evidence of smear or blood film on the surface, indicating an antithrombogenic nature. Furthermore, platelet adhesion studies showed remarkably low platelet adhesion density, affirming UHMWPE's ability to minimize platelets adhesion and prevent thrombus formation. [GRAPHICS] .

This study investigates the rupture mechanism of layered Fe-Cr-Ni alloy under multiaxial tensile deformation using molecular dynamics simulations. The results found that the presence of layered orientation of Fe-Cr-Ni significantly impacts nanovoid formation, growth, and coalescence during multiaxial (uniaxial, biaxial, and triaxial) deformation. During triaxial deformation, nanovoids nucleate early and grow rapidly, leading to material failure, with body-centered cubic structure forming around void surfaces due to strain-induced phase transformations. Biaxial tensile deformation facilitates minor amount of face-centered cubic to body-centered cubic transformations with rectangular and square-shaped stacking faults. Uniaxial tensile deformation produces the highest degree of dislocation interactions, leading to complex defect structures. Our study highlights that the yield stress, dislocation density, surface area, and solid volume vary across different deformation modes. Layered or twin boundaries act as barriers for movement of dislocation, reducing the plasticity and enhancing void nucleation. Our findings provide critical insights into atomic-scale mechanisms driving void formation, phase transformation, and material failure in Fe-Cr-Ni alloys with twin boundaries, contributing to improved material design under multiaxial loading conditions.

Additive manufacturing enables the customization of parts according to user requirements. However, additive manufacturing of soft polymeric materials using melt‐based fused deposition modeling is challenging due to issues such as low column strength, high melt viscosity, poor adhesion with the print bed, and weak layer‐to‐layer adhesion. This work focused on the development of soft thermoplastic elastomeric nanocomposite materials based on reduced graphene oxide (rGO) and styrene‐isoprene‐styrene (SIS) triblock copolymer by direct ink writing (DIW) based additive manufacturing technique. The extrudability and printability of the developed SIS‐rGO inks with varying rGO loading are investigated from shear viscosity and pressure drop analysis across different zones of the nozzle. Developed 3D printed nanocomposites showed good mechanical properties such as high elongation at break (≥ 2000%) and high tensile strength (5–11 MPa). Microstructures of 3D printed samples and the distribution of rGO nanosheets in the SIS matrix are analyzed from XRD and TEM. Dielectric constant of 3D printed nanocomposites increased ≈6 times for the 7 wt.% loaded rGO nanocomposite compared to the pristine SIS. Additionally, the electromagnetic interference shielding effectiveness (EMI SE) by absorption is also found to increase with rGO loading in the 3D‐printed samples.

This study introduces a novel graphene-graphullerene heterostructure as a promising material for high-performance capacitors. Compared to pristine graphene, this heterostructure exhibits a significantly larger surface area and porosity which enhance its energy storage capacity. Pristine graphullerene is a semiconductor with a bandgap of 0.92 eV and its integration with graphene effectively modifies its electronic properties, rendering it conductive as confirmed by band structure analysis. The unique combination of graphene's high conductivity and graphullerene's extended surface area and porosity presents a promising avenue for developing capacitors with exceptional performance characteristics.

Background Newcastle Disease (ND), caused by the Newcastle Disease Virus (NDV) poses a significant threat to poultry, leading to severe economic losses. Understanding the molecular interactions between NDV proteins and avian mucins is crucial for developing targeted interventions. Material and Methods In this study, twelve NDV proteins were systematically assessed for their interactions with sixteen quail and eight chicken mucin types, revealing diverse and species-specific binding patterns. Results High-affinity interactions between mucins (Muc5A, Muc5B, and Muc6) and NDV hemagglutinin-neuraminidase, was observed in addition to significant interactions with NDV fusion glycoprotein. Notably, chicken Muc4 displayed mid-range interactions exclusively with NDV fusion glycoprotein, highlighting potential species-specific differences in viral entry mechanisms between quails and chickens. Furthermore, the study investigated the number of binding sites on NDV proteins and chicken/quail mucins. Chicken Muc5B emerged as a standout with the highest number (20) of binding sites, suggesting its crucial role in NDV infection. The binding site analysis identified key regions in NDV fusion glycoprotein and hemagglutinin-neuraminidase, indicating potential targets for vaccine development. Conclusion This study provides a foundation for future research into optimizing diagnostic approaches and therapeutic strategies for NDV infections. Validation of these interactions with real-world clinical data, coupled with an exploration of tissue-specific mucin expression patterns, could further enhance our understanding of host-virus dynamics. The identified interactions offer promising avenues for developing vaccines that target specific binding sites, thereby contributing to the effective control and prevention of Newcastle Disease in poultry populations. ### Competing Interest Statement The authors have declared no competing interest.

The recent rise in xylazine use disorders (XUD) in humans is a significant cause for concern as a comprehensive understanding of its molecular pathology is limited, and hence, the ability to reverse the potential adverse effects is lacking. To address this gap, this study evaluates the dose-dependent impact of xylazine and its interactions with various potential targets to identify an optimal reversal strategy. A trichotomized (Low, medium, and high) dose, volume of distribution, and predicted plasma concentration of xylazine were defined. A detailed analysis of xylazine's network protein targets and their tissue-specific expression was performed using classical pharmacoinformatic tools. Molecular docking was used to assess the drug-target affinities and identify potential reversal agents. The study categorized xylazine plasma concentrations ranging from 5-8 mu M, 14-20 mu M, and 28-40 mu M as low, medium, and high concentrations, respectively. Xylazine displayed a preferential affinity for hydrolases, kinases, transporters, and ion channels. Xylazine's network analysis revealed the following proteins: ABCC9, RET, RAPGEF4, ACHE, TGFBR1, PGR, KCNH2, KCNN2, and TRPM8 as its high-affinity targets. The tissue-specific expression of these high-affinity targets suggested potential adverse effects on various organs, particularly skeletal and smooth muscles and the adrenal gland. The study further explored the potential reversal of xylazine pharmacology using alpha2AR-antagonists and CNS stimulants. Prazosin emerged as the most promising candidate, exhibiting a 200 to 2000-fold superior affinity against all high-affinity targets of xylazine. This study contributes to our understanding of xylazine's molecular mechanisms, which could be relevant to its pharmacological effects in all species, and suggests that prazosin can serve as an effective therapeutic option for mitigating xylazine-induced adverse effects in XUD patients, which warrants clinical investigation.

A network analysis of canonical microRNA (miRNA) biogenesis identified DROSHA, Exportin-5, and DICER1 as essential proteins for both precursor and mature miRNA processing. The analysis revealed strong interactions between these proteins and others involved in miRNA biogenesis, suggesting a complex regulatory network. Ligand binding sites on these key proteins were identified, suggesting potential targets for therapeutic intervention. Our findings indicate that modulating miRNA biogenesis through these proteins could influence cellular protein production and function, providing a promising avenue for developing advanced therapy medicinal products (ATMPs) to impact protein expression in diseases such as cancer. ### Competing Interest Statement The authors have declared no competing interest.

Background and Aim: In avian and other species, mucins (MUCs) play a crucial role in the gastrointestinal tract (GIT), and constitute a large group of O-glycosylated glycoproteins, are glycoconjugate proteins. MUCs present in two forms: (1) membrane-attached on cell surfaces to repel external threats and (2) detachable, gel-forming proteins in the soluble form. In quail GIT, the specific types of MUCs that are expressed remain largely unknown. We investigated the expression of MUC1 and MUC4 MUCs in the GIT of Iraqi common quails and conducted network and structural analyses of all known MUC types across quail breeds. Materials and Methods: Histological and gene expression analyses of MUC1 and MUC4 were conducted using fresh small intestine and large intestine samples from 10 quails. Using the STRING Database, Chimera software, and PrankWeb-ligand binding site prediction tool, network and structural analyses of all reported types of quail MUCs were conducted. Results: Most intestinal MUCs in quails were acidic, with few neutral MUCs detectable through Alcian blue and periodic acid-schiff stains. Acidic MUCs were more expressed in the duodenum, ileum, cecum, and colon, whereas neutral MUCs were more expressed in the jejunum. MUC1 and MUC4 messenger RNA expression was significantly higher in the jejunum and colon than in the duodenum and ileum. The analysis of the network revealed that MUC 1, 15, 16, and 24 formed homologous networks, while MUC 2, 4, 5, and 6 formed heterologous networks. Specific MUC combinations, including MUC5A-MUC6, MUC5A-MUC5B, and MUC5B-MUC6, show higher intermolecular hydrogen bond formation affinity. MUC15, MUC16, and MUC24 showed minimal interaction with other MUC types. Among the analyzed MUCs, MUC5B, and MUC6 had the highest probability for binding, while MUC2, MUC4, and MUC5A showed lower probabilities despite greater numbers of binding sites. Conclusion: This study’s results offer significant insights into quails’ MUCs’ composition, expression, network interactions, and binding sites, advancing knowledge of MUC-related processes in gastrointestinal physiology and their potential connection to gastrointestinal diseases.

Background Artificial sweeteners (ASwt) are widely consumed sugar substitutes, but their long-term health effects remain a subject of debate. While regulatory bodies generally consider them safe at recommended doses, concerns persist regarding potential adverse effects. This study aimed to investigate the interactions between ASwt and biological targets using in silico analysis, focusing on target affinity, selectivity, and tissue expression. Methods Five common ASwt – acesulfame K (Ac), aspartame (As), sucralose (Su), steviol (St), and saccharin (Sa) were evaluated. Their target interactions were predicted using a cheminformatics approach, analysing affinity towards functional groups and protein targets. Concentration/affinity (C/A) ratios were calculated to assess the likelihood of target activation at achievable doses. Expression of high-affinity targets with significant C/A ratios in various organs was assessed using the Human Protein Atlas database. Results : The ASwt displayed potential to modulate most of the functional groups at physiologically feasible affinities. Ac exhibited a broad range of targets, while St showed a preference for kinases and proteases. Notably, As and Su demonstrated interactions with membrane receptors and kinases. C/A ratio analysis revealed potential concerns for As and Su. Several of its targets, including ROCK2, ACE, ITGA2/5, PIM2, KDM5C, PIM1, SLC1A2, SETD2, CAPN1, LTA4H, MKNK2, HDAC1 and CDK, showed high C/A ratios, suggesting possible functional modulation at achievable intake levels. Organ specific expression analysis identified the endocrine, respiratory, renal, reproductive, central nervous, digestive, and musculoskeletal systems as a region particularly susceptible due to the high expression of high affinity targets linked to cell growth, extracellular matrix, epigenetic regulations, and inflammation. Interestingly, 30 tissues expressed high-affinity targets for both As and Su, while 14 tissues exclusively expressed targets for As. Conclusion : This study highlights the potential for ASwt to interact with various biological targets, particularly As and Su. The high C/A ratios of some As targets and the tissue-specific expression patterns suggest potential safety concerns that require in vivo validation. ### Competing Interest Statement The authors have declared no competing interest.

Background: Sortilin1 (SORT1) is a ubiquitously expressed transporter involved in sorting or clearing proteins and is pathologically linked to tissue fibrosis and calcification. Targeting SORT1 may have potential clinical efficacy in controlling or reversing cardiovascular fibrosis and/or calcification. Hence, this study assessed the protein–protein network of human SORT1 and its targetability using known nutra-/pharmaceuticals. Material and methods: Network proteins of human SORT1 were identified using the String database, and the affinity of the protein–protein interaction of this network was analysed using Chimera software (Chimera-1.17.3-mac64). The tissue-specific expression profile of SORT1 was evaluated and assessed for enrichment in different cell types, including immune cells. A library of in-house small molecules and currently used therapeutics for cardiovascular diseases were screened using AutoDock Vina to assess the targetability of human SORT1. The concentration affinity (CA) ratio of the small molecules was estimated to assess the clinical feasibility of targeting SORT1. Results: IGF2R, NTRK2, GRN and GGA1 were identified as high-affinity interaction networks of SORT1. Of these high-affinity interactions, IGF2R and GRN can be considered relevant networks in regulating tissue fibrosis or the microcalcification process due to their influence on T-cell activation, inflammation, wound repair, and the tissue remodelling process. The tissue cell-type enrichment indicated major expression of SORT1 in adipocytes, specialised epithelial cells, monocytes, cardiomyocytes, and thyroid glandular cells. The binding pocket analysis of human SORT1 showed twelve potential drug interaction sites with varying binding scores (0.86 to 5.83) and probability of interaction (0.004 to 0.304). Five of the drug interaction sites were observed to be targetable at the therapeutically feasible concentration of the small molecules evaluated. Empagliflozin, sitagliptin and lycopene showed a superior affinity and CA ratio compared to established inhibitors of SORT1. Conclusion: IGF2R and GRN are relevant networks of SORT1, regulating tissue fibrosis or the microcalcification process. SORT1 can be targeted using currently approved small-molecule therapeutics (empagliflozin and sitagliptin) or widely used nutraceuticals (lycopene), which should be evaluated in a randomised clinical trial to assess their efficacy in reducing the cardiac/vascular microcalcification process.

Papillomaviruses infect cutaneous tissue in various species including bovines and from benign warts to malignant squamous cell carcinoma causing severe economic losses to the farmers. The mechanisms by which bovine papillomaviruses interact with host tissue are unclear. Hence in this study using classical network analysis tools, we evaluated interactions of Bovine papilloma (BPV) variants, with markers and receptors implicated in squamous cell carcinoma. Additionally, the Thuja phytoconstituents were also evaluated for its potential to target the BPV and squamous cell carcinoma network interactions to understand the mechanism of its clinical benefits. Various protein composition of 14 different virus variants of BPV were assessed against 24 markers of squamous cell carcinoma. Among these interactions EGFR consistently exhibited high-affinity interactions with the E1 protein in all isoforms of BPV. Type 4 BPV displayed the maximum number of binding sites (14) with a binding pocket score ranging from 15.47 to 141.34 and a probability score of 0.75 to 0.99. The comparison of the binding pockets identified that BPV types 2 and 13 had the highest number of common amino acid sequences. Further the alpha helix structure of specific common amino acid sequences contributes to a more robust and widespread affinity interaction with both E1 of various BPV types and EGFR. Analysis of Thuja phytochemicals suggested superior efficacy of Beyerene and Terpinene-4-ol towards all ten BPV targets and bEGFR. In conclusion, our comprehensive study leading to identification of E1 protein of BPV as a major interacting network with bEGFR, their key binding sites, and efficacy of Thuja phytoconstituents offer valuable insight into further experimental validation and development of novel therapeutic strategies against BPV-associated diseases.

Background:Sialic acid-binding immunoglobulin-like lectin 1 (Siglec-1) is a transmembrane glycoprotein involved in the sialic acid (Sia)-dependent regulation of the immune system. Siglec-1 expression has recently been identified in the male reproductive tract (MRT) of several species, including humans, cattle, horses, and sheep, and may play a role in modulating fertility in a Sia-dependent manner. Materials and Methods:In this study, protein-protein interaction (PPI) analysis of Siglec-1 was conducted to identify associated network protein conservation, and the expression of Siglec-1 in the MRT of mice and rats, including their accessory sex glands and spermatozoa was determined by immunostaining. Results:Network analysis of proteins with Siglec-1 in mice and rats demonstrated significant similarity to human Siglec-1 networks, suggesting a similar conservation of network proteins between these species and, hence, a potential conservation role in immune modulation and function. Specific immunostaining patterns of mouse and rat testes, epididymis, ductus deferens, accessory sex gland tissues, and sperm were detected using human Siglec-1. These results confirmed that the human Siglec-1 antibody could cross-react with mouse and rat Siglec-1, suggesting that the specific expression patterns of Siglec-1 in the MRT and sperm of both mice and rats are similar to those observed in other species. Conclusions:The conservation of Siglec-1 expression patterns in sperm and within the MRT and the similarity of protein networks for Siglec-1 across species suggest that Siglec-1 may function in a similar manner across species. These results also suggest that rodents may serve as a valuable model system for exploring the function of Siglecs in the reproductive system across species and their potential role in modulating fertility in a Sia-dependent manner.

Background Mucins have vital pathophysiological role in gastrointestinal tract (GIT) of avian and other species. However, despite this very little is known about the types of mucins expressed in quail GIT. Hence in this study we examined the expression pattern of mucins (MUC1, and MUC4) in the GIT of the Iraqi Common Quail (Coturnix Coturnix) and performed the network and structural analysis of all reported types of mucins in various breeds of quails. Materials and methods This study protocol was approved by the animal ethics research committee of the College of Veterinary Medicine, University of Al-Qadisiyah, Iraq. Fresh samples of small and large intestines were used for histological and gene expression analysis of MUC1, and MUC4. Network and structural analysis of all reported types of mucins in quails was performed using the STRING Database, Chimera software and PrankWeb-Ligand Binding Site Prediction tool. Results The histological analysis using Alcian blue and PAS stains indicated that most mucins in the intestines of quails were of the acidic mucin type, with minimal prevalence of neutral mucins. The expression of acidic mucins was relatively higher in the duodenum, ileum, caecum, and colon, while the jejunum showed a relatively higher expression of neutral mucins. Gene expression analysis revealed higher expression levels of MUC1 and MUC4 mRNA in the jejunum and colon, with its least expression in the duodenum and ilium. Network analysis indicated predominantly mucin-mucin interactions, with MUC 1, 15, 16 and 24 showing preferential homologous networks while the MUC 2, 4, 5 and 6 showed heterologous networks. Detailed evaluation of intermolecular hydrogen bond formation highlighted the interactions between specific mucin combinations, with certain combinations showing higher affinity, such as MUC5A-MUC6, MUC5A-MUC5B, and MUC5B-MUC6. In contrast, MUC15, MUC16, and MUC24 exhibited limited interactions with other mucin types. Binding site analysis indicated that MUC5B and MUC6 had the most number of binding sites with high probability scores, while MUC2, MUC4, and MUC5A showed lower probability scores despite having more binding sites. In contrast MUC 1, 15, and 16 had very few binding sites (<3 binding sites) all with very low probability scores. Conclusion The findings of this study provide valuable insights into the composition, expression, network interactions, and binding sites of mucins in the quails, contributing to the understanding of mucin-related processes in gastrointestinal physiology and potential implications for gastrointestinal diseases.

Background: The development of safe and biocompatible nanoparticles has always been a major concern in nanomedicine applications. Various studies on the size-dependent toxicity of na-noparticles have been reported but are still controversial. The potential of small-sized nanoparticles can be utilized for imaging and diagnostics. However, insufficient toxicity data on these nanoparti-cles prevents researchers from utilizing their potential in diagnostics. More studies are needed on the toxicity of small-sized nanoparticles to present unanimous report for safe systemic use. The pre-sent study aimed to investigate the toxicity concerns of very small-sized AuNPs (2 ± 0.5 nm, 5 ± 1 nm, and 10 ± 2 nm) and provide a platform for their safe in vivo use. Methods: The cellular interactions of these three small-sized AuNPs with regard to cytotoxicity were investigated on hepatocellular carcinoma (HepG2) and epithelial kidney (HEK-293) cell lines. The cytotoxicity investigation of both cell lines was done through MTT assays, PI & DAPI, and cy-tology. Cellular stress was investigated by Catalase, TBARS, GSH, SOD & ROS parameters. The AuNPs incubated cells were also assessed for immunogenicity by ELISA, protein interaction by BSA, and cellular internalization by TEM (Edax). Results: All three-sized AuNPs were not toxic on cell viability, apoptosis, necrosis, or cytology as-sessment. No oxidative stress was noted in both cell types in the presence of 2 and 5-nm-sized AuNPs, whereas 10 nm-sized AuNPs showed little oxidative stress. AuNPs of size 2 and 5 nm were immunologically inert, but 10 nm-sized AuNPs elicited interleukin (IL-4 and IL-10) and interferon IFN gamma response. AuNPs of sized 2 nm showed 4 times the adsorption of albumin protein as compared to AuNPs of sized 5 nm. The TEM micrographs and peak of gold in the Edax graph con-firmed the presence of AuNPs in cells. Conclusion: Our results are suggestive of utilizing the potential of these three-sized AuNPs safely in preclinical drug delivery applications.

Melatonin gummies have gained popularity as a sleep aid and are widely available over-the-counter.1,2 However, a recent analysis of 25 melatonin gummy products has revealed a concerning trend of inaccurate labelling, raising important questions about product quality, consumer safety, and regulatory oversight.3 This editorial aims to highlight the findings of the analysis and discuss the implications for both manufacturers and consumers. Read more...

Background: Berberine, a naturally occurring alkaloid, is widely explored for several health benefits, including weight management and metabolic disorders. The major pharmacological action of berberine is reported to be by activation of AMP-activated protein kinase, while its other clinical outcomes are devoid of clear mechanism of action/s. Hence in this study a detailed pharmacology of berberine and its two major metabolites (berberrubine, and jatrorrhizine) in humans was evaluated using well established Insilco tools. Materials and Methods: The targets of berberine and its metabolites were identified in SwissTargetPrediction server and their affinity was assed using AutoDock vina 1.2.0. The binding pockets of the highest ligand receptor combinations was assessed using the PrankWeb: Ligand Binding Site Prediction tool. Results: Kinases, enzymes and family A GPCR’s were identified as the top three target category of berberine and its metabolites. ROCK2, PIK3CD, KCNMA1, CSF1R, and KIT were observed to be the high affinity targets of berberine and its metabolites with affinity values of <4 uM. The affinity of berberine and its metabolites against all AMPKs and lipid/glucose regulator targets (LDLR, DDP4 and PCSK9) were >10 uM. The IC50 value of berberine and its metabolites against ROCK2 was the least (<1 uM), while their other high affinity targets (PIK3CD, KCNMA1, CSF1R and KIT) showed IC50 values <5 uM. Conclusion: The diverse range of protein targets and the observed novel high affinity targets (ROCK2, PIK3CD, KCNMA1, CSF1R and KIT) offer valuable insights into the potential mechanisms of action and therapeutic effects of berberine and its metabolites in various disease conditions, which warrants validation in suitable efficacy analysis studies.

To the best of our knowledge, we are the first to report the existence of two dispersion turning points (DTPs) in an optimized planar waveguide long-period grating (LPG) sensor for the lowest order cladding mode. Using numerical simulation, we investigate the potential of the sensor structure for bulk refractive index (RI) and surface sensing, with the goal of predicting its possible application as an integrated photonic biosensor. The proposed sensor exhibits an exceptionally high RI sensitivity of $\approx 7500$ nm/RIU ( $\approx 10$ 000 nm/RIU) near lower (higher) DTP. The surface sensitivity, which is incredibly high in this form of structure, is found to be 6.5 nm/nm (7 nm/nm) near lower (higher) DTP for the RI relevant for biosensing. Utilizing the sensing characteristics of both the DTP, we propose a dual-slot biosensor by cascading two LPGs having different grating periods. The proposed biosensor shows two independent dual-resonance phenomena and is, therefore, capable of simultaneous detection of dual analytes. Utilizing the proposed dual-slot biosensor, we present simulation results for specific detection of Hepatitis B antigen and deoxyribonucleic acid (DNA) hybridization simultaneously. The proposed biosensor will reduce the sensor cost as well as detection time, since a single source and detector are required to sense two different analytes at once.