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This review focuses on the role of reactive oxygen species (ROS) on the development of type 1 and type 2 diabetes and its treatment with secoisolariciresinol diglucoside (SDG) isolated from flaxseed which is an antioxidant and suppresses phosphoenolpyruvate carboxykinase (PEPCK) gene expression, a ratelimiting enzyme in the gluconeogenesis in the liver. Role of ROS in the development of type 1 diabetes [diabetic prone Bio Breeding (BBdp) rats and streptozotocin-induced diabetic (STZ) rats and type 2 diabetes (Zucker diabetic fatty female rats, ZDF rats)] has been discussed. Oxidative stress has been assessed by measuring serum and pancreatic malondialdehyde (MDA), pancreatic chemiluminescence (pancreatic-CL) and oxygen radical producing activity of white blood cells (WBCCL). Diagnosis of diabetes was made by hyperglycaemia and glucosuria. Incidence of diabetes was 100 % in SDZ rats, 72 % in BBdp rats and 100 % in ZDF rats by the age of 72 days. Development of diabetes was associated with increases in the serum and pancreatic MDA, WBC-CL and pancreatic-CL and glycated haemoglobin (HbA1 c). SDG prevented the development of diabetes by 75 % in STZ rats, by 71 % in BBdp rats and by 20 % at 72 days of age in ZDF rats. However, 80 % of the rats which did not develop diabetes by 72 days of age, developed diabetes later on, suggesting that SDG treatment delays the development of diabetes in ZDF rats. Treatment with SDG decreased the levels of serum and pancreatic MDA, WBC-CL and pancreatic-CL. In conclusion, development of type 1 and type 2 diabetes is mediated through oxidative stress and the prevention or delay in the development of diabetes with SDG could be due to its antioxidant activity and its suppressant effect on PEPCK enzyme. Lignan complex which contains 34 % to 38 % of SDG is effective in lowering serum glucose and HbA1 c in type 2 diabetes in humans.

Current production trends necessitate extensive use of cutting fluids, resulting in adverse climatic changes and increasing industry expenses. Modern manufacturing businesses are looking for new ways to meet the demands for faster machining rates, less waste, and improved product quality while also lowering manufacturing costs. Material removal rate (MRR) and surface roughness (SR) of the work piece machined with coated tools are all evaluated. Cutting speed (CS), pressure flow (PF), and depth of cut(DOC), are the input parameters. An aerosol mixture of air and oil was used to give the least amount of lubrication. To assess the relative performance tuning with the MQL setup, an investigation was conducted. When compared to dry turning, the MQL system for turning super duplex stainless steel UNS 32750 has shown to be more effective. The MQL technique significantly improves cutting performance in terms of increasing tool life and improving machined component quality.

The goal of this research is to create a QCA-based reversible priority encoder. It is one of the most crucial parts of the encoding and decoding process. This novel nanotechnology, known as quantum-dot cellular automata (QCA), shows promise as a foundation for the development of reversible circuits. This paper proposes a simple, reversible, 4-2 line priority encoder design for the QCA platform. Using the simple and cheap Toffoli gate architecture, a reversible encoder circuit may be built. To analyze the proposed designs’ structural soundness, the simulation program QCA Designer is used.

Nearly one third of the population diagnosed with major depressive disorder (MDD) fail to respond to two or more antidepressant drugs of adequate dose and duration. This necessitates identification of confounding psychological and physiological factors that could contribute to treatment resistant depression (TRD). The present longitudinal study investigated the influence of behavioural inhibition system (BIS) and behavioural approach system (BAS) in treatment resistance. Further, the association of depression severity with physiological factors contributing to arterial stiffness was also investigated. Baseline data was acquired from 101 middle-aged (36–56 years) patients on immediate diagnosis with MDD using DSM-V criteria. Follow ups were conducted at 06 months and 12 months during treatment. Psychological assessment battery at baseline and follow ups comprised of Hamilton depression rating (HAM-D) for depression severity, WHODAS-2 and BIS-BAS score. Atherosclerosis and central arterial stiffness were measured by intima-media thickness of internal carotid artery and brachial-ankle pulse wave velocity. Physiological factors influencing central vascular function viz., body-mass index, estimated glomerular filtration rate, HbA1c, central systolic and diastolic blood pressure, heart rate and tetrahydrobiopterin were also investigated. Our results show lower reward responsiveness (BAS-RR) and higher BIS scores in TRD patients along with differentially higher intima-media thickness of left internal carotid artery. Higher depression severity at all stages of the study was correlated with lower tetrahydrobiopterin and BAS-RR scores. We, therefore, suggest that vascular depression resulting due to increased intima-media thickness of left carotid artery and lower tetrahydrobiopterin could be contributing factors for treatment resistance in middle-aged MDD patients.

Abstract Background Macrophages, besides resting latently infected CD4+ T cells, constitute the predominant stable, major non-T cell HIV reservoirs. Therefore, it is essential to eliminate both latently infected CD4+ T cells and tissue macrophages to completely eradicate HIV in patients. Until now, most of the research focus is directed towards eliminating latently infected CD4+ T cells. However, few approaches have been directed at killing of HIV-infected macrophages either in vitro or in vivo. HIV infection dysregulates the expression of many host genes essential for the survival of infected cells. We postulated that exploiting this alteration may yield novel targets for the selective killing of infected macrophages. Methods We applied a pooled shRNA-based genome-wide approach by employing a lentivirus-based library of shRNAs to screen novel gene targets whose inhibition should selectively induce apoptosis in HIV-infected macrophages. Primary human MDMs were infected with HIV-eGFP and HIV-HSA viruses. Infected MDMs were transfected with siRNAs specific for the promising genes followed by analysis of apoptosis by flow cytometry using labelled Annexin-V in HIV-infected, HIV-exposed but uninfected bystander MDMs and uninfected MDMs. The results were analyzed using student’s t-test from at least four independent experiments. Results We validated 28 top hits in two independent HIV infection models. This culminated in the identification of four target genes, Cox7a2, Znf484, Cstf2t, and Cdk2, whose loss-of-function induced apoptosis preferentially in HIV-infected macrophages. Silencing these single genes killed significantly higher number of HIV-HSA-infected MDMs compared to the HIV-HSA-exposed, uninfected bystander macrophages, indicating the specificity in the killing of HIV-infected macrophages. The mechanism governing Cox7a2-mediated apoptosis of HIV-infected macrophages revealed that targeting respiratory chain complex II and IV genes also selectively induced apoptosis of HIV-infected macrophages possibly through enhanced ROS production. Conclusions We have identified above-mentioned novel genes and specifically the respiratory chain complex II and IV genes whose silencing may cause selective elimination of HIV-infected macrophages and eventually the HIV-macrophage reservoirs. The results highlight the potential of the identified genes as targets for eliminating HIV-infected macrophages in physiological environment as part of an HIV cure strategy.

The global COVID-19 pandemic continues with continued cases worldwide and the emergence of new SARS-CoV-2 variants. In our study, we have developed novel tools with applications for screening antivirals, identifying virus–host dependencies, and characterizing viral variants. Using reverse genetics, we rescued SARS-CoV-2 Wuhan1 (D614G variant) wild type (WTFL) and reporter virus (NLucFL) using molecular BAC clones. The replication kinetics, plaque morphology, and titers were comparable between viruses rescued from molecular clones and a clinical isolate (VIDO-01 strain). Furthermore, the reporter SARS-CoV-2 NLucFL virus exhibited robust luciferase values over the time course of infection and was used to develop a rapid antiviral assay using remdesivir as proof-of-principle. In addition, as a tool to study lung-relevant virus–host interactions, we established novel human lung cell lines that support SARS-CoV-2 infection with high virus-induced cytopathology. Six lung cell lines (NCI-H23, A549, NCI-H1703, NCI-H520, NCI-H226, and HCC827) and HEK293T cells were transduced to stably express ACE2 and tested for their ability to support virus infection. A549ACE2 B1 and HEK293TACE2 A2 cell lines exhibited more than 70% virus-induced cell death, and a novel lung cell line, NCI-H23ACE2 A3, showed about ~99% cell death post-infection. These cell lines are ideal for assays relying on live–dead selection, such as CRISPR knockout and activation screens.

This paper describes the detailed digital control of a Distribution Static Synchronous shunt Compensator (DSTATCOM) using a MATLAB embedded coder for compensation to be in command of Voltage Source Converter (VSC) input voltage, reactive power compensation and the power factor improvement of a secondary radial distribution system with a voltage rating of 11kV/415V and with a capacity of 750 kW. The model has been simulated and tested in MATLAB/Simulink using the Simscape tool block set version of MATLAB R2019a. The same is achieved using a 32-bit DSP TMS320F2812 controller programmed with CCS V 6.1 software and tested with MATLAB embedded coder generation using Texas Instrument C2000 processors. Using this embedded code is developed and dumped into the CCS V 6.1. Real and Reactive power control (PQ) and Back Propagation Control Algorithm (BPCA) are the control methods. BPCA controller is based on the elementary extracted biased value of Reactive Power (Q) and Active Power (P) components of load currents. These current values are necessary for the reference source's current estimation. The reference source currents are estimated from the available source currents to generate firing pulses for the PQ and BPCA controllers. The real and reactive power controller is based on the transformation of synchronously rotating load currents in alpha and beta frames. The BPCA-based DSTATCOM is simulated for linear and non-linear load circumstances and that helps in restoring the power system networks sustainability.

This study investigates composites and intermetallic, examining their microstructure, characteristics, and applications. The research demonstrates the complicated link between these materials’ fundamental features and their possible practical applications by analysing mechanical strength, thermal conductivity, microstructure, and reinforcement percent. The study discovers a positive relationship between mechanical strength and thermal conductivity, implying the possibility of capitalising on increased strength for enhanced heat transfer. Furthermore, the impact of matrix phases on mechanical properties emphasises the strategic significance of matrix selection. The impact of reinforcement fraction in fine-tuning characteristics highlights the importance of microstructure as a silent architect affecting material behaviour. In conclusion, this study provides insights into the intricate interaction of material characteristics, opening the way for informed material design and application engineering.

PMMA Composites have become the most popular materials due to its excellent strength-to-weight ratio, graphite reinforced for engineering applications. Researchers have used a variety of reinforcements to enhance the mechanical and tribological characteristics of various polymer matrixes, including carbon fiber, glass fiber, and carbon-based nanoparticles, graphite, alumina, silica, silicon carbide, titanium oxide, bacterial cellulose, Nano-cellulose, and zirconium oxide.This project focuses on the characteristics of composites made with graphite reinforcements that are based on polymethyl methacrylate. Die casting was used to manufacture this reinforced composite. To enhance the mechanical qualities (impact strength and hardness), tribological parameters (slide distance, normal load, and sliding velocity are employed for wear rate). Therefore, in this study, greater focus has been placed on on PMMA-based composites with graphite reinforcement.

Nowadays, the increasing growth of technology contributes various organisations to storing a huge amount of records using web servers in the form of big data. The big database possesses a vast amount of relevant and irrelevant features, and the less significant features are difficult to remove which makes the process time-consuming and more complex. Hence, this paper proposes an optimisation algorithm, named the Taylor Jellyfish Search Optimisation (TaylorJSO) for selecting the relevant features. Here, an optimisation-based deep learning approach called Taylor Jellyfish Search Optimisation-Deep Maxout Network (TaylorJSO-DMN) is introduced to classify big data more effectively by selecting optimal features. In this model, the input database is preprocessed using quantile normalisation and uses the oversampling of imbalanced classes for data augmentation. In the MapReduce framework, the selection of optimal features is performed in the mapper phase, whereas in the reducer phase, the DMN is used for the classification of big data. The DMN is trained using the introduced TaylorJSO algorithm to improve the classification performance of big data classification. Moreover, the TaylorJSO-DMN model attained greater performance with a maximum of 92.5% accuracy, 91.6% sensitivity, and 92.9% specificity than other traditional approaches. [ABSTRACT FROM AUTHOR]

Jamal Moideen Muthu Mohamed,1 Ali Alqahtani,2 Fazil Ahmad,3 V Krishnaraju,2 K Kalpana4 1Department of Pharmaceutical Technology, BIT Campus, Anna University, Tiruchirappalli, Tamil Nadu 620024, India; 2Department of Pharmacology, College of Pharmacy, King Khalid University, Guraiger, Abha 62529, Saudi Arabia; 3Department of Anesthesia Technology, College of Applied Medical Sciences in Jubail, Imam Abdulrahman Bin Faisal University, Jubail, Saudi Arabia; 4Department of Pharmaceutical Analysis, Erode College of Pharmacy, Veppampalayam, Erode, Tamil Nadu 638112, IndiaCorrespondence: Jamal Moideen Muthu MohamedBIT Campus, Anna University, Tiruchirappalli, Tamil Nadu 620024, IndiaTel +91-9080018534Fax +91 431-2407988Email jmuthumohamed@gmail.comBackground: Colorectal cancer (CRC) is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women. Curcumin (CMN) is obtained from a natural source and has no toxicity, even at high doses (8,000 mg/kg body weight in 24 hours) and was determined to have anticancer potency on several kinds of carcinoma. However, its medical applications were limited because of its low solubility and poor bioavailability.Materials and Methods: To improve the medical applications of CMN, various hydrophilic carriers such as poloxamer 407 (PMX-407), poloxamer 188 (PMX-188), Gelucire 50/13 (Gel-50/13), and mannitol (MNL) were used to prepare a binary complex solid dispersion (SD). These binary SDs were characterized for aqueous solubility in various solvents. Physical stability, thermal behaviors, and morphology were determined by Fourier transform infrared spectrophotometric analysis, powder X-ray diffraction analysis, thermogravimetric analysis, differential scanning calorimetric analysis, scanning electron microscopy, dynamic light scattering study, and the novel dyeing test. In vitro drug release was determined by dissolution study. Based on the characterization, the better SD complex was optimized using Box-Behnken design (BBD). The cytotoxicity and apoptosis study of prepared CMN (C-SD) were used to test for colorectal adenocarcinoma cell lines.Results: These results showed that the solubility of CMN is greatly improved after complexation with PXM-407 in SD. CMN is practically insoluble in water at acidic and neutral pH; however, the SD of CMN with PXM-407 produced significant improvement in solubility (1.266± 0.0242 mg/mL) and dissolution (91.36± 0.431% at 30 minutes); similarly, these data fit with a phase solubility study and in silico molecular modeling. Moreover, the solid-state characterization revealed that the SD complex exhibits the intermolecular hydrogen bond with drug and carrier. Also, the complex does not undergo any chemical modification owing to the amorphous form, and the dye test showed better coloring impact indicating the solubility of CMN. The cell cycle arrest confirmed at G2/M phase from flow cytometry analysis, and Western blot investigation was recognized molecular level cell death and the complex induced more exploit DNA during apoptosis.Conclusion: This study confirmed that the ideal stoichiometric ratio of CMN with carrier to enhance its solubility was 1:1. This molecular complex of PXM-407 was found to be more effective against colorectal cancer (CRC) than pure CMN.Keywords: curcumin, phase solubility, MTT assay, colorectal cancer, in silico interaction, dissolution comparison

Neuroendocrine prostate cancer (NEPC) represents a highly aggressive form of prostate tumors. NEPC results from trans-differentiated castration-resistant prostate cancer (CRPC) with increasing evidence indicating that the incidence of NEPC often results from the adaptive response to androgen deprivation therapy. Recent studies have shown that a subset of NEPC exhibits overexpression of the MYCN oncogene along with the loss of tumor suppressing TP53 and RB1 activities. N-MYC is structurally disordered with no binding pockets available on its surface and so far, no clinically approved drug is available. We adopted a drug-repurposing strategy, screened ~1800 drug molecules, and identified fludarabine phosphate to preferentially inhibit the proliferation of N-MYC overexpressing NEPC cells by inducing reactive oxygen species (ROS). We also show that fludarabine phosphate affects N-MYC protein levels and N-MYC transcriptional targets in NEPC cells. Moreover, enhanced ROS production destabilizes N-MYC protein by inhibiting AKT signaling and is responsible for the reduced survival of NEPC cells and tumors. Our results indicate that increasing ROS production by the administration of fludarabine phosphate may represent an effective treatment option for patients with N-MYC overexpressing NEPC tumors.

OBJECTIVE: Alzheimer's disease (AD) is identified by neuropathological symptoms, and there is now no effective treatment for the condition. A lack of the brain neurotransmitter acetylcholine has been related to the etiology of Alzheimer's disease. Acetylcholinesterase is an enzyme that breaks down acetylcholine to an inactive form and causes the death of cholinergic neurons. Conventional treatments were used but had less effectiveness. Therefore, there is a crucial need to identify alternative compounds with potential anti-cholinesterase agents and minimal undesirable effects. MATERIALS AND METHODS: Fluoroquinolones and benzimidazole-benzothiazole derivatives offer antimicrobial, anti-inflammatory, anti-oxidant, anti-diabetic, and anti-Alzheimer activities. To enhance the chemical portfolio of cholinesterase inhibitors, a variety of fluoroquinolones and benzimidazole-benzothiazole compounds were evaluated against acetylcholinesterase (AChE) butyrylcholinesterase (BChE) enzymes. For this purpose, molecular docking and adsorption, distribution, metabolism, excretion, and toxicology ADMET models were used for in-silico studies for both AChE and BChE enzymes to investigate possible binding mechanisms and drug-likeness of the compounds. The inhibitory effect of docked heterocyclic compounds was also verified in vitro against AChE and BChE enzymes. Fluoroquinolones (Z, Z3, Z4, Z6, Z8, Z12, Z15, and Z9) and benzimidazole-benzothiazole compounds (TBIS-16, TBAF-1 to 9) passed through the AChE inhibition assay and their IC50 values were calculated. RESULTS: The compound 1-ethyl-6-fluoro-7-(4-(2-(4-nitrophenylamino)-2-oxoethyl)piperazin-1-yl) -4-oxo-1,4 di-hydroquinoline-3-carboxylic acid and 2-((1H-benzo[d]imidazol-2-yl) methyl)-N'-(3-bromobenzyl)-4-hydroxy-2H-thiochromene- 3-carbohydrazide 1,1-dioxide (Z-9 and TBAF-6) showed the lowest IC50 values against AChE/BChE (0.37±0.02/2.93±0.03 µM and 0.638±0.001/1.31±0.01 µM, respectively) than the standard drug, donepezil (3.9±0.01/4.9±0.05 µM). During the in-vivo investigation, behavioral trials were performed to analyze the neuroprotective impact of Z-9 and TBAF-6 compounds on AD mouse models. The groups treated with Z-9 and TBAF-6 compounds had better cognitive behavior than the standard drug. CONCLUSIONS: This study found that Z-9 (Fluoroquinolones) and TBAF-6 (benzimidazole- benzothiazole) compounds improve behavioral and biochemical parameters, thus treating neurodegenerative disorders effectively. [ABSTRACT FROM AUTHOR]