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Background : Breast cancer influences more than 2 million women worldwide annually. Since apoptotic dysregulation is a cancer hallmark, targeting apoptotic regulators encompasses strategic drug development for cancer therapy. One such class of apoptotic regulators is inhibitors of apoptosis proteins (IAP) which are a class of E3 ubiquitin ligases that actively function to support cancer growth and survival. Methods : The current study reports design, synthesis, docking analysis (based on binding to IAP-BIR3 domains), anti-proliferative and anti-tumor potential of the azomethine derivative, 1-(4-chlorophenyl)-N-(4-ethoxyphenyl)methanimine ( BCS3 ) on breast cancer (in vitro and in vivo) and its possible mechanisms of action. Results : Strong selective cytotoxic activity was observed in MDA-MB-231, MCF-7, and MDA-MB-468 breast cancer cell lines that exhibited IC50 values, 1.554 µM, 5.979 µM, and 6.462 µM, respectively, without affecting normal breast cells, MCF-10A. For the evaluation of the cytotoxic potential of BCS3 , immunofluorescence, immunoblotting, and FACS (apoptosis and cell cycle) analyses were conducted. BCS3 antagonized IAPs, thereby causing MDM2-p53 and Bcl-2-Caspase-mediated intrinsic and extrinsic apoptosis. It also modulated p53 expression causing p21-CDK1/cyclin B1-mediated cell cycle arrest at S and G2/M phases. The in vitro findings were consistent with in vivo findings as observed by reduced tumor volume and apoptosis initiation (TUNEL assay) by IAP downregulation. BCS3 also produced potent synergistic effects with doxorubicin on tumor inhibition. Conclusions : Having witnessed the profound anti-proliferative potential of BCS3 , the possible adverse effects related to anti-cancer therapy were examined following OECD 407 guidelines which confirmed its systemic safety profile and well tolerability. The results indicate the promising effect of BCS3 as an IAP antagonist for breast cancer therapy with fewer adverse effects.

Peste des petits ruminants (PPR) presents economic challenges in enzootic countries impacting small ruminant productivity. The state of Karnataka, India, implemented a mass vaccination campaign in alignment with the PPR-Global Eradication Programme (GEP) and the National Strategic Plan for PPR eradication. This study was conducted from January to March 2023 to assess seroconversion in post-vaccinated goats and sheep at the epidemiological unit (epi-unit) level, aligning with the World Organisation for Animal Health (WOAH) and the Food and Agriculture Organization (FAO) guidelines in the PPR Global Control and Eradication Strategy (GCES). Before vaccination, 3466 random serum samples were collected from small ruminants of three age groups (6-12 months, 1-2 years, and >2 years) across 116 epi-units, spanning 82 taluks in 28 districts. Post-vaccination sero-monitoring included 1102 serum samples collected from small ruminants of the 6-12-month age group only, across 111 epi-units covering 64 taluks in 23 districts. The PPRV antibody status was determined using an indigenous hemagglutinin (H) protein monoclonal antibody-based competitive ELISA kit. Pre-vaccination, the PPR seropositivity rates were 55%, 62%, and 66% in the age groups of 6-12 months, 1-2 years, and >2 years, respectively, with a 61% PPRV antibody prevalence across all the age groups. Notably, 41% of the epi-units exhibited antibody prevalence rates of ≥70%, indicating a substantial population immunity, possibly attributed to the previous vaccination program in the state since 2011. In contrast, only 17% of the epi-units had below 30% seroprevalence rates, emphasizing the need for intensified vaccination. Statistical analysis of the data revealed significant correlations ( p < 0.05) between the presence of PPRV antibodies and host factors such as species, breed, and sex. Post-vaccination seroprevalence in the 6-12 months age group was found to be 73.4%, indicating the use of an efficacious vaccine. On the evaluation of vaccination immunity in the 6-12 months age group, it was revealed that over 69% of the epi-units achieved a response surpassing ≥70%, indicating a significant improvement from 42% of the epi-units in pre-vaccination. For active PPR eradication, a mass vaccination campaign (>95% coverage) targeting small ruminant populations aged >4 months is advocated, aiming to achieve the desired herd immunity of >80%. This study offers crucial insights into PPR baseline seroprevalence/immunity status and vaccine efficacy, guiding national strategies towards a PPR-free India and further supporting the global eradication initiative.

The present work elucidates the fabrication of Barium Lanthanum Oxide nanosheets (BaLa 2 O 4 NSs) via a simple one-pot precipitation method. The acquired results show an orthorhombic crystal system with an average crystallite size of 27 nm. The morphological studies revealed irregular-shaped sheets stacked together in a layered structure, with the confirmation of the precursor elements. The diffused reflectance studies revealed a strong absorption between 200 nm and 350 nm, from which the band-gap energy was evaluated to be 4.03 eV. Furthermore, the fluorescence spectrum was recorded for the prepared samples; the excitation spectrum shows a strong peak at 397 nm, attributed to the 4 F 7/2 → 4 G 11/2 transition, while the emission shows two prominent peaks at 420 nm ( 4 G 7/2 → 4 F 7/2 ) and 440 nm ( 4 G 5/2 → 4 F 7/2 ). The acquired emission results were utilized to confirm the color emission using a chromaticity plot, which found the coordinates to be at (0.1529 0.1040), and the calculated temperature was 3171 K. The as-prepared nanosheets were utilized in detecting latent fingerprints (LFPs) on various non-porous surfaces. The powder-dusting method was used to develop latent fingerprints on various non-porous surfaces, which resulted in detecting all the three ridge patterns. Furthermore, the as-synthesized nanosheets were used to degrade methyl red (MR) dye, the results of which show more than 60% degradation at the 70th minute. It was also found that there was no further degradation after 70 min. All the acquired results suggest the clear potential of the prepared BaLa 2 O 4 NSs for use in advanced forensic and photocatalytic applications.

Colorectal carcinoma (CRC) is a prevalent cancer worldwide with a high mortality rate. Evidence suggests that increased expression of Cyclin-dependent kinase 5 ( CDK5 ) contributes to cancer progression, making it a promising target for treatment. This study examined the efficacy of selectively inhibiting CDK5 in colorectal carcinoma using TP5, a small peptide that selectively inhibits the aberrant and hyperactive CDK5/p25 complex while preserving physiological CDK5/p35 functions. We analyzed TP5's impact on CDK5 activity, cell survival, apoptosis, the cell cycle, DNA damage, ATM phosphorylation, and reactive oxygen species (ROS) signaling in mitochondria, in CRC cell lines, both alone and in combination with chemotherapy. We also assessed TP5's efficacy on a xenograft mouse model with HCT116 cells. Our results showed that TP5 decreased CDK5 activity, impaired cell viability and colony formation, induced apoptosis, increased DNA damage, and led to the G1 phase arrest of cell cycle progression. In combination with irinotecan, TP5 demonstrated a synergy by leading to the accumulation of DNA damage, increasing the γH2A.X foci number, and inhibiting G2/M arrest induced by Sn38 treatment. TP5 alone or in combination with irinotecan increased mitochondrial ROS levels and inhibited tumor growth, prolonging mouse survival in the CRC xenograft animal model. These results suggest that TP5, either alone or in combination with irinotecan, is a promising therapeutic option for colorectal carcinoma.

Earlier studies with montelukast (M) and telmisartan (T) have revealed their potential antiviral properties against SARS-CoV-2 wild-type (WT) but have not assessed their efficacy against emerging Variants of Concern (VOCs) such as Omicron. Our research fills this gap by investigating these drugs' impact on VOCs, a topic that current scientific literature has largely overlooked. We employed computational methodologies, including molecular mechanics and machine learning tools, to identify drugs that could potentially disrupt the SARS-CoV-2 spike RBD-ACE2 protein interaction. This led to the identification of two FDA-approved small molecule drugs, M and T, conventionally used for treating asthma and hypertension, respectively. Our study presents an additional potential use for these drugs as antivirals. Our results show that both M and T can inhibit not only the WT SARS-CoV-2 but also, in the case of M, the Omicron variant, without reaching cytotoxic concentrations. This novel finding fills an existing gap in the literature and introduces the possibility of repurposing these drugs for SARS-CoV-2 VOCs, an essential step in responding to the evolving global pandemic.

Groundwater arsenic (As) pollution is a naturally occurring phenomenon posing serious threats to human health. To mitigate this issue, we synthesized a novel bentonite-based engineered nano zero-valent iron (nZVI-Bento) material to remove As from contaminated soil and water. Sorption isotherm and kinetics models were employed to understand the mechanisms governing As removal. Experimental and model predicted values of adsorption capacity ( q e or q t ) were compared to evaluate the adequacy of the models, substantiated by error function analysis, and the best-fit model was selected based on corrected Akaike Information Criterion (AICc). The non-linear regression fitting of both adsorption isotherm and kinetic models revealed lower values of error and lower AICc values than the linear regression models. The pseudo-second-order (non-linear) fit was the best fit among kinetic models with the lowest AICc values, at 57.5 (nZVI-Bare) and 71.9 (nZVI-Bento), while the Freundlich equation was the best fit among the isotherm models, showing the lowest AICc values, at 105.5 (nZVI-Bare) and 105.1 (nZVI-Bento). The adsorption maxima ( q max ) predicted by the non-linear Langmuir adsorption isotherm were 354.3 and 198.5 mg g -1 for nZVI-Bare and nZVI-Bento, respectively. The nZVI-Bento successfully reduced As in water (initial As concentration = 5 mg L -1 ; adsorbent dose = 0.5 g L -1 ) to below permissible limits for drinking water (10 µg L -1 ). The nZVI-Bento @ 1% ( w / w ) could stabilize As in soils by increasing the amorphous Fe bound fraction and significantly diminish the non-specific and specifically bound fraction of As in soil. Considering the enhanced stability of the novel nZVI-Bento (upto 60 days) as compared to the unmodified product, it is envisaged that the synthesized product could be effectively used for removing As from water to make it safe for human consumption.

The prognosis of pancreatic ductal adenocarcinoma (PDAC) is exceedingly poor. Although surgical resection is the only curative treatment option, multimodal treatment is of the utmost importance, as only about 20% of tumors are primarily resectable at the time of diagnosis. The choice of chemotherapeutic treatment regimens involving gemcitabine and FOLFIRINOX is currently solely based on the patient's performance status, but, ideally, it should be based on the tumors' individual biology. We established two novel patient-derived primary cell lines from surgical PDAC specimens. LuPanc-1 and LuPanc-2 were derived from a pT3, pN1, G2 and a pT3, pN2, G3 tumor, respectively, and the clinical follow-up was fully annotated. STR-genotyping revealed a unique profile for both cell lines. The population doubling time of LuPanc-2 was substantially longer than that of LuPanc-1 (84 vs. 44 h). Both cell lines exhibited a typical epithelial morphology and expressed moderate levels of CK7 and E-cadherin. LuPanc-1, but not LuPanc-2, co-expressed E-cadherin and vimentin at the single-cell level, suggesting a mixed epithelial-mesenchymal differentiation. LuPanc-1 had a missense mutation (p.R282W) and LuPanc-2 had a frameshift deletion (p.P89X) in TP53 . BRCA2 was nonsense-mutated (p.Q780*) and CREBBP was missense-mutated (p.P279R) in LuPanc-1. CDKN2A was missense-mutated (p.H83Y) in LuPanc-2. Notably, only LuPanc-2 harbored a partial or complete deletion of DPC4 . LuPanc-1 cells exhibited high basal and transforming growth factor (TGF)-β1-induced migratory activity in real-time cell migration assays, while LuPanc-2 was refractory. Both LuPanc-1 and LuPanc-2 cells responded to treatment with TGF-β1 with the activation of SMAD2; however, only LuPanc-1 cells were able to induce TGF-β1 target genes, which is consistent with the absence of DPC4 in LuPanc-2 cells. Both cell lines were able to form spheres in a semi-solid medium and in cell viability assays, LuPanc-1 cells were more sensitive than LuPanc-2 cells to treatment with gemcitabine and FOLFIRINOX. In summary, both patient-derived cell lines show distinct molecular phenotypes reflecting their individual tumor biology, with a unique clinical annotation of the respective patients. These preclinical ex vivo models can be further explored for potential new treatment strategies and might help in developing personalized (targeted) therapy regimens.

In the present study, the binding affinity of 52 bioactive secondary metabolites from Wedelia trilobata towards the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein (PDB: 2W3L) structure was identified by using in silico molecular docking and molecular dynamics simulation. The molecular docking results demonstrated that the binding energies of docked compounds with Bcl-2 protein ranged from -5.3 kcal/mol to -10.1 kcal/mol. However, the lowest binding energy (-10.1 kcal/mol) was offered by Friedelin against Bcl-2 protein when compared to other metabolites and the standard drug Obatoclax (-8.4 kcal/mol). The molecular dynamics simulations revealed that the Friedelin-Bcl-2 protein complex was found to be stable throughout the simulation period of 100 ns. Overall, the predicted Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties of Friedelin are relatively better than Obatoclax, with the most noticeable differences in many parameters where Friedelin has no AMES toxicity, hepatotoxicity, and skin sensitization. The ADMET profiling of selected compounds supported their in silico drug-likeness properties. Based on the computational analyses, the present study concluded that Friedelin of W. trilobata was found to be the potential inhibitor of the Bcl-2 protein, which merits attention for further in vitro and in vivo studies before clinical trials.

Bacterial infections are one of the leading causes of morbidity, mortality, and healthcare complications in patients. Leptospirosis is found to be the most prevalent, re-emergent, and neglected tropical zoonotic disease worldwide. The adaptation to various environmental conditions has made Leptospira acquire a large genome (~4.6 Mb) and a complex outer membrane, making it unique among bacteria that mimic the symptoms of jaundice and hemorrhage. Sph2 is another important virulence factor that enhances hemolytic sphingomyelinase-capable of moving inside mitochondria-which increases the ROS level and decreases the mitochondrial membrane potential, thereby leading to cell apoptosis. In the present study, 25 suspected bovine serum samples were subjected to the Microscopic Agglutination Test (MAT) across the Mysuru region. Different samples, such as urine, serum, and aborted materials from the confirmed MAT-positive animals, were used for isolation and genomic detection by conventional PCR targeting virulence gene, Lipl32, using specific primers. Further, in vitro and in silico studies were performed on isolated cultures to assess the anti-leptospiral, anti-hemolytic, and sphingomyelinase enzyme inhibition using novel pseudopeptides. The microdilution technique (MDT) and dark field microscope (DFM) assays revealed that at a concentration of 62.5 μg/mL, the pseudopeptide inhibited 100% of the growth of Leptospira spp., suggesting its efficiency in the treatment of leptospirosis. The flow cytometry analyses show the potency of the pseudopeptide against sphingomyelinase enzymes using human umbilical vein endothelial cells (HUVECs). Thus, the present study demonstrated the efficacy of the pseudopeptide in the inhibition of the growth of Leptospira , and therefore, this can be used as an alternative drug for the treatment of leptospirosis.

The emerging interest in the field of coordination chemistry and their biological applications has created a novel impact in the field of chemical biology. With this motivation, in this work we have synthesized a novel benzimidazole derived imine ligand, 2-((E)-((1H-benzo[d]-2-yl)methylimino)methyl)-4-fluorophenol ( HBMF ) and its Co(III) and Cu(II) complexes. The metal complexes ( C1 - C4 ) were synthesized in 2:1 ( HBMF : metal ion) and 1:1:1 ( HBMF : metal ion: 1,10-phen) ratios. Structural elucidations of all the synthesized compounds were performed using FT-IR, UV-Visible, NMR, Mass spectroscopy and elemental analysis techniques. A combination of first principles calculations and molecular dynamics simulations was applied to computationally investigate the structural, reactive, and spectroscopic properties of the newly synthesized HBMF ligand and its complexes with copper and cobalt metal ions. Quantum-mechanical calculations in this study were based on the density functional theory (DFT), while molecular dynamics (MD) simulations were based on the OPLS4 force field. The DFT calculations were used to obtain the reactive and spectroscopic properties of the ligand and its complexes, while molecular dynamics (MD) simulations were used to address the ligand's reactivity with water. Further, the in vitro anti-proliferative activity of the compounds was tested against the A549, Ehrlich-Lettre ascites carcinoma (EAC), SIHA and NIH3T3 cell lines. The biological results depicted that the compound C4 , with molecular formula C 27 H 23 Cl 2 CoFN 5 O 3 exhibited profound anti-proliferative activity against the EAC cell line with a significant IC 50 value of 10 µm when compared to its parent ligand and other remaining metal complexes under study. Various assays of hematological parameters (alkaline phosphate, creatinine, urea, RBC and WBC) were performed, and significant results were obtained from the experiments. Furthermore, the effect of C4 on neovascularization was evaluated by stimulating the angiogenesis with rVEGF 165 , which was compared with non-tumor models. The EAC cells were cultured in vivo and administrated with 50 and 75 mg/kg of two doses and tumor parameters were evaluated.

The present work describes the chemical preparation of Schiff bases derived from 4,4'-diaminodiphenyl sulfone (L 1 -L 5 ) and their Co(II) metal complexes. The evaluation of antimicrobial and anticancer activities against MCF-7 cell line and human lung cancer cell line A-549 was performed. The aforementioned synthesized compounds are characterized by spectroscopic techniques and elemental analysis confirms successful synthesis. The results from the above analytical techniques revealed that the complexes are in an octahedral geometry. The antimicrobial activity of the synthesized Schiff base ligands and their metal complexes under study was carried out by using the agar well diffusion method. The ligand and complex interactions for biological targets were predicted using molecular docking and high binding affinities. Further, the anticancer properties of the synthesized compounds are performed against the MCF-7 cell line and human lung cancer cell line A-549 using adriamycin as the standard drug.

The Japanese encephalitis virus (JEV) is the most common cause of neurodegenerative disease in Southeast Asia and the Western Pacific region; approximately 1.15 billion people are at risk, and thousands suffer from permanent neurological disorders across Asian countries, with 10-15 thousand people dying each year. JEV crosses the blood-brain barrier (BBB) and forms a complex with receptors on the surface of neurons. GRP78, Src, TLR7, caveolin-1, and dopamine receptor D2 are involved in JEV binding and entry into the neurons, and these receptors also play a role in carcinogenic activity in cells. JEV binds to GRP78, a member of the HSP70 overexpressed on malignant cells to enter neurons, indicating a higher chance of JEV infection in cancer patients. However, JEV enters human brain microvascular endothelial cells via an endocytic pathway mediated by caveolae and the ezrin protein and also targets dopamine-rich areas for infection of the midbrain via altering dopamine levels. In addition, JEV complexed with CLEC5A receptor of macrophage cells is involved in the breakdown of the BBB and central nervous system (CNS) inflammation. CLEC5A-mediated infection is also responsible for the influx of cytokines into the CNS. In this review, we discuss the neuronal and macrophage surface receptors involved in neuronal death.

The ever-expanding pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has gained attention as COVID-19 and caused an emergency in public health to an unmatched level to date. However, the treatments used are the only options; currently, no effective and licensed medications are available to combat disease transmission, necessitating further research. In the present study, an in silico-based virtual screening of anti-HIV bioactive compounds from medicinal plants was carried out through molecular docking against the main protease (M pro ) (PDB: 6LU7) of SARS-CoV-2, which is a key enzyme responsible for virus replication. A total of 16 anti-HIV compounds were found to have a binding affinity greater than -8.9 kcal/mol out of 150 compounds screened. Pseudohypericin had a high affinity with the energy of -10.2 kcal/mol, demonstrating amino acid residual interactions with LEU141, GLU166, ARG188, and GLN192, followed by Hypericin (-10.1 kcal/mol). Moreover, the ADME (Absorption, Distribution, Metabolism and Excretion) analysis of Pseudohypericin and Hypericin recorded a low bioavailability (BA) score of 0.17 and violated Lipinski's rule of drug-likeness. The docking and molecular simulations indicated that the quinone compound, Pseudohypericin, could be tested in vitro and in vivo as potent molecules against COVID-19 disease prior to clinical trials.This was also supported by the theoretical and computational studies conducted. The global and local descriptors, which are the underpinnings of Conceptual Density FunctionalTheory (CDFT) have beenpredicted through successful model chemistry, hoping that they could be of help in the comprehension of the chemical reactivity properties of the molecular systems considered in this study.

Agricultural residues are suitable to make useful products that can potentially replace the non-biodegradable polymeric materials. In the present work, corn cob and rice S=straw is quantitatively transformed to cellulose by alkali treatment preceded by bleaching. The obtained cellulose is changed into nanocellulose (NC) by the acid hydrolysis method followed by ultrasonication. Further NC was characterized by FTIR to study its functional regions and XRD for crystallinity. Thermal properties have been studied using TGA/DTA. The surface morphology of nanocellulose was done using SEM and TEM. The obtained results revealed remarkable thermal stability, semi-crystalline and fibrous nature of both corn cob and rice straw. The size of the cellulose is in the nanoscale dimension. This work provides the way to utilize corn cob and rice straw as a more useful raw material for many applications.

Herein we describe the synthesis of a series of nickel(II) complexes (C1-C3) with Schiff bases (HL1-HL3) derived from 4-amino-5-mercapto-3-methyl-1,2,4-triazole and ortho/meta/para-nitrobenzaldehyde having composition [Ni(L) 2 (H 2 O) 2 ]. The obtained ligands and their complexes were characterized using physico-chemical techniques viz., elemental analysis, magnetic moment study, spectral (electronic, FT-IR, 1H-NMR) and thermal analysis. The elemental analysis and spectral analysis revealed that Schiff bases behave as monoanionic bidentate ligands towards the Ni(II) ion. Whereas, the magnetic moment study suggested the octahedral geometry of all the Ni(II) complexes. The thermal behavior of the complexes has been studied by thermogravimetric analysis and agrees well with the composition of complexes. Further, the biological activities such as antimicrobial and antifungal studies of the Schiff bases and Ni(II) complexes have been screened against bacterial species ( Staphylococcus aureus and Pseudomonas aeruginosa ) and fungal species ( Aspergillus niger and Candida albicans ) activity by MIC method, the results of which revealed that metal complexes exhibited significant antimicrobial activities than their respective ligands against the tested microbial species. Furthermore, the molecular docking technique was employed to investigate the active sites of the selected protein, which indeed helped us to screen the potential anticancer agents among the synthesized ligand and complexes. Further, these compounds have been screened for their in vitro anticancer activity using OVCAR-3 cell line. The results revealed that the complexes are more active than the ligands.

Inadequate water, sanitation, and hygiene (WASH) among urban poor women is a major urban policy concern in low- and middle-income countries (LMICs). There was a paucity of systematic information on WASH among the urban poor during the pandemic. We reviewed the opportunities and challenges faced by the urban poor in LMICs during the COVID-19 pandemic. We used the PRISMA guidelines to conduct a comprehensive search of 11 databases, including MEDLINE, Embase, Web of Science, and CINAHL, between November 2019 and August 2021. We used thematic analysis to synthesize the qualitative data and meta-analyses to estimate the pooled prevalence. We screened 5008 records, conducted a full-text review of 153 studies, and included 38 studies. The pooled prevalence of shared water points was 0.71 (95% CI 0.37-0.97), non-adherence to hygiene practices was 0.15 (95% CI 0.08-0.24), non-adherence to face masks was 0.27 (95% CI 0.0-0.81), and access to shared community toilets was 0.59 (95% CI 0.11-1.00). Insufficient facilities caused crowding and long waiting times at shared facilities, making physical distancing challenging. Women reported difficulty in maintaining privacy for sanitation, as men were present due to the stay-at-home rule. Due to unaffordability, women reported using cloth instead of sanitary pads and scarves instead of masks.

A hybrid blood-brain barrier (BBB)-on-chip cell culture device is proposed in this study by integrating microcontact printing and perfusion co-culture to facilitate the study of BBB function under high biological fidelity. This is achieved by crosslinking brain extracellular matrix (ECM) proteins to the transwell membrane at the luminal surface and adapting inlet-outlet perfusion on the porous transwell wall. While investigating the anatomical hallmarks of the BBB, tight junction proteins revealed tortuous zonula occludens (ZO-1), and claudin expressions with increased interdigitation in the presence of astrocytes were recorded. Enhanced adherent junctions were also observed. This junctional phenotype reflects in-vivo-like features related to the jamming of cell borders to prevent paracellular transport. Biochemical regulation of BBB function by astrocytes was noted by the transient intracellular calcium effluxes induced into endothelial cells. Geometry-force control of astrocyte-endothelial cell interactions was studied utilizing traction force microscopy (TFM) with fluorescent beads incorporated into a micropatterned polyacrylamide gel (PAG). We observed the directionality and enhanced magnitude in the traction forces in the presence of astrocytes. In the future, we envisage studying transendothelial electrical resistance (TEER) and the effect of chemomechanical stimulations on drug/ligand permeability and transport. The BBB-on-chip model presented in this proposal should serve as an in vitro surrogate to recapitulate the complexities of the native BBB cellular milieus.

This paper shows the novel approach of Taguchi-Based Grey Relational Analysis of Ti6Al4V Machining parameter. Ti6Al4V metal matrix composite has been fabricated using the powder metallurgy route. Here, all the components of TI6Al4V machining forces, including longitudinal force (F x ), radial force (F y ), tangential force (F z ), surface roughness and material removal rate (MRR) are measured during the facing operation. The effect of three process parameters, cutting speed, tool feed and cutting depth, is being studied on the matching responses. Orthogonal design of experiment (Taguchi L9) has been adopted to execute the process parameters in each level. To validate the process output parameters, the Grey Relational Analysis (GRA) optimization approach was applied. The percentage contribution of machining parameters to the parameter of response performance was interpreted through variance analysis (ANOVA). Through the GRA process, the emphasis was on the fact that for TI6Al4V metal matrix composite among all machining parameters, tool feed serves as the highest contribution to the output responses accompanied by the cutting depth with the cutting speed in addition. From optimal testing, it is found that for minimization of machining forces, maximization of MRR and minimization of Ra, the best combinations of input parameters are the 2nd stage of cutting speed (175 m/min), the 3rd stage of feed (0.25 mm/edge) as well as the 2nd stage of cutting depth (1.2 mm). It is also found that hardness of Ti6Al4V MMC is 59.4 HRA and composition of that material remain the same after milling operation.

β3-adrenergic receptor (β3-AR) is expressed predominantly in mature white and brown/beige adipocytes. Although the lipolytic and thermogenic role of β3-AR in brown/beige adipocytes is well defined, the adipogenic role of β3-AR in white adipocytes remains unclear at present. In this study, we investigated the expression and function of β3-AR in differentiating 3T3-L1 cells, murine white preadipocytes. Of note, the expression of β3-AR at the protein and mRNA levels was highly induced in a time-dependent manner during 3T3-L1 preadipocyte differentiation. Interestingly, the results of the pharmacological inhibition study demonstrated the roles of p38 MAPK and PKC in the induction of β3-AR expression in differentiating 3T3-L1 cells. Knockdown of β3-AR led to less lipid accumulation and triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. Furthermore, knockdown of β3-AR resulted in a decrease in not only expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FASN), perilipin A, and leptin but also phosphorylation levels of signal transducer and activator of transcription-5 (STAT-5) during 3T3-L1 preadipocyte differentiation. In summary, these results demonstrate firstly that β3-AR expression is highly up-regulated in p38 MAPK and PKC-dependent manners, and the up-regulated β3-AR plays a crucial role in lipid accumulation in differentiating 3T3-L1 cells, which is mediated through control of expression and phosphorylation levels of C/EBP-α, PPAR-γ, STAT-5, FASN, and perilipin A.

Cancer is one of the leading causes of death worldwide, accountable for a total of 10 million deaths in the year 2020, according to GLOBOCAN 2020. The advancements in the field of cancer research indicate the need for direction towards the development of new drug candidates that are instrumental in a tumour-specific action. The pool of natural compounds proves to be a promising avenue for the discovery of groundbreaking cancer therapeutics. Elaeocarpus ganitrus (Rudraksha) is known to possess antioxidant properties and after a thorough review of literature, it was speculated to possess significant biomedical potential. Green synthesis of nanoparticles is an environmentally friendly approach intended to eliminate toxic waste and reduce energy consumption. This approach was reported for the synthesis of silver nanoparticles from two different solvent extracts: aqueous and methanolic. These were characterized by biophysical and spectroscopic techniques, namely, UV-Visible Spectroscopy, FTIR, XRD, EDX, DLS, SEM, and GC-MS. The results showed that the nanoconjugates were spherical in geometry. Further, the assessment of antibacterial, antifungal, and antiproliferative activities was conducted which yielded results that were qualitatively positive at the nanoscale. The nanoconjugates were also evaluated for their anticancer properties using a standard MTT Assay. The interactions between the phytochemicals (ligands) and selected cancer receptors were also visualized in silico using the PyRx tool for molecular docking.

Researchers are interested in Schiff bases and their metal complexes because they offer a wide range of applications. The chemistry of Schiff bases of heterocompounds has got a lot of attention because of the metal's ability to coordinate with Schiff base ligands. In the current study, a new bidentate Schiff base ligand, N -((1 H -pyrrol-2-yl)methylene)-6-methoxypyridin-3-amine (MPM) has been synthesized by condensing 6-methoxypyridine-3-amine with pyrrole-2-carbaldehyde. Further, MPM is used to prepare Cu(II) and Co(II) metal complexes. Analytical and spectroscopic techniques are used for the structural elucidation of the synthesized compounds. Both MPM and its metal complexes were screened against Escherichia coli , Bacillus subtilis , Staphylococcus aureus and Klebsiella pneumoniae species for antimicrobial studies. Furthermore, these compounds were subjected to in silico studies against bacterial proteins to comprehend their best non-bonded interactions. The results confirmed that the Schiff base ligand show considerably higher binding affinity with good hydrogen bonding and hydrophobic interactions against various tested microbial species. These results were complemented with a report of the Conceptual DFT global reactivity descriptors of the studied compounds together with their biological scores and their ADMET computed parameters.

NAD(P)H:quinone acceptor oxidoreductase-1 (NQO1) is a ubiquitous flavin adenine dinucleotide-dependent flavoprotein that promotes obligatory two-electron reductions of quinones, quinonimines, nitroaromatics, and azo dyes. NQO1 is a multifunctional antioxidant enzyme whose expression and deletion are linked to reduced and increased oxidative stress susceptibilities. NQO1 acts as both a tumor suppressor and tumor promoter; thus, the inhibition of NQO1 results in less tumor burden. In addition, the high expression of NQO1 is associated with a shorter survival time of cancer patients. Inhibiting NQO1 also enables certain anticancer agents to evade the detoxification process. In this study, a series of phytobioactives were screened based on their chemical classes such as coumarins, flavonoids, and triterpenoids for their action on NQO1. The in silico evaluations were conducted using PyRx virtual screening tools, where the flavone compound, Orientin showed a better binding affinity score of -8.18 when compared with standard inhibitor Dicumarol with favorable ADME properties. An MD simulation study found that the Orientin binding to NQO1 away from the substrate-binding site induces a potential conformational change in the substrate-binding site, thereby inhibiting substrate accessibility towards the FAD-binding domain. Furthermore, with this computational approach we are offering a scope for validation of the new therapeutic components for their in vitro and in vivo efficacy against NQO1.

The edible parts of the plants Camellia sinensis , Vitis vinifera and Withania somnifera were extensively used in ancient practices such as Ayurveda, owing to their potent biomedical significance. They are very rich in secondary metabolites such as polyphenols, which are very good antioxidants and exhibit anti-carcinogenic properties. This study aims to evaluate the anti-cancerous properties of these plant crude extracts on human liver cancer HepG2 cells. The leaves of Camellia sinensis , Withania somnifera and the seeds of Vitis vinifera were collected and methanolic extracts were prepared. Then, these extracts were subjected to DPPH, α- amylase assays to determine the antioxidant properties. A MTT assay was performed to investigate the viability of the extracts of HepG2 cells, and the mode of cell death was detected by Ao/EtBr staining and flow cytometry with PI Annexin- V FITC dual staining. Then, the protein expression of BAX and BCl2 was studied using fluorescent dye to determine the regulation of the BAX and BCl2 genes. We observed that all the three extracts showed the presence of bioactive compounds such as polyphenols or phytochemicals. The W. somnifera bioactive compounds were found to have the highest anti-proliferative activity on human liver cancer cells.

Candida albicans , an opportunistic fungal pathogen, frequently colonizes immune-compromised patients and causes mild to severe systemic reactions. Only few antifungal drugs are currently in use for therapeutic treatment. However, evolution of a drug-resistant C. albicans fungal pathogen is of major concern in the treatment of patients, hence the clinical need for novel drug design and development. In this study, in vitro screening of novel putative pyrrolo[1,2-a]quinoline derivatives as the lead drug targets and in silico prediction of the binding potential of these lead molecules against C. albicans pathogenic proteins, such as secreted aspartic protease 3 (SAP3; 2H6T), surface protein β-glucanase (3N9K) and sterol 14-alpha demethylase (5TZ1), were carried out by molecular docking analyses. Further, biological activity-based QSAR and theoretical pharmacokinetic analysis were analyzed. Here, in vitro screening of novel analogue derivatives as drug targets against C. albicans showed inhibitory potential in the concentration of 0.4 µg for BQ-06, 07 and 08, 0.8 µg for BQ-01, 03, and 05, 1.6 µg for BQ-04 and 12.5 µg for BQ-02 in comparison to the standard antifungal drug fluconazole in the concentration of 30 µg. Further, in silico analysis of BQ-01, 03, 05 and 07 analogues docked on chimeric 2H6T, 3N9K and 5TZ1 revealed that these analogues show potential binding affinity, which is different from the therapeutic antifungal drug fluconazole. In addition, these molecules possess good drug-like properties based on the determination of conceptual Density Functional Theory (DFT)-based descriptors, QSAR and pharmacokinetics. Thus, the study offers significant insight into employing pyrrolo[1,2-a]quinoline analogues as novel antifungal agents against C. albicans that warrants further investigation.

Nanoworld is an attractive sphere with the potential to explore novel nanomaterials with valuable applications in medicinal science. Herein, we report an efficient and ecofriendly approach for the synthesis of Nickel oxide nanoparticles (NiO NPs) via a solution combustion method using Areca catechu leaf extract. As-prepared NiO NPs were characterized using various analytical tools such as powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and UV-Visible spectroscopy (UV-Vis). XRD analysis illustrates that synthesized NiO NPs are hexagonal structured crystallites with an average size of 5.46 nm and a hexagonal-shaped morphology with slight agglomeration. The morphology, size, and shape of the obtained material was further confirmed using SEM and TEM analysis. In addition, as-prepared NiO NPs have shown potential antidiabetic and anticancer properties. Our results suggest that the inhibition of α-amylase enzyme with IC 50 value 268.13 µg/mL may be one of the feasible ways through which the NiO NPs exert their hypoglycemic effect. Furthermore, cytotoxic activity performed using NiO NPs exhibited against human lung cancer cell line (A549) proved that the prepared NiO NPs have significant anticancer activity with 93.349 μg/mL at 50% inhibition concentration. The biological assay results revealed that NiO NPs exhibited significant cytotoxicity against human lung cancer cell line (A549) in a dose-dependent manner from 0-100 μg/mL, showing considerable cell viability. Further, the systematic approach deliberates the NiO NPs as a function of phenolic extracts of A. catechu with vast potential for many biological and biomedical applications.

The present work describes a facile and convenient procedure for synthesizing zinc oxide nanoparticles using luteolin isolated from Eclipta alba plant (L-ZnONPs) at room temperature. The formation of as-grown L-ZnONPs was confirmed by X-ray diffraction analysis (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HR-TEM), and selected area electron diffraction (SAED). The Wurtzite structure of ZnO was observed by its hexagonal phases in diffraction patterns. The SEM images revealed the different sizes and morphologies of L-ZnONPs, with diameters between 12 and 25 nm. The HR-TEM result showed that the inter-planar distance between two lattice fringes was 0.262 nm, which coincides with the d-spacing of (002) and (101) lattice planes of the as-obtained material. The anticancer activity of L-ZnONPs against the breast cancer cell line MCF-7 was greater as compared to that of luteolin or ZnO alone. The mechanistic evaluation of such an activity carried out using in silico methods suggested that the anti-breast cancer activity of L-ZnONPs was mediated by polo-like kinase 1 (PLK1) proteins.

Herein, we report the synthesis and characterization of a new Schiff base ligand 3-[[( E )-(3-hydroxyphenyl )- methylidene]amino] -2- methyl - quinazolin - 4 ( 3 H)- one (HAMQ) and its Cd(II), Ni(II), Zn(II), and Cu(II) complexes ( C 1 - C 4 ). The ligand HAMQ was synthesized by reacting 3-hydroxybenzaldehyde and 3-amino-2-methyl-4(3 H)- quinazolinone in a 1:1 molar ratio. The structure of the ligand and its complexes ( C 1 - C 4 ) were evaluated using ultraviolet (UV)-visible (Vis) light spectroscopy, 1 H-NMR, Fourier-transform infrared (FT-IR) spectroscopy, MS, elemental analysis, conductance data, and thermogravimetric analysis (TGA). The characterization results suggested that the bidentate ligand, HAMQ, coordinated to the metal center through the lactum oxygen and the azomethine nitrogen. Moreover, all the metal complexes were analyzed using powder X-ray diffraction studies, which revealed that all of them belong to a triclinic crystal system. The research was supplemented by density functional theory (DFT) studies on the IR and UV-Vis spectra, as well as the chemical reactivity of the HAMQ and its four metallic derivatives making use of conceptual density functional theory (CDFT) by means of KID (Koopmans in DFT) methodology. The synthesized complexes displayed significant in vitro anticancer activity against human cancer cell lines (HeLa and HCT-115).

The increasing interest in developing potent non-toxic drugs in medicine is widening the opportunities for studying the usage of nanostructures in the treatment of various diseases. The present work reports a method for a facile and an eco-friendly synthesis of silver nanoparticles (AgNPs) using Terminalia chebula fruit extract (TCE). The obtained AgNPs was characterized by using different spectroscopic and microscopic techniques. The analysis of the results revealed that the as-obtained AgNPs have spherical morphology with an average diameter of 22 nm. Furthermore, the preliminary bioactivity evaluations revealed that the bio-conjugation of AgNPs, using TCE, significantly enhanced the antibacterial and anti-breast cancer potentials of the latter. The antibacterial activity of the as-prepared AgNPs showed that B. subtilis was more sensitive towards the AgNPs, followed by P. aeruginosa ; while, E. coli and S. mutans showed comparatively minimal sensitivity toward the AgNPs. The IC 50 values of TCE, AgNPs and TCE + AgNPs treatment of MCF-7 were found to be 17.53, 14.25 and 6.484 µg/mL, respectively. Therefore, it can be ascertained that the bio-conjugation may provide a headway with regard to the therapeutic employment of T. chebula , upon mechanistically understanding the basis of observed antibacterial and anticancer activities.

Cell cytotoxicity assays, such as cell viability and lactate dehydrogenase (LDH) activity assays, play an important role in toxicological studies of pharmaceutical compounds. However, precise modeling for cytotoxicity studies is essential for successful drug discovery. The aim of our study was to develop a computational modeling that is capable of performing precise prediction, processing, and data representation of cell cytotoxicity. For this, we investigated protective effect of quercetin against various mycotoxins (MTXs), including citrinin (CTN), patulin (PAT), and zearalenol (ZEAR) in four different human cancer cell lines (HeLa, PC-3, Hep G2, and SK-N-MC) in vitro. In addition, the protective effect of quercetin (QCT) against various MTXs was verified via modeling of their nonlinear protective functions using artificial neural networks. The protective model of QCT is built precisely via learning of sparsely measured experimental data by the artificial neural networks (ANNs). The neuromodel revealed that QCT pretreatment at doses of 7.5 to 20 μg/mL significantly attenuated MTX-induced alteration of the cell viability and the LDH activity on HeLa, PC-3, Hep G2, and SK-N-MC cell lines. It has shown that the neuromodel can be used to predict the protective effect of QCT against MTX-induced cytotoxicity for the measurement of percentage (%) of inhibition, cell viability, and LDH activity of MTXs.

This paper presents a vision sensor-based solution to the challenging problem of detecting and following trails in highly unstructured natural environments like forests, rural areas and mountains, using a combination of a deep neural network and dynamic programming. The deep neural network (DNN) concept has recently emerged as a very effective tool for processing vision sensor signals. A patch-based DNN is trained with supervised data to classify fixed-size image patches into "trail" and "non-trail" categories, and reshaped to a fully convolutional architecture to produce trail segmentation map for arbitrary-sized input images. As trail and non-trail patches do not exhibit clearly defined shapes or forms, the patch-based classifier is prone to misclassification, and produces sub-optimal trail segmentation maps. Dynamic programming is introduced to find an optimal trail on the sub-optimal DNN output map. Experimental results showing accurate trail detection for real-world trail datasets captured with a head mounted vision system are presented., Competing Interests: The authors declare no conflict of interest.

A hybrid learning method of a software-based backpropagation learning and a hardware-based RWC learning is proposed for the development of circuit-based neural networks. The backpropagation is known as one of the most efficient learning algorithms. A weak point is that its hardware implementation is extremely difficult. The RWC algorithm, which is very easy to implement with respect to its hardware circuits, takes too many iterations for learning. The proposed learning algorithm is a hybrid one of these two. The main learning is performed with a software version of the BP algorithm, firstly, and then, learned weights are transplanted on a hardware version of a neural circuit. At the time of the weight transplantation, a significant amount of output error would occur due to the characteristic difference between the software and the hardware. In the proposed method, such error is reduced via a complementary learning of the RWC algorithm, which is implemented in a simple hardware. The usefulness of the proposed hybrid learning system is verified via simulations upon several classical learning problems., Competing Interests: The authors declare no conflict of interest.

This paper proposes an extension of the weak classifiers derived from the Haar-like features for their use in the Viola-Jones object detection system. These weak classifiers differ from the traditional single threshold ones, in that no specific threshold is needed and these classifiers give a more general solution to the non-trivial task of finding thresholds for the Haar-like features. The proposed quadratic discriminant analysis based extension prominently improves the ability of the weak classifiers to discriminate objects and non-objects. The proposed weak classifiers were evaluated by boosting a single stage classifier to detect rear of car. The experiments demonstrate that the object detector based on the proposed weak classifiers yields higher classification performance with less number of weak classifiers than the detector built with traditional single threshold weak classifiers.