For over a decade, endoscopic hemostatic powders have been used to manage upper gastrointestinal bleeding (UGIB). Various preclinical benchtop and animal models have been developed to evaluate these devices. Multiple companies have released hemostatic powders to market, assessing their safety and efficacy using an established porcine gastric vessel bleed model. This model simulates an aggressive arterial bleed, allowing prototypes to be tested under challenging conditions. It requires a surgeon to insert an artery segment into the gastric lumen and puncture it to produce a bleed. In our study, we tested a control group not included in prior research. We aimed to evaluate the relationship between intragastric pressure and bleed severity by injecting gas used to deliver hemostatic powder to the bleed site, without administering hemostatic powder. Our results indicate that elevated intragastric pressures alone can cause bleed cessation. Additional findings suggest that other factors in the model can lead to false positive hemostasis. This study highlights flaws in the porcine gastric vessel bleed model and underscores the need to develop more robust models for testing hemostatic devices, as no valid endoscopic bleed model currently exists. These experiments stress the importance of vetting preclinical models before acquiring efficacy data.

The acetylcholinesterase (AChE) inhibitors are the main drugs for symptomatic treatment of neurodegenerative disorders like Alzheimer’s disease. A recently designed, synthesized and tested hybrid compound between the AChE inhibitor galantamine (GAL) and the antioxidant polyphenol curcumin (CU) showed high AChE inhibition in vitro. Here, we describe tests for acute and short-term toxicity in mice as well as antioxidant tests on brain homogenates measured the levels of malondialdehide (MDA) and glutathione (GSH). Haematological and serum biochemical analyses were also performed. In the acute toxicity tests, the novel AChE inhibitor given orally in mice showed LD50 of 49 mg/kg. The short-term administration of 2.5 and 5 mg/kg did not show toxicity. In the ex vivo tests, the GAL-CU hybrid performed better than GAL and CU themselves. In a dose of 5 mg/kg, it demonstrates 25% reduction in AChE activity, 28% and 73% increase in the levels of MDA and GSH, respectively. No significant changes in blood biochemical data were observed. The GAL-CU hybrid is a novel non-toxic AChE inhibitor with high antioxidant activity which makes it a perspective multitarget drug candidate for treatment of Alzheimer’s disease.

Piceatannol is a naturally occurring polyphenolic compound that is widely found in grapes, blueberries, mushrooms, passion fruit and other edible fruits and vegetables. It has a variety of biological activities and pharmacological effects, including anti-inflammatory, antioxidation, antiaging, antiviral, antitumor, anticancer, antiatherosclerosis, antiparasitic, immunoregulatory, and cardiovascular protection effects. The aim of this study was to investigate the antiherpesvirus effects of piceatannol. Pseudorabies virus (PRV) belongs to the family Herpesviridae. PRV has a wide host range and can cause cytopathic effects (CPEs) in PK-15 cells. Therefore, PRV was used as a model to study the antiherpesvirus effect of piceatannol. In this study, we evaluated the antiviral activity of piceatannol against PRV in vitro and in vivo. The results showed that piceatannol could reatrain PRV multiplication in PK-15 cells in a dose-dependent manner. The 50% inhibitory concentration (IC50) was 0.0307 mg/mL, the IC50 was 0.0307 mg/mL, and the selectivity index (SI, CC50/IC50) was 3.68. The addition of piceatannol at different stages of PRV infection inhibited the viral adsorption and intracellular replication phases of PRV. Piceatannol significantly reduced the expression levels of the IE180, EP0, UL29, UL44, US6 and UL27 genes of PRV within 48 h, significantly reduced the expression levels of the PRV gB and gD proteins, and reduced PRV-induced apoptosis. Molecular docking showed that piceatannol had good binding activity with the PRV gB and gD proteins. The results of animal experiments in vitro indicated that piceatannol could delay the onset of disease, improve the survival rate of the mice (14.3%), reduce the viral load in the brain and kidney of the mice, alleviate the pathological changes in the mouse tissues and organs, and increase the levels of TNF-α, IEN-γ and IL-4 in the serum of the mice. These data indicate that piceatannol has good anti-PRV activity in vitro and in vivo, indicating that it could be a novel antiherpesvirus infection agent in the future.

The development of CRISPR associated proteins, such as Cas9, has led to increased accessibility and ease of use in genome editing. However, additional tools are needed to quantify and identify successful genome editing events in living animals. We developed a method to rapidly and quantitatively monitor gene editing activity non-invasively in living animals that also facilitates confocal microscopy and nucleotide level analyses at the end of study. Here we report a new CRISPR “footprinting” approach to activate luciferase and fluorescent proteins in mice as a function of gene editing. This system is based on experience with our prior Cre-detector system and is designed for Cas editors able to target LoxP including gRNAs including SaCas9 and ErCas12a [1, 2]. These CRISPRs cut specifically within LoxP, an approach that is a departure from previous gene editing in vivo activity detection techniques that targeted adjacent stop sequences. In this sensor paradigm, CRISPR activity was monitored non-invasively in living Cre reporter mice (FVB.129S6(B6)-Gt(ROSA)26Sortm1(Luc)Kael/J and Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/J, which will be referred to as LSL and mT/mG throughout the paper) after intramuscular or intravenous hydrodynamic plasmid injections, demonstrating utility in two diverse organ systems. The same genome-editing event was examined at the cellular level in specific tissues by confocal microscopy to determine the identity and frequency of successfully genome-edited cells. Further, SaCas9 induced targeted editing at efficiencies that were comparable to Cre recombinase demonstrating high effective delivery and activity in a whole animal. This work establishes genome editing tools and models to track CRISPR editing in vivo non-invasively and to fingerprint the identity of targeted cells. This approach also enables similar utility for any of the thousands of previously generated LoxP animal models.

Diabetes mellitus is a global health issue that necessitates the development of novel therapeutic approaches. Today numerous experimental methods have been used and set up to evaluate novel drugs with antidiabetic effects. In addition, several research studies have been done to induce diabetes under in vitro and in vivo conditions, but only a small number of these efforts are currently in a usable stage. This review aims to provide useful guidance for researchers who seek to evaluate the antidiabetic potential of drugs, agents, or new medications using the standard methods published by authorities and academics worldwide organizations and research centers. In this review, we collected 132 relevant articles from prominent databases such as PubMed, ScienceDirect, Scopus and others to summarize in vitro and in vivo experimental validation of antidiabetic treatment from 1943 to present.

This literature review was aimed to collect investigations on the in vivo evidences for bacteria associated to fermented dairy foods to behave as probiotics with beneficial effects in the prevention and treatment of various diseases. All main bacterial groups commonly present in high numbers in fermented milks or cheeses were taken into account, namely starter lactic acid bacteria (SLAB) Lactobacillus delbrueckii subsp. bulgaricus and lactis, L. helveticus, Lactococcus lactis, Strepto-coccus thermophilus, non starter LAB (NSLAB) Lacticaseibacillus spp., Lactiplantibacillus plantarum, dairy propionibacteria and other less frequently encountered species. Only studies regarding strains of proven dairy origin were considered. Studies in animal models and clinical studies showed that dairy bacteria ameliorate symptoms of inflammatory bowel disease (IBD), mucositis, metabolic syndrome, aging and oxidative stress, cancer, bone diseases, atopic dermatitis, allergies, infections and damages caused by pollutants, mild stress and depression. Immunomodulation and changes in the intestinal microbiota were the mechanisms most often involved in the observed effects. The results of the studies considered indicated that milk and dairy products are a rich source of beneficial bacteria that should be further exploited to the advantage of human and animal health.

Nociceptive innervation of the thoracolumbar fascia (TLF) has been investigated over decades, however these studies have not been compiled or collectively appraised. The purpose of this scoping review was to assess current knowledge regarding nociceptive innervation of the TLF to better inform future mechanistic and clinical TLF research targeting low back pain (LBP) treatment. PubMed, ScienceDirect, Cochrane and Embase databases were searched in January 2021 using relevant descriptors encompassing fascia and pain. Eligible studies were: (a) published in English; (b) preclinical and clinical (in vivo and ex vivo) studies; (c) original data; (d) included quantification of at least one TLF nociceptive component. Two-phase screening procedures were conducted by a pair of independent reviewers, data were extracted and summarized from eligible studies. The search resulted in 257 articles of which 10 met inclusion criteria. Studies showed histological evidence of nociceptive nerve fibers terminating in low back fascia, suggesting a TLF contribution to LBP. Noxious chemical injection or electrical stimulation into fascia resulted in longer pain duration and higher pain intensities than injections into subcutaneous tissue or muscle. Pre-clinical and clinical research provides histological and functional evidence of nociceptive innervation of TLF. Greater knowledge of fascial neurological components could impact LBP treatment.

During the preclinical research process, multiple factors can be difficult to implement without the careful consideration and planning of each step. As research has become more advanced with the use of increasingly complex technology, animal models have also become essential for understanding the potential impact of devices, drug therapies, and surgical techniques on humans before clinical trials are conducted. The use of an in vivo animal model is a key and necessary step in the progression of preclinical research studies that will lead to future medical inventions and innovation. Here, we describe the three phases of effectively designing a preclinical research protocol: the research, preprocedural planning, and experimental phases. Furthermore, we provide researchers with guidance through these phases and discuss important considerations.

Far-red fluorescent reporter genes can be used for tracking cells non-invasively in vivo using fluorescence imaging. Here, we investigate the effectiveness of the far-red fluorescent protein, E2-Crimson (E2C), for tracking mouse embryonic cells (mESCs) in vivo following subcutaneous administration into mice. Using a knock-in strategy, we introduced E2C into the Rosa26 locus of an E14-Bra-GFP mESC line, and after confirming that the E2C had no obvious effect on the phenotype of the mESCs, we injected them into mice and imaged them over 9 days. The results showed that fluorescence intensity was weak, and cells could only be detected when injected at high densities. Furthermore, intensity peaked on day 4 and then started to decrease, despite the fact that tumour volume continued to increase beyond day 4. Histopathological analysis showed that although E2C fluorescence could barely be detected in vivo at day 9, analysis of frozen sections indicated that all mESCs within the tumours continued to express E2C. We hypothesise that the decrease in fluorescence intensity in vivo was probably due to the fact that the mESC tumours became more vascular with time, thus leading to increased absorbance of E2C fluorescence by haemoglobin. We conclude that the E2C reporter has limited use for tracking cells in vivo, at least when introduced as a single copy into the Rosa26 locus.

Silicon nanoparticles (SiNPs) are highly promising for biological and biomedical applications, including bioimaging, due to their unique opltical properties (i.e. strong fluorescence and very high photostability). Their low or negligible in vitro toxicity has been reported, but in vivo toxicity and biological effects of SiNPs are still uncertain. Uncoated SiNPs were dispersed in distilled water via sonication, and their rapid aggregation was observed (319.0 ± 2.4 nm particle size). In vivo toxicity was studied using Danio rerio embryos and larvae. Rapid aggregation in their incubation medium was observed; besides that, SiNPs at 25 mg/L or higher concentration induced swim bladder malformation and/or death of the fish. The estimated LC50 value for 7-day larvae was 180 mg/L. This is the first in vivo toxicity study of uncoated and unfunctionalized SiNPs. To achieve better stability in biological media and lower toxicity, SiNPs should be covered with hydrophilic layers, but their absorption by cellular membranes may be weaker in this case.

Infections due to Candida spp., they are a threat to global health, with high rates of morbidity and mortality due to their drug resistance, especially in immunocompromised people. Thus, the search for new alternatives is urgent today. In recent years, combined therapy with compounds of natural origin has been proposed as an alternative. Considering the biological potential of isoespintanol (ISO) and continuing with its study, the objective of this research was to assess the effect of ISO in combination with the antifungals, fluconazole (FLZ), amphotericin B (AFB) and caspofungin (CASP), against clinical isolates of C. tropicalis and evaluate the cytotoxic effect of this compound in the acute phase (days 0 and 14) and chronic phase (days 0, 14, 28, 42, 56, 70 and 84), in female mice (Mus musculus) of the Balb/c lineage. The results show that ISO can potentiate the effect of FLZ, AFB and CASP, showing synergism with these antifungals. Evaluation of the mice by direct vision showed no behavioral changes or variation in weight during treatment; furthermore, the analysis of the cytokines IFN-γ and TNF in plasma, peritoneal cavity lavage (PCL) and bronchoalveolar lavage (BAL) indicated that there was no inflammation process and histopathological studies of lung, liver and kidney showed no signs of toxicity caused by ISO; this was consistent with the analysis of oxaloacetic transaminases (GOT) and pyruvic transaminases (GPT), which remained in the standard range. These findings indicate that ISO does not have a cytotoxic effect at the doses evaluated. Our results place ISO as a monoterpene of interest in the search for compounds with pharmacological potential.

The inhibition of alpha-glucosidase and alpha-amylase is one of clinic strategies for remedy the type II diabetes. Herbal medicines are reported to alleviate hyperglycemia. However, the constituents from those sources whether are targeted to the alpha-glucosidase and alpha-amylase still unexplored. This study attempted to select the compounds for efficacy of hypoglycemia via cellular and mouse levels. The results illustrated that the cytotoxicity in all tested compounds at various concentrations except the concentration of 16-hydroxy-cleroda-3,13-dine-16,15-olide (HCD) at 30 µM were not significant difference (p > 0.05) when compared with the untreated control. Acarbose (reference drug), Antroquinonol, Catechin, Quercetin, Actinodaphnine, Curcumin, HCD, Docosanol, Tetracosanol, Berberine, and Rutin could effectively inhibit the alpha-glucosidase activity of Caco-2 cells when compared with the control (maltose). The compounds (Curcumin, HCD, Tetracosanol, Antroquinonol, Berberine, Catechin, Actinodaphnine, and Rutin) could reduce blood sugar level at 30 min in tested mice. The effects of tested compounds on area under curve (AUC) were significant (p < 0.05) among Acarbose, Tetracosanol, Antroquinonol, Catechin, Actinodaphnine, and Rutin along with Berberine and Quercetin. In in vitro (alpha-glucosidase) with in vivo (alpha-amylase) experiments suggest that bioactive compounds can be a potential inhibitor candidate of alpha-glucosidase and alpha-amylase for the alleviation of type II diabetes.

Malassezia is a lipid-dependent genus of yeasts known for being an important part of the skin mycobiota. These yeasts have been associated in the development of skin disorders and cataloged as a causal agent of systemic infections under specific conditions, making them opportunistic pathogens. Little is known about the host-microbe interaction of Malassezia spp., and unraveling this implies the implementation of infection models. In this mini review we present different models that have been implemented in the fungal infections study with greater attention in Malassezia spp. infections. These models range from in vitro (cell cultures and ex vivo tissue), to in vivo (murine models, rabbits, guinea pigs, insects, nematodes, and amoebas). We additionally highlight the alternative models that reduce the use of mammals as model organisms, which have been gaining importance in the study of fungal host-microbe interactions. This is due to the fact that these systems have shown to have reliable results, which correlate with those obtained from mammalian models. Example of alternative models are Caenorhabditis elegans, Drosophila melanogaster, Tenebrio molitor, and Galleria mellonella. These are invertebrates that have been implemented in the study of Malassezia spp. infections in order to identify differences in virulence between Malassezia species.

Disulfiram (DSF), an anti-alcoholism medicine, exerts treatment effects in patients suffering from persistent Borreliosis and also exhibits anti-cancer effects by its copper chelating derivatives. Since chronic/persistent borreliosis is characterized by increased amounts of proinflammatory macrophages, this study investigated opsonin-independent phagocytosis, migration and surface marker expression of in vivo activated human monocyte-derived macrophages and dendritic cells with and without DSF treatment. Phagocytosis of non-opsonized Dynabeads® M-450 and migration of macrophages and dendritic cells were monitored using live cell analyzer Juli™ Br for 24h by imaging every 3.5 min. Results were analyzed by a newly developed software based on the differential phase contrast images of cells before and after ingestion of Dynabeads bearing an electron dense iron core. As a control, phagocytosis was also monitored by visual counting of ingested beads. DSF decreased the phagocytic capacities exhibited by global macrophages and dendritic cells. DSF also impaired the migration of human monocyte-derived macrophages and dendritic cells (hMDMD) and significantly reduced the expression densities of surface antigens CD45 and CD14. In cells consisting of anti-inflammatory M2 macrophages, DSF led to a remarkable cell death and also increased oxidative stress as determined by MitoSox staining. Mitochondrial oxidative stress was a prominent feature in M2 macrophages which were more sensitive to DSF-induced cytotoxicity.

Low efficiency of in vivo transfection of a few fibers revealed a novel tissue network which temporally amplified growth stimulation in the entire regenerating rat soleus muscle. This acupuncture-like effect was demonstrated when the fibers began to grow after complete fiber degradation, synchronous inflammation, myoblast and myotube formation. The first detection of neonatal sarcoplasmic/endoplasmic reticulum ATPase (SERCA1b) has been made in this system. The neonatal, fast and slow SERCA isoforms displayed consequent change with innervation and differentiation, recapitulating events in muscle development. In vivo transfection of myotubes with plasmids expressing dominant negative Ras or a calcineurin inhibitor peptide (Cain/cabin) proved that the expression of the slow myosin heavy chain and the slow muscle type SERCA2a are dif-ferently regulated. In vivo transfection of a few nuclei of myotubes with dnRas or SER-CA1b shRNA stimulated fiber size growth in the whole regenerating muscle but only until the full size had been reached. Growth stimulation by Ras and SERCA1b antisense was abolished in co-transfection with Cain or in case of perimuscular injection with IL4 antibody. This revealed a novel signalling network resembling to scale-free networks which, starting from transfected fiber myonuclei as “hubs”, can amplify growth stimula-tion uniformly in the entire regenerating muscle.

The present work aims to demonstrate that colloidal dispersions of magnetic iron oxide nanoparticles stabilized with dextran macromolecules placed in an alternating magnetic field can not only produce heat, but also that these particles could be used in vivo for local and non-invasive deposition of a thermal dose sufficient to trigger thermo-induced gene expression. Iron oxide nanoparticles were first characterized in vitro on a bio-inspired setup, and then they were assayed in vivo using a transgenic mouse strain expressing the luciferase reporter gene under transcriptional control of a thermosensitive promoter. Iron oxide nanoparticles dispersions were applied topically on the mouse skin or injected sub-cutaneously with Matrigel™ to generate so called pseudo tumors. Temperature was monitored continuously with a feedback loop to control the power of the magnetic field generator and to avoid overheating. Thermo-induced luciferase expression was followed by bioluminescence imaging 6 hours after heating. We showed that dextran-coated magnetic iron oxide nanoparticles dispersions were able to induce in vivo mild hyperthermia compatible with thermo-induced gene expression in surrounding tissues and without impairing cell viability. These data open new therapeutic perspectives for using mild magnetic hyperthermia as non-invasive modulation of tumor microenvironment by local thermo-induced gene expression or drug release.

Background: The identification of novel therapeutic strategies for Ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-Hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with cyste-ine-dependent deubiquitinating enzymes (DUBs), thus affecting the ubiquitin-proteasome de-pendent degradation of proteins. Methods: 2c phenotypic/molecular effects were studied in two OC cell lines, primary tumor cells cultured in 2D/3D and in a mouse xenograft model. We also propose an in-silico model of 2c interaction with DUBs. Finally, we tested the effect of 2c conju-gated to several linkers to generate 2c-derivatives usable for improved drug delivery. Results: 2c effectively impairs OC cell line and primary tumor cell viability in both 2D and 3D conditions. The effectiveness is confirmed in a xenograft mouse model of OC. We show that 2c impairs pro-teasome activity and triggers apoptosis most likely by interacting with DUBs; we propose a mechanism for the interaction with a model DUB via an in-silico evaluation of the en-zyme-inhibitor complex. 2c also reduces cell growth by down-regulating the level of the transcrip-tion factor E2F1. Finally, 2c activity is often retained after the conjugation with linkers. Conclu-sion: Our data strongly support the potential therapeutic value of 2c/derivatives in OC.

The potential of A. baumannii for acquired resistance to last resort antibiotics (colistin and tigecycline) during treatment has important clinical implications, especially when dealing with patients failing to improve despite treatment with an active antimicrobial. However, the relevant literature remains scattered. Therefore, a systematic search was conducted in PubMed and Scopus. Several studies reported emergence of resistance to colistin or tigecycline during treatment, in most cases (86%) resulting in persistent or recurrent infections, especially in cases of emergent resistance without fitness cost. Lipopolysaccharide modification in the case of colistin and overexpression of efflux pumps in the case of tigecycline were the main mechanisms of resistance. Emergent colistin resistance is often associated with fitness cost resulting in re-emergence of the fitter and more virulent colistin susceptible strain after cessation of antibiotic pressure. Prospective studies are needed to determine the frequency of emergent resistance during treatment and its impact on patient outcomes.

This study aimed to develop extended–release tablets containing 25 mg IMM−H014, an original drug formulated by a direct powder pressing method based on pharmaceutical–grade hydrophilic matrix polymers, such as hydroxypropyl methylcellulose, to establish an in vitro−in vivo corre-lation (IVIVC) to predict bioavailability. The tablets’ mechanical properties and in vitro and in vivo performance were studied. The formulation was optimized using a single factor experiment and the reproducibility was confirmed. The in vitro dissolution profiles of the tablet were de-termined in five dissolution media, in which the drug released from the hydrophilic tablets fol-lowed Ritger–Peppas model kinetics in 0.01 N HCl medium for the first 2 h, and in phosphate buffer saline medium (pH 7.5) for further 24 h. Accelerated stability studies (40°C, 75% relative humidity) proved that the optimal formulation was stable for 6 months. The in vivo pharmaco-kinetics study in beagle dogs showed that compared to the IMM−H014 immediate release prep-aration, the maximum plasma concentration of the extended release (ER) preparation was sig-nificantly decreased, while the maximum time to peak and mean residence time were significantly prolonged. The relative bioavailability was 97.9% based on an area under curve, indicating that the optimal formulation has an obvious ER profile. And a good IVIVC was established, which could be used to predict in vivo pharmacokinetics from the formulation composition.

Ceratonia siliqua L. is a medicinal plant that has long been used in traditional Moroccan medicine to treat many diseases. This study aimed to assess the impact of the stages of the immature phase of carob pulp (M1, M2, M3, M4, and M5) on phytochemical composition, antioxidant activity, and antidiabetic activity of Ceratonia siliqua L. The identification of the phenolic profile by HPLC-UV/MS-MS and the study of the antidiabetic effect by in silico, in vitro, and in vivo studies were carried out for extracts with a high content of phenolic compounds from immature wild carob pulp from the communes of Timoulit (TM), Bin Elouidane (AW), and Ouaouizerth (TG) in the province of Azilal in the Beni Mellal-Khenifra region. The results revealed a gradual increase in total sugar content over the pulp's ripening period, reaching a value of 2134 ±56.23 mg GE/100 g fresh matter (FM) for TG. The three locations showed peak values for total polyphenol content (TPC), total flavonoid content (TFC), and total condensed tannin (TCT) at the M2 stage. AW has the highest concentrations of TPC (3819 ± 226.4 mg GAE/100 g FM), TFC (1034 ± 57.08 mg QE/100 g FM), and TCT (1472 ± 28.46 mg CE/100 g FM). The DPPH assay (7892 ± 296.1 mg TE/100 g FM) and the FRAP assay (278.2 ± 7.85 mg TE/100 g FM) both demonstrate that the TG zone is a highly potent antioxidant zone. In contrast, the AW site exhibits a markedly elevated value of 725.4 ± 103.6 mg TE/100 g FM in the ABTS assay. HPLC-UV-MS/MS analysis showed that the methanolic extracts of immature carob pulp (MEICP) from the three areas contained several different chemical compounds. The most prevalent were 3-O-p-coumaroyl-5-O-caffeoylquinic acid, quercetin 3-methyl ether, gallic acid, and galloylquinic acid. Immature carob pulp extract. (ICPE) from AW showed the strongest in vitro inhibition of pancreatic α-amylase (IC50 = 0.405 µg/mL) and TG extracts were most potent against intestinal α-glucosidase (IC50 = 0.063 µg/mL). In vivo, AW, TG, and TM extracts significantly reduced postprandial glycemia in rats, with AW having the greatest effect. These results highlight the antidiabetic potential of ICPE. The 3-O-p-Coumaroyl-5-O-caffeoylquinic acid showed a better affinity for α-amylase compared to acarbose and interacted significantly with several amino acid residues of the enzyme. Similarly, this molecule and 3,4-Dicaffeoylquinic acid demonstrated a strong affinity for α-glucosidase, suggesting their potential as natural inhibitors of enzymes involved in carbohydrate metabolism. Most of the compounds are not substrates of P-glycoprotein and exhibit high intestinal absorption. Furthermore, the majority of these compounds do not act as inhibitors or substrates of CYP450 enzymes, reinforcing their suitability for development as oral medications. These results underscore the potential of immature carob pulp as a promising antidiabetic agent.

Background/Objective: In-vivo diabetes detection of glucose were sought using square-wave anodic stripping voltammetry (SW), with bismuth-immobilized carbon nanotube paste electrode (BCE). Methods: The optimum analytical results indicated sensitive peak signals on the BCE. The raw voltammogram was approached within the 1 mgL^-1-14 mgL^-1 and 10 ugL^-1-140 ugL^-1, detection limits with preconcentration times of 100 and 200 sec. Results: The relative standard deviation was 0.02 % (n = 15) of 10.0 mgL^-1 under optimum conditions. The analytical detection limit (S/N) was attained at 8 ugL^-1. The handmade microsensor was directly used in vivo on the living fish brain and human urine.Conclusion: The method was applied at real time in vivo, without requiring any pretreatment and other ionic electrolyte solutions. It can be used for medicinal and other materials requiring biological-fluid detection in real time. This study was designed to be suitable for real-time unmanned remote diagnosis and therapeutic drug injection into the body, micro-needle long-term administration, wearable artificial skin tattoo sensor, and real-time control. In addition, the glasses monitor was designed to be suitable for multitasking and multi-user control.

In silico prediction of the in vivo efficacy of siRNA ionizable-lipid nanoparticles is desirable yet never achieved before. This study aims to computationally predict siRNA nanoparticles in vivo efficacy, which saves time and resources. A data set containing 120 entries was prepared by combining molecular descriptors of the ionizable lipids together with two nanoparticles formulation characteristics. Input descriptor combinations were selected by an evolutionary algorithm. Artificial neural networks, support vector machines and partial least squares regression were used for QSAR modeling. Depending on how the data set is split, two training sets and two external validation sets were prepared. Training and validation sets contained 90 and 30 entries respectively. The results showed the successful predictions of validation set log(dose) with R2val = 0.86 – 0.89 and 0.75 – 80 for validation sets one and two respectively. Artificial neural networks resulted in the best R2val for both validation sets. For predictions that have high bias, improvement of R2val from 0.47 to 0.96 was achieved by selecting the training set lipids lying within the applicability domain. In conclusion, in vivo performance of siRNA nanoparticles was successfully predicted by combining cheminformatics with machine learning techniques.

Background: One of the main diseases of worldwide concern is non–insulin dependent Diabetes mellitus. 90-95% of patients with diabetes suffers from Type II diabetes, a metabolic diabetes whose prevalence is increasing in the world.Given the current prevalence of diabetes type II in society, research of natural compounds able to regulate glycaemia and insulin–resistance is nowadays covering importance, as alternative or co–adjuvant treatment to existing hypoglycaemic medicines. In pre–clinical steps of research, C. elegans is considered a promising in vivo model for the study of the molecular mechanism of glucose as part of anti–diabetic bioactivity.Most of the studies of insulin resistance with this in vivo model are carried out by using mutant strains such as daf-2 and the effects of the compounds are attributed a posteriori, after a physiological response of the worms rather than directly measuring preservation of activity inside the worm. Methods: The in vitro α-glucosidase inhibition of two oral formulations with Origanum vulgare extract before and after a simulated process of gastrointestinal digestion was evaluated. After confirming the in vitro activity, the α-glucosidase inhibition was tested in vivo through the new method proposed. Results: The crude extract showed an IC50 value similar to acarbose (positive control), before and after the gastrointestinal digestion. The encapsulated extract (111.86±1.25 µg/mL) did not present statistical differences with the positive control (110.10±1.15 µg/mL) after digestion. However, the powder formulation showed the highest hypoglycaemic activity (59.55±0.85 µg/mL).In vivo, the IC50 values showed similar profile than in vitro. Conclusion: A new simple and reliable method has been developed to determine pharmacological activities inside in vivo model C. elegans.The method has been evaluated with a hydroalcoholic extract of O. vulgare. The method is accurate and valid for the quantification of the inhibition of in vivo, allowing the direct attribution of this in vivo hypoglycaemic activity to the treatment. In addition, it opens the door to further research into in vitro pharmacological activities that require an in vivo counterpart.

In the recent years, Cannabis and hemp-based products have become increasingly popular for various applications ranging from recreational use, edibles, beverages to health care products and medicines. The rapid detection and differentiation of phytocannabinoids is, therefore, essential to assess the potency, therapeutic and nutritional values of cannabis cultivars. Here, we implemented the SpiderMass technology for the in vivo detection of cannabidiol acid (CBDA) and tetrahydrocannabinol acid (THCA) and other endogenous organic plant compounds to access distribution gradients within the plants and differentiate cultivars. The SpiderMass system is composed of an IR- laser handheld microsampling probe connected to the mass spectrometer through a transfer tube. The analysis was performed in situ on different plant organs from freshly cultivated Cannabis plants in only a few seconds. SpiderMass analysis easily discriminated the two acid phytocannabinoid isomers by MS/MS and the built statistical models differentiated between four Cannabis cultivars. Different abundancies of acid phytocannabinoids were also found along the plant as well as between different cultivars. All together, these results introduce the direct analysis by SpiderMass as a compelling analytical alternative for forensic and hemp industrial analysis.

Hepatocellular carcinoma (HCC) results in high mortality due to ineffective systemic therapy. Human immortalized cell lines are commonly used to study anti-tumour effects in the context of new anti-tumour therapies and tumour biology. As immortalized cell lines have limited biological relevance and heterogeneity compared to primary cells, patient-derived tumour tissues and corresponding immune cells are the gold standards for studying the complexity of individual tumour entities. However, culturing primary HCC cells has a low success rate. Here, we aimed to establish a reproducible approach to preserve the patient-derived liver cancer cells for in vitro and in vivo studies. The underlying study aimed to establish an in vitro pre-screening platform to test treatment options' effectivity and dosage, e.g., for new substances, autologous modified immune cells, or combined therapies in HCC. We initially employed 15 surgical resection specimens from patients with different HCC entities for isolation and preservation. The isolated liver cancer cells from four HCC-diagnosed patients were used for orthotopic transplantation into the healthy liver of immunodeficient mice, allowing them to grow for six months before human liver cancer cells were isolated and cultured. As a result, we generated and characterized four new primary-like liver cancer cell lines. Compared to immortalized HCC cell lines, freshly generated liver cancer cells displayed individual morphologies and heterogenous protein-level characteristics. We assessed their ability to proliferate, migrate, form spheroids, and react to common medications compared to immortalized HCC cell lines. All four liver cancer cell lines exhibit strong migration and colony-forming characteristics in vitro, comparable to extensively investigated immortalized HCC cell lines. Moreover, the four etiological different liver cancer cell lines displayed differences in the response to 5-FU, Sorafenib, Axitinib and Interferon-alpha treatment, ranking from non-responders to responders depending on the applicated medication. In sum, we generated individual patient-derived liver cancer cell lines suitable for predictive in vitro drug screenings and moreover for xenograft transplantations to realize the in vivo investigation of drug candidates. We overcame the low cultivation success rate of liver cancer cells derived from patients and analyzed their potential to serve a pre-clinical model.

Leptospirosis remains an important worldwide zoonotic disease caused by Leptospira spp affecting human and animals. This research aims to study the virulent-associated secreted proteins (protein secretome) of pathogenic Leptospira interrogans serovar Icterohemorrhagiae strain RGA (Leptospira RGA) transition from the environment to mammalian physiological osmolarity, temperature (37 °C) and carbon dioxide concentration (5% CO2) conditions for 24 h. Mass Spectrometry and bioinformatics approaches, we identified 69 potential secreted proteins from the culture supernatant of the Leptospira RGA isolate. We discovered transporters and porins such as phosphate porin, outer membrane efflux, ompA family protein, and polymer-forming cytoskeletal family protein under hyperosmotic condition. Under heat stress, degradation enzymes included zinc metallopeptidase, M23 family (LA3456, LA0709), Rhs family protein (LA1765), thermolysin metallopeptidase; / hydrolase family (LA1345, LA2501). Oxidative stress response proteins induced by osmolarity and temperature shifts included chaperon GrpE, DnaK (LA3705), antioxidants, i.e., thiol-specific redoxin, and peroxiredoxin (LA2809). In response to the in vivo transition, metabolic and other enzymes involved in energy production (COG:C), amino acid metabolism and transport (COG:E), and lipid metabolism and transport (COG:I), as well as moonlighting proteins functionally binding to plasminogen and fibronectin and regulating transcription, were also discovered. An overview of secreted proteins will supplement our understanding of Leptospira biology and pathogenesis during infection and also in response to environmental stimuli and their potential virulent determinants have the potential for developing leptospirosis vaccines and diagnosis.

Bioactive fractions were isolated from the leaves extract of Kalanchoe pinnata and subjected to scrutiny for their prospective anti-obesity properties. An array of in vitro phytochemical, antioxidant, and enzyme inhibition assays were executed, which dis-cerned fractions F1 and F2 as the most effective fractions. These fractions were sub-sequently studied through in vivo experiments, affirming that F2 as the most potent fraction. Further characterization of F2 was conducted via HPTLC MS-MSn tech-niques. The outcomes demonstrated that F2 produced a notable anti-obesity effect in obese mice, reducing their body weight and lipid metrics, and leading to advanta-geous changes in their organs. An analytical examination of F2 revealed the existence of four principal compounds, which were subsequently subjected to in silco molecular docking and dynamic analysis, confirming their aptitude for binding to selected pro-teins. These findings imply that the utilization of Kalanchoe pinnata leaves could pro-vide a promising therapeutic strategy for the treatment of obesity.

Analysing the human body by direct observation can lead to misinterpretation of underlying trends, whereas in vitro organ models facilitate their understanding. Likewise, in vitro organ models serve as valuable tools for assessing the toxicity of compounds. However, none of the existing models had the features we considered critical for toxicity assessment, so we developed an in vitro liver model for toxicity assessment. We used four different types of primary liver cells: Hepatic sinusoidal endothelial cells, hepatic stellate cells, Kupffer cells and hepatocytes. We cultured them in different combinations of composition and volume of cell medium, hepatocyte proportion of total cells, and addition of extracellular matrix. We added rifampicin, ibuprofen and 5-fluorouracil to this model and observed the microanatomy and physiology changes for a week with preclinical and clinical instruments. Among the different model configurations, we selected the feature combination of the in vitro model that had similar biomarker values to those measured by the clinical instruments used in clinical diagnostics. When we exposed the selected model configuration to rifampicin, ibuprofen and 5-fluorouracil, the viability of Kupffer cells and liver sinusoidal endothelial cells was significantly lower than in the untreated samples. In contrast, we observed negligible viability of hepatocytes compared to the untreated samples. We have built an in vitro liver model that resembles the liver microenvironment and we have analysed it with clinical instrumentation to facilitate the data translation. In this sense, we have established that Kupffer and LSEC cells are suitable candidates for the search for clinical diagnostic markers of liver function.

The Oxford English Dictionary includes 17 definitions for the word “model” as a noun and other 11 as a verb. Therefore, context is necessary to understand the meaning of the word model. For in-stance, “model railways” refer to replicas of railways and trains at a smaller scale and a “model student” refers to an exemplar individual. In some cases, a specific context, like cancer research, may not be sufficient to provide one specific meaning of a model. Even if the context is narrowed, specifically to the research related to the tumour microenvironment, a “model” can be understood in a wide variety of ways, from an animal model, to a mathematical expression. This paper presents a review of the different “models” of the tumour microenvironment grouped by the different def-initions of the word into four categories: model organisms, in vitro models, mathematical models, and computational models. Then, the frequency of different meanings of the word “model” related to the tumour microenvironment is measured from the number of entries in the MEDLINE database of the United States National Library of Medicine at the National Institutes of Health. The frequency of the main components of the microenvironment and the organ-related cancers modelled are also assessed quantitatively with specific keywords. Whilst animal models, in particular xenografts and mouse models are the most common used “models”, the number of entries have been slowly de-creasing. Mathematical models, prognostic and risk models follow in frequency and these have been growing in use.

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) often causes severe viral pneumonia, especially among older individuals and those with underlying health conditions. The C57BL/6 mouse is widely used to develop mouse models of obesity, diabetes, hypertension, and immune disorders, conditions that are associated with increased risk of severe COVID-19. Although many studies using these mouse models have examined the pathogenicity of SARS-CoV-2, COVID-19 pathogenesis remains poorly understood. In vivo imaging analysis using two-photon excitation microscopy is useful for elucidating the pathology of COVID-19, providing pathological insights that are not available from conventional histological analysis. However, there is no reporter SARS-CoV-2 that demonstrates pathogenicity in C57BL/6 mice and emits sufficient light intensity for two-photon in vivo imaging. Here, we generated SARS-CoV-2 expressing the fluorescent protein Venus to facilitate in vivo pathological studies using C57BL/6 mouse models. We generated a mouse-adapted strain of SARS-CoV-2, by performing sequential lung-to-lung passages in BALB/c mice, followed by in C57BL/6 mice. We observed that the C57BL/6-adapted SARS-CoV-2 (named MASCV2-p25) replicated efficiently in the lungs of C57BL/6 mice, causing fatal pneumonia. Histopathologic analysis revealed severe inflammation and infiltration of immune cells in the lungs of MASCV2-p25-infected C57BL/6J mice, not unlike that observed in COVID-19 patients with severe pneumonia. Subsequently, we generated a mouse-adapted reporter SARS-CoV-2 (named MASCV-Venus-p9) by inserting the fluorescent gene Venus into MASCV2-p25, and sequential lung-to-lung passages in C57BL/6 mice. C57BL/6 mice infected with MASCV2-Venus-p9 exhibited severe pneumonia similar to that induced by MASCV2-p25. In addition, two-photon excitation microscopy of the lungs of the infected C57BL/6J mice showed that the infected cells emitted sufficient levels of fluorescence for easy observation. These findings suggest that MASCV2-Venus-p9 will be useful for two photon in vivo imaging studies of the pathogenesis of severe COVID-19 and for the development of therapeutic agents for severe pneumonia.

The World Anti-Doping Agency has prohibited gene doping in the context of progress in gene therapy. There is a risk that the artificial regulation of genes using plasmids could be applied for gene doping. However, no gold standard method to detect this has been established. Here, we aimed to develop a method to detect multiple transgene fragments as proof of gene doping. First, gene delivery model mice as a mimic of gene doping were created by injecting firefly luciferase plasmid with polyethylenimine (PEI) into the abdominal cavity. The results confirmed successful establishment of the model, with sufficient luminescence upon in vivo imaging. Next, multiple transgene fragments in the model were detected in plasma cell-free (cf)DNA, blood-cell-fraction DNA, and stool DNA using the TaqMan-qPCR assay, with the highest levels in plasma cfDNA. Using just a single drop of whole blood from the model, we also attempted long-term detection. The results showed that multiple transgene fragments were detected until 11 days. These findings indicate that the combination of plasma cfDNA or just one drop of whole blood with TaqMan-qPCR assay is feasible to detect plasmid-PEI-based gene doping. Our findings could accelerate the development of methods for detecting gene doping in humans.

Tinnitus is a debilitating auditory disorder commonly described as a ringing in the ears in the absence of an external sound source. Although various risk factors have been reported to be related to the perception of tinnitus, sound trauma is considered the primary cause. Neuronal hyperactivity is one of the potential mechanisms for the genesis of tinnitus and has been identified within major regions of the central auditory system, including the cochlear nucleus (CN) and the auditory cortex (AC). An imbalance of excitatory and inhibitory neu-rotransmission has been attributed to this hyperactivity. However, no study has directly cor-related tinnitus with the extracellular levels of amino acids in the CN and the AC using mi-crodialysis, which reflects the functions of these neurochemicals. In the present study, rats were exposed to either a sham condition or acoustic trauma and then subjected to behavioral confirmation of tinnitus after one month. They were further divided into sham (aged n=6; young n=6), tinnitus-positive (aged n=7; young n=7), and tinnitus-negative (aged n=3; young n=3) groups. In vivo microdialysis was utilized to collect samples from the CN and the AC simultaneously in the same rat. Extracellular levels of amino acids were quantified using high-performance liquid chromatography (HPLC) coupled with an electrochemical detector (ECD). The effects of sound stimulation and age on neurochemical changes associ-ated with tinnitus were also examined. It was found that there were no significant differ-ences in either the basal levels or the sound stimulation-evoked changes of any of the amino acids examined in the CN and the AC, between sham and tinnitus animals. However, the ba-sal levels of serine and threonine exhibited age-related alterations in the AC and significant differences in threonine and glycine levels were observed in the responses to 4 kHz and 16 kHz stimuli in the CN. These results demonstrated a lack of a direct link between extracellu-lar levels of amino acids in the CN and the AC and tinnitus perception in a rat model of tin-nitus. Further studies investigating a wide range of neurochemicals in both auditory and non-auditory brain regions are needed in order to understand tinnitus-related changes in neuro-transmission.

L-17 is a thiadiazine derivative with putative anti-inflammatory, neuroprotective, and antidepressant-like properties. In this study, we applied combined in silico and in vivo electrophysiology techniques to reveal the potential mechanism of action of L-17. PASS 10.4 Professional Extended software suggested that L-17 might have pro-cognitive, antidepressant, and antipsychotic effects. Docking energy assessment with AutoDockVina predicted that the binding affinities of L-17 to the serotonin transporter (SERT) and serotonin receptors 3 and 1A (5-HT3 and 5-HT1A) are compatible to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and selective antagonists of 5-HT3 and 5-HT1A receptors, granisetron and WAY100135, respectively. However, while the binding mechanisms of L-17 to the SERT and 5-HT1A receptor were similar to fluoxetine and WAY100135, its interacting with 5-HT3 receptor might be substantially different from this of granisetron. Acute administration of L-17 led to dose-dependent inhibition of firing activity of 5-HT neurons of the dorsal raphe nucleus. This inhibition was partially reversed by subsequent administration of WAY100135. Based on both in silico and in vivo electrophysiology assessments, we suggest that L-17 is a potent 5-HT reuptake inhibitor and a putative partial agonist of 5-HT1A receptors. As such, L-17 in particular and thiadiazine derivatives, in general, might be a representative of a new class of antidepressant drugs. Since L-17 also possesses neuro- and cardioprotective properties, it can be useful in affective illness developing due to the general medical condition, such as post-stroke and post-myocardial infarction (MI) depression.

There is a growing need for novel in vitro corneal models to replace animal-based ex vivo test in drug permeability studies. In this study we demonstrate a corneal mimetic that models the stromal and epithelial compartments of human cornea. Human corneal epithelial cells (HCE-T) were grown on top of a self-supporting porcine collagen-based hydrogel. Cross sections of the multilayers were characterized by histological staining and immunocytochemistry of zonula occludens-1 protein (ZO-1) and occludin. Furthermore, water content and elastic properties of the synthetized collagen type I-based hydrogels were measured. The apparent permeability coefficient (Papp) values of a representative set of ophthalmic drugs were measured and correlated to rabbit cornea Papp values found in the literature. Multilayered structure of HCE-T cells and expression of ZO-1 and occludin in full thickness of multilayer were observed. The hydrogel-based corneal model exhibited excellent correlation to rabbit corneal permeability (r=0.96), whereas insert-grown HCE-T multilayer was more permeable and the correlation to the rabbit corneal permeability was lower (r=0.89). The hydrogel-based human corneal model predicts the rabbit corneal permeability more reliably in comparison to HCE-T cells grown in inserts. This in vitro human corneal model can be successfully employed for drug permeability tests whilst avoiding ethical issues and reducing costs.

Despite past efforts towards therapeutical innovation, cancer remains a highly incident and lethal disease, with current treatments many times lacking efficiency and leading to severe side-effects. Hence, it is imperative to develop new, more efficient, and safer therapies. Bee venom has proven to have multiple and synergistic bioactivities, including antitumor effects. Nevertheless, some toxic effects have been associated with its administration. To tackle these issues, in this work, bee venom-loaded niosomes were developed, for cancer treatment. The vesicles had a small (150.4 ± 3.7 nm) and homogeneous (PDI of 0.162 ± 0.008) particle size, and revealed good therapeutic efficacy in in vitro gastric, colorectal, breast, lung, and cervical cancer models, with GI50 values between 12.37 ng/mL and 14.72 ng/mL. Additionally, they also revealed substantial anti-inflammatory activity, with an IC50 of 28.98 ng/mL, effects that have been reported to be complementary to direct antitumor activity. Finally, the niosomes' safety was assessed, both in vitro, on skin, liver and kidney cells, and ex vivo, in a HET-CAM assay, and results showed that compound encapsulation increased its safety. Hence, small and homogeneous bee venom-loaded niosomes were successfully developed, with substantial anticancer and anti-inflammatory effects, making them potentially promising primary or adjuvant cancer therapies.

This work presents the possibility of using a synthetic membrane for pretracing mucosal penetration studies. The permeability of two types of membranes, porcine oral mucosa and a synthetic Nuclepore membrane, to water was compared. Moreover, the water permeability of membranes modified with waterproofing formulations was measured to study their ability to protect against the penetration of viruses, toxins, etc. A very good correlation was obtained between the transmucosal water loss (TMWL) values of the artificial membrane and the mucosa. These results support the possible use of this synthetic membrane in the screening of the water permeability of formulations. In addition, studies of the permeation of different actives, drugs and biocides through the two membranes were carried out, and these results were compared with their skin permeation data. The synthetic membrane does not seem to discern between compounds in terms of permeability, which could be due to the lack of lipids in the composition of this synthetic membrane. Therefore, Nuclepore alone cannot be used as a model for the release of actives. Additionally, the permeation of caffeine through intact or modified membranes incorporating waterproofing formulations was also studied. In this case, similar permeation profiles through the synthetic membrane and mucosa were found. The results from these assays should lend support to the use of this synthetic membrane when screening formulations to be applied in oral penetration studies.

Preeclampsia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation that is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to variability and unpredictability of disease manifestation when studied in animal models. After preeclampsia, both mothers and offspring have a higher risk of cardiovascular disease (CVD) including myocardial infarction or heart attack and heart failure (HF). Myocardial infarction is an acute myocardial damage that can be treated through reperfusion, however, that therapeutic approach leads to ischemic/reperfusion injury (IRI) often leading to HF. In this review, we compared the current in vivo, in vitro and ex vivo model systems used to study preeclampsia, IRI and HF. Future studies aiming at evaluating CVD in preeclampsia patients could benefit from novel models that better mimic the complex scenario described in this article.

Pandemic human influenza detections are dependent on complex, time-consuming DNA molecular amplifications that require sophisticated PCR electrophoresis, cell culture amplification and complex spectrophotometric absorption techniques. In this study, simplified rapid electrochemical sensing methods were sought via a remote cyclic voltammetry and stripping amplifier circuit using our workstation systems. A sensing probe was prepared using human DNA and a Covid 19 antigen immobilized antibody sensing amplifier with rapid accumulation time of 30 sec. Optimal experimentation was performed using a telematics WiFi wearable circuit equipped with a bioelectrochemical analyzer-2 amplifier three electrode system. Diagnostic accumulation voltammetry and cyclic redox scanning were attempted at -2.0V~2.0V potential windows and 0.2V/Sec scan rate. Anodic and cathodic real time assay was performed using saliva swab from female patients that tested negative and positive. Diagnostic results are expected to be useful for non-contact analysis and for rapid personal testing anytime, anywhere.

The article presents the issues related to the operation and modelling of the ship main propulsion steam boiler. Such objects are used widely in seagoing ships especially the very large crude oil carriers as a main propulsion turbine feed. The advantages of such along with simple construction thus great reliability make oil feed boilers an excellent source of power for chosen type of the large ships. It must be pointed out that a lot of research work was done in the previous years regarding automatic control of boiler automation but since then this technology was not in the focus of the researchers. In the future the fossil fuels will become less important than they are now, but the control techniques of boilers would eventually change due to different fuel parameters therefore, development of such is necessary. The article presents the results of research collected in real ship boilers during their operation and then, based on the results, a digital model of such an object was created. This model was implemented into Hardware-In-Loop which is the initial step for preparing the full model (including sensors etc.) of a steam heated boiler. Theoretical background along with chosen simulation and experimental results of control implemented into HIL were presented to validate assumptions...

In this paper, we propose a new mathematical model based on the association between susceptible and recovered individual, where the association between susceptible and recovered individual is disturbed by white noise. This model is based on demographic changes and is used for long term behavior. We study the stability of equilibria of the deterministic model and prove the conditions for the extinction of diseases. Then, we investigate and obtain the critical condition of the stochastic epidemic model for the extinction and the permanence in mean of the disease with the white noise. To verify our results, we present some numerical simulations for real data related to disease.

Obesity, a chronic disorder of global prevalence, is associated with major health problems leading to mortality. Because of the presence of diverse types of bioactive molecules in plants, attention is being concentrated on the exploration of plant-based drugs to treat the disease. Inhibition of pancreatic lipase by the natural compounds in plants is one of the popular mechanisms for the management of obesity. The current study investigates the mechanism of the anti-obesity effect of the ethanol extract of seeds of Syzygium cumini seeds and roots of Dioscoria bulbifera in fatty diet-induced obese white albino Wister rats (age 8-9 weeks, average weight 110±8 gm). The total phenolic substances present in the ethanol extract of S. cumini was 103.79±3.45 and that of and D. bulbifera was 69.31 ± 2.99 mg GAE/g of dry extract. Correlating the phenolic contents, we also got the DPPH antioxidant activity of the plant extracts. The IC50 value of ethanol extract of S. cumini, D. bulbifera and standard Butyrated hydroxyl toluene (BHT) was found to be 93.03±6.23, 177.13±7.52, and 10.84±0.92 µg/mL, respectively. The body weight of fatty diet-induced rats was significantly reduced by S. cumini, D. bulbifera ethanol extract with a dose of 500 mg/kg bw during 12 weeks of treatment. The anti-obesity effect of the plant extracts is comparable to that of Orlistat with a dose of 10 mg/kg bw. The Orlistat at a concentration of 0.1 mg/ml could be able to inhibit 95.71% activity of Porcine pancreatic lipase while the ethanol extract of S. cumini, D. bulbifera with a concentration of 1.0 mg/ml showed 60.84% and 54.59% of anti-lipase activity. Moreover, the increased TG, LDL and cholesterol in HFD induced rats were significantly reduced by the plant extract as well as Orlistat. Molecular Docking study reveals that quercetin and isoquercetin bind with the rat lipase enzyme at the same site as that of orlistat with high affinity. Taken together, we can conclude that the ethanol extracts of causes anti-obesity effect by inhibiting the pancreatic lipase enzyme.

Songorine (SON) is a diterpenoid alkaloid from Aconitum plants. Preparations of Aconitum roots have been employed in traditional oriental herbal medicine, however, their mechanisms of action are still unclear. Since GABA-receptors are possible brain targets of SON, we investigated which subtypes of GABA-receptors contribute to the effects of SON, and how SON affects anxiety-like trait behavior and psychomotor cognitive performance of rats. First, we investigated the effects of microiontophoretically applied SON alone and combined with GABA-receptor agents picrotoxin and saclofen on neuronal firing activity in various brain areas. Next, putative anxiolytic effects of SON (1.0-3.0 mg/kg) were tested against the GABA-receptor positive allosteric modulator refer-ence compound diazepam (1.0-5.0 mg/kg) in the elevated zero maze (EOM). Furthermore, basic cognitive effects were assessed in a rodent version of the psychomotor vigilance task (PVT). Local application of SON predominantly inhibited the firing activity of neurons. This inhibitory effect of SON was successfully blocked by GABA(A)-receptor antagonist picrotoxin but not by GABA(B)-receptor antagonist saclofen. Similar to GABA(A)-receptor positive allosteric modulator diazepam, SON increased the time spent by animals in the open quadrants of the EOM without any signs of adverse psychomotor and cognitive effects observed in the PVT. We showed that, under in vivo conditions SON acts as a potent GABA(A)-receptor agonist and effectively decreases anxiety without observable side effects. The present findings facilitate the deeper understanding of the mechanism of action and the widespread pharmacological use of diterpene alkaloids in various CNS indications.

In an era characterized by technological disruption and unprecedented challenges posed by the COVID-19 pandemic, this scholarly investigation explores the role of Artificial Intelligence (AI) in shaping Leadership Dynamics in Higher Education Institutions (LDHE) within the specific socio-cultural and regulatory environment of China. Utilizing Structural Equation Modeling (SEM) as operationalized through the SMART_PLS software, this research harnessed data from a robust sample of 381 key stakeholders in China higher education. The study's empirical findings indicate a noteworthy impact of AI-informed decision-making processes on LDHE, which was further mediated by the variable of AI Literacy among leadership. Moreover, the consequences of the ongoing pandemic served as a moderating factor in this relationship. These nuanced outcomes not only contribute to the theoretical discourse surrounding educational leadership and technological integration but also provide actionable insights for policy formulation and institutional strategies in an increasingly complex educational landscape.

Chlamydia trachomatis (CT) is an obligate intracellular bacterial pathogen known to cause trachoma, sexually transmitted infections, and reactive arthritis. The more serious sequelae of these diseases, blindness from trachoma and pelvic inflammatory disease from chlamydial STD are immunopathological responses to chronic infections. With the abundance of dendritic cells in CT infection sites and their central importance in immune regulation, the susceptibility of dendritic cells to CT infection was investigated in vitro. CT (serovar F) was grown and extracted from HeLa 229 cells for infection of human dendritic cells (DCs). Human DCs were generated from peripheral blood mononuclear cells in the presence of GM-CSF and IL-4. Infected DCs were harvested at 0, 4, 24, and 48 h after infection and immunostained. Results from fluorescence microscopy showed that DC can be infected and can support the growth of CT in vitro. Intracellular elementary and reticulate bodies of CT were detected, and reticulate bodies were shown to multiply over the 48 h-cycle in DC. At 48 h, intracellular elementary bodies were detected in some DCs. These results may provide new insights into the possible participation of DC in sustaining chronic or latent infection, or even dissemination of CT infection to other sites.

CAMx-LPiG (Comprehensive Air Quality Model with Extensions – Linear Plume in Grid) is an online hybrid model, based on the Chemistry and Transport Model (CTM) CAMx, that includes a sub-grid scale module to simulate the dispersion of linear road traffic emissions, called LPiG. LPiG is a plume in grid module specifically developed by extending the capabilities of the Lagrangian puff sub-grid model available in CAMx. The online integration of the local scale model within the Eulerian CTM allows for a multiscale simulation of air quality from the regional scale to the urban scale, preserving a coherent description of the chemical state of the atmosphere at all spatial scales and avoiding any double counting of the emissions simulated by the sub-grid module. In this work the model is presented and evaluated against measured NO2 concentrations for the city of Milan for the month of January 2017. The model is able to introduce road traffic induced gradient in NO2 concentration at sub-grid resolution. Moreover, CAMx-LPiG is shown to reduce the bias compared to CAMx stand-alone simulations.

To address the deficiency of existing relation extraction models in effectively extracting relational triplets pertaining to railway traffic knowledge in Tibet, this paper constructs a Tibet Railway Traffic text dataset and provides an enhanced relation extraction model. The proposed model incorporates subject feature enhancement and relational attention mechanisms. It leverages a pre-trained model as the embedding layer to obtain vector representations of text. Subsequently, the subject is extracted and its semantic information is augmented using an LSTM neural network. Furthermore, during object extraction, the multi-head attention mechanism enables the model to prioritize relations associated with the aforementioned features. Finally, objects are extracted based on the subjects and relations. The proposed method has been comprehensively evaluated on multiple datasets, including the Tibet Railway Traffic text dataset and two public datasets. The results on the Tibet dataset achieves an F1-score of 93.3\%, surpassing the baseline model CasRel by 0.8\%, indicating a superior applicability of the proposed model. On the other hand, the model achieves F1-scores of 91.1\% and 92.6\% on two public datasets, NYT and WebNLG, respectively, outperforming the baseline CasRel by 1.5\% and 0.8\%, which highlights the good generalization ability of the proposed model.

We have recently shown that the sphere-in-contact model can be used as an educational and research tool in various contexts, such as the visualization of carbon structures (e.g. graphene, carbon nanotubes, carbon nanocones and graphite), heterogeneous catalysts, metal nanoparticles and organic molecules. In this communication we present how it can be used to model the adsorbate structure of a monoatomic element on the hexagonal close-packed surface of the metal. We have used atoms of varying radius to represent the metal surface atoms and the adsorbate atoms. The study reveals that many surface symmetries are possible for a fixed adsorbate coverage by the movement of the adsorbate atoms in response to surface adsorbate-adsorbate repulsions. The movement of the particles (e.g. particle diffusion) can be seen directly in the model and this is caused by the user intervention. This has great educational but also research value as one can directly see how the adsorbate atoms reorder on the surface of a metal. We believe that this model will be useful in the rational design of catalytic materials and materials coatings with new technological applications.

Vitamin D3 deficiency is a global phenomenon, which can be coped with supplementation and food fortification. However, vitamin D3 bioaccessibility may depend on factors, such as matrix composition and interactions throughout the gastrointestinal tract. This research focused on the effect of different matrices on vitamin D3 content during digestion, and the effect of pH on its bioaccessibility. The INFOGEST protocol was employed to simulate digestion. Three different types of commercial supplements, two foods naturally rich in vitamin D3, and three fortified foods were investigated. High-Performance Liquid Chromatography was used to determine the vitamin D3 initial content in supplements and foods, as well as after each digestion stage. Results indicated that foods exhibited higher bioaccessibility indices compared to supplements, and a higher percentage retention at the end of the gastric phase. The pH study revealed a positive correlation between increased gastric pH and the corresponding content of vitamin D3. Interestingly, exposing the matrix to low pH during the gastric phase resulted in an increased intestinal content of D3. Vitamin D3 is more bioaccessible from foods than supplements, and its bioaccessibility is susceptible to changes in gastric pH. Fasting conditions (i.e. gastric pH=1) enhances vitamin’s bioaccessibility.

The poor success rate of preclinical drugs which target the nervous system is related to the highly complex nature of brain physiology and pathophysiology. For in vitro drug screening in this field, the two-dimensional (2D) approach - where cells are incubated in a monolayer - is not physiologically relevant. In contrast, in vivo rodent models are very low throughput and expensive. As such, improved, well-characterised three dimensional (3D) in vitro models should be employed to bridge the gap between 2D in vitro primary screening and rodent models by incorporating aspects of the in vivo brain environment. These key features include the extracellular matrix (ECM) and a multidimensional relationship of supporting cells. In this study, a neural progenitor cell line was differentiated into the main types of cells found in brain, including neurons and astrocytes. This model was designed in a 3D extracellular matrix replacement in a minimalised manner. Different culture formats using multi-well plates were explored and a high-throughput cellular imaging platform was applied. Next, we applied this model to assess neural toxicity of a newly synthesised dual-specificity tyrosine-regulated kinase 1 (DYRK1) inhibitor derived from natural compounds, which is structurally related to a natural DYRK1A inhibitor harmine, K04179. Chemical studies have already shown that K04179 has higher specificity to DYRK1A compared with previously reported DYRK1 inhibitors, such as INDY. We have produced the first report of the biological effects of this new compound on the new 3D minimalised mid-brain model with quantification of both neuronal and astrocyte populations in tandem, revealing differential toxic effects of DYRK1 inhibitor compounds K04179 and INDY on neurons and glia.

Free-of-charge HCV screening in some key populations and in 1969–1989 birth cohorts have been funded in Italy as the first step to diagnosing individuals unaware of their infection. The aim of this study is to use available in-hospital routine screening data to understand the inpatients HCV screening in a region of North Italy. A retrospective search of in-hospital patients tested for HCV-antibody (HCV-Ab) from January 2017 to the end of December 2022, was conducted according to age categories (older than 76 years, birth group 1947-1968; birth group1969-1989 and two other categories with patients younger than 33 years) using the TriNetX network. Of 42,805 in-hospital patients tested, 1,297 (3.03%) resulted HCV-Ab positive. The proportion decreased from 2017 to 2022 (from 2.03% to 0.36%) years). The higher prevalence of HCV-Ab was in patients older than 76 years (5.3%) while, the lowest was in the younger birth cohort (2000-2022, 0.16%). Of 1,297 patients found HCV-Ab positive, only 198 (15.3%) were tested for the presence of HCV RNA. Although the birth cohort 1969-1989 had a lower seroprevalence (1.5%), they represented the most affected age group with 44.4% of HCV RNA positivity. The in-hospital HCV screening including birth cohort 1947-1989 could be a valuable option respect to the screening for birth group 1969-1989 in the general population. Since a high proportion of patients were not tested for HCV RNA during hospitalization, reflex testing promptly ascertaining an active infection could facilitate linkage to care to stop the burden of HCV.

Generating executable code from natural language instructions using Large Language Models (LLMs) poses challenges such as semantic ambiguity and understanding task- specific contexts. To address these issues, we propose a system called DemoCraft, which enhances code generation by leveraging in-context learning and demonstration selection, combined with latent concept learning. Latent concept learning introduces additional concept tokens, which are trainable embeddings that capture task-specific knowledge. We then test our system on two major datasets: MBPP and HumanEval. Our experimental results demonstrate that the proposed system achieves an approximate 2x increase in the pass@k metric compared to baseline models. Furthermore, we introduce two novel evaluation metrics: correctness@k and similarity@k. Our empirical studies indicate that our system attains nearly a 3x improvement in these metrics as well.

We continue in this paper to illustrate the implications of the Dual Model of Liquids (DML) by deriving the expression for the isochoric specific heat as function of the collective degrees of freedom available at a given temperature and analyzing its dependence on temperature. Two main tasks will be accomplished. First, we show that the expression obtained for the isochoric specific heat in the DML is in line with the experimental results. Second, the expression will be compared with the analogous one obtained in another theoretical dual model of the liquid state, the Phonon Theory of Liquid Thermodynamics. This comparison will allow to get interesting insights about the number of collective degrees of freedom available in a liquid and on the value of the isobaric thermal expansion coefficient, two quantities that are related to each other in this framework.

Software-In-The-Loop (SITL) simulation tools have been extensively used in development of safety-critical software. Utilizing these tools substantially accelerates software development eliminating potential risks and resource costs of physical experiments. This paper investigates the effects of model specific parameters on the development and testing of custom module in PX4 SITL environment. Models of a fixed-wing unmanned aerial vehicle with vertical takeoff and landing capabilities and steerable sensor platform/gimbal are used as case study for this investigation. The effects of parameters of these aerial vehicle and sensor platform models are taken into consideration in the development of custom module that controls the dynamics of steerable sensor platform mounted on the vehicle model. The work also presents steps necessary to customize PX4 SITL and Gazebo simulation environment to incorporate parameters of the vehicle and sensor platform models in the development and testing process of custom module. Based on these instances, simulation results are obtained and discussed. The results show that reliability of PX4 SITL simulation framework is justified by proper customization and integration of PX4 SITL and Gazebo simulator.

Aggregation of the protein α-Synuclein (αSyn) is a hallmark of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple systems atrophy, and alleviating the extent of αSyn pathology is an attractive strategy against neurodegeneration. The engineered binding protein β-wrapin AS69 binds monomeric αSyn. AS69 reduces primary and secondary nucleation as well as fibril elongation in vitro. It also mitigates aSyn pathology in a mouse model based on intrastriatal injection of aSyn pre-formed fibrils (PFF). Since the PFF-based model does not represent all aspects of PD, we tested here whether AS69 can reduce neurodegeneration resulting from αSyn overexpression. Human A53T-αSyn was overexpressed in the mouse Substantia nigra (SN) by using recombinant adeno-associated viral vector (rAAV). AS69 was also expressed by rAAV transduction. Behavioral tests and immunofluorescence stainings were used as outcomes.Transduction with rAAV-αSyn resulted in αSyn pathology as reported by phospho-αSyn staining and caused degeneration of dopaminergic neurons in the SN. The co-expression of rAAV-AS69 did not reduce αSyn pathology or degeneration of dopaminergic neurons. We conclude that αSyn monomer binding by rAAV-AS69 was insufficient to protect from aSyn pathology resulting from αSyn overexpression.

This study investigates how students' well-being relates to sustainable development and education for sustainability at Prince Mohammad Bin Fahd University, Saudi Arabia. The authors endeavor to answer the question "How Does Students' Well-Being Relate to Sustainable Development Via Education for Sustainable Development?" and four sub-questions. Primary data were collected by semi-structured interviews exploring the viewpoints of twenty female and male students (n=26) aged between 18 and 26. The content analysis results have identified additional well-being and education for sustainability factors that influence sustainable education and, therefore, sustainable development. These antecedents include workload, transparency, grading criteria, fairness, belonging, work-life balance, mental health support, missing emotional intelligence factors, factors related to Education for Sustainable Development, such as instructors' role models, institutional commitment, leadership, and collaboration with government. In addition, the study developed a theoretical model for the relationship between antecedents for Education for Sustainable Development, Education for Sustainable Development, and Sustainable Development in the Saudi context. Finally, the study answers four research questions: What factors contribute to education for sustainable development? What are the antecedents of education for sustainable development? How do university educators contribute to sustainable education? How do the antecedents of education for sustainable development, education for sustainable development, and sustainable development relate?

This review article deals with the pathways of cellular and global molybdate distribution in plants, especially with a full overview for the model plant Arabidopsis thaliana. In its oxidized state as bioavailable molybdate, molybdenum can be absorbed from the environment. Especially in higher plants, molybdenum is indispensable as part of the molybdenum cofactor (Moco), which is responsible for functionality as a prosthetic group in a variety of essential enzymes like nitrate reductase and sulfite oxidase. Therefore, plants need mechanisms for molybdate import and transport within the organism, which is accomplished via high-affinity molybdate transporter (MOT) localized in different cells and membranes. Two different MOT-families were identified. Especially legumes like Glycine max or Medicago truncatula have an increased numbers of MOT1-family members for supplying their symbionts with molybdate for nitrogenase activity. In Arabidopsis thaliana especially, the complete way of molybdate through the plant is traceable. Not only the uptake from soil by MOT1.1 and its distribution to leaves, flowers and seeds by MOT2-family members was identified, but also inside the cell the transport trough the cytoplasm and the vacuolar storage mechanisms depending on glutathione were described. Finally, supplying the Moco biosynthesis complex by MOT1.2 and MOT2.1 was demonstrated.

Mutations in epidermal growth factor receptor (EGFR) occur in about 48% of Asian and 19% of Western patients with lung adenocarcinoma (LUAD), leading to its constitutive activation and subsequent uncontrolled cell proliferation. To counteract this, tyrosine kinase inhibitors (TKIs) have been developed, targeting EGFR activity. However, the emergence of metastases and resistance mutations often undermines the durability of the treatment response. Knowledge-based mechanistic models that replicate existing clinical trial outcomes, tailored to specific population characteristics, provide invaluable assistance in designing future clinical trials. These models are particularly effective in identifying optimal responders to specific treatments, thereby enhancing therapeutic efficacy. We have developed physiologically based pharmacokinetic (PBPK) models for gefitinib and osimertinib, representing two distinct generations of EGFR TKIs, to accurately simulate the drugs’ distribution within the primary tumor and metastatic sites following oral administration. These models were integrated with a pathophysiological mechanistic model of EGFR-mutant LUAD, enabling the representation of the effects of both gefitinib and osimertinib on EGFR activation-induced signaling pathways. This comprehensive model outputs detailed evolutions of the primary tumor and each metastatic site, facilitating the evaluation of patient progression in alignment with RECIST guidelines (version 1.1). Notably, the model encapsulates the heterogeneity within the tumor, through the representation of various subclones, each characterized by unique mutation profiles, thereby reflecting differential responses to treatment. Calibration of the model was achieved using publicly available data from the NEJ002 and FLAURA clinical trials. Rigorous visual predictive checks and statistical tests were employed to ensure the proper behavior of the model. The model adeptly replicated the time to progression observed in real clinical trials in EGFR-mutant LUAD patients receiving gefitinib or osimertinib as first-line therapy. In addition, the model was able to reproduce the results from a retrospective study comparing gefitinib and osimertinib, a study that was not used to inform the model. With a consistent virtual population as a reference, the combined model facilitated a comparative analysis of the efficacy of both treatments, thereby underscoring its utility in evaluating therapeutic strategies. The faithful replication of real-world data significantly enhances the credibility of our model, rendering it a vital investigational tool for deriving pertinent insights and informing treatment strategies, particularly in identifying optimal responders to various generations of EGFR TKIs. Following its consecutive prospective validations in the FLAURA2 and MARIPOSA trials, the model is poised to facilitate the generation of synthetic control arms in future clinical trials. This advancement promises a more nuanced analysis of covariate relationships, especially when comparing investigational treatments to established standards of care. Additionally, it potentially reduces the required patient cohort size in such trials, optimizing resource utilization.

An extension of the models used to generate fractal traffic flows is presented by means of the formulation of a model that considers the use of one-dimensional chaotic maps. Based on the disaggregation of the temporal series generated by the model, a valid explanation of behavior of the values of Hurst exponent is proposed and the feasibility of their control from the parameters of the proposed model is shown.

We compare Chiral Perturbation Theory (ChPT) and the Linear Sigma Model (LSM) as realizations of low energy QCD for light mesons in a chirally imbalanced medium. The relations between the low-energy constants of the Chiral Lagrangian and the corresponding constants of the Linear Sigma Model are established as well as the expressions for the decay constant of $\pi $-meson in the medium and for the mass of the $a_0$. In the large $N_c$ count taken from QCD the correspondence of ChPT and LSM is remarkably good and give a solid ground for search of chiral imbalance manifestation in pion physics. A possible experimental detection of chiral imbalance (and therefore a phase with Local Parity Breaking) is outlined in the charged pion decays inside the fireball.

The Model-View-Controller (MVC) architecture, a cornerstone of modern software engineering, offers a robust framework for developing dynamic user interfaces. This paper conducts a broad analysis of MVC’s deployment across various sectors, emphasizing its critical role in technological advancement and market integration. By examining implementation strategies in web development, mobile applications, and enterprise solutions, the study illustrates how MVC enhances application manageability, promotes efficient code reuse, and facilitates parallel development. The paper explores the adoption of MVC principles within major technologies such as Java, .NET, and JavaScript frameworks, underlining its widespread acceptance. Additionally, the analysis covers the preferential use of MVC frameworks within diverse market sectors including technology enterprises, educational institutions, e-commerce, and financial services, which leverage MVC for superior data management and user experience. Emerging trends such as the shift towards the Model-View-ViewModel (MVVM) architecture and the integration of MVC with artificial intelligence and machine learning technologies are also discussed. This comprehensive review not only reaffirms MVC’s enduring relevance but also its adaptive evolution in response to emerging technological demands and market needs.

Non-alcoholic fatty liver (NAFLD) is a metabolic disorder related with a chronic lipid accumulation within the hepatocytes. This disease is the most common liver disorder worldwide and it is estimated that is present in up to 25% of the world's population. However, the real prevalence of this disease and the associated disorders is unknown mainly because reliable and applicable diagnostic tools are lacking. It is known that the level of albumin, a pleiotropic protein synthetized by hepatocytes, is correlated with the correct function of the liver. The development of a complementary tool that allow the direct, sensitive, and label-free monitoring of albumin secretion in hepatocyte cell culture can provide insight about the mechanism and drugs action in NAFLD. With this aim, we have developed a simple integrated plasmonic biosensor based on gold nanogratings from periodic nanostructures present in commercial Blu-ray optical disc. This sensor allows the direct and label-free monitoring of albumin in a 2D fatty liver disease model under flow conditions using highly specific polyclonal antibody. This technology avoids both the amplification and blocking steps showing a limit of detection within pM range (≈ 0.39 ng/mL). Thanks to this technology, we identified the optimal fetal bovine serum (FBS) concentration to maximize the lipid accumulation within the cells. Moreover, we discovered that at third day from lipids challenge, the hepatocytes increased the amount of albumin secreted. These data demonstrate the ability of hepatocytes to respond to the lipid stimulation releasing more albumin. Further investigation needed to unveil the biological significance of that cell behaviour.

The classical Lotka-Volterra predator-prey model is globally stable and uniformly persistent. However, in real-life biosystems extinction of species due to stochastic effects is possible. In this paper, we consider the classical Lotka-Volterra predator-prey model under stochastic perturbations. For this model, using an analytical technique based on the direct Lyapunov method and a development of the ideas of R.Z. Khasminskii, we find the precise sufficient conditions for the stochastic extinction of one and both species and the precise necessary conditions for the stochastic system persistence. The stochastic extinction occurs via a process known as the stabilization by noise of the Khasminskii type, and, in order to establish the sufficient conditions for extinction, we found the conditions for the stabilization. The analytical results are illustrated by numerical simulations. {\bf Keywords:} stochastic perturbations, white noise, Ito's stochastic differential equation, the Lyapunov functions method, stability in probability, stabilization by noise, stochastic extinction, persistence.

Much remains to be understood for delayed ultraweak photon emission (UPE) from organism in association with oxidative burst following external perturbation, a phenomenon that has been experimented for over three decades. Delayed UPE often decays hyperbolically; yet, it is not uncommon to have delayed UPE that reveals first-order kinetic patterns characterized by single-exponential, double exponential, or multi-exponential changes. Some delayed UPEs also presented transient patterns that are characteristic of second-order responses. A soliton-based photon-storage model has addressed the hyperbolic decaying pattern of delayed UPE; however, there are questions outstanding regarding modeling other non-hyperbolic kinetics as well as the large range of temporal scales of delayed UPE that can vary from 8.5 microseconds to many hours. This work proposes an alternative, phenomenological model-framework for interpreting the various kinetic patterns of delayed UPE following stress. The delayed UPE is considered to be governed by two sequential phases: a stress-transfer phase that transforms the external stress to photo-genesis for emitting photons, and a photon-diffusion phase that transmits the photons emitted by the photo-genesis to the surface of organism for being detected as delayed UPE. Time-resolved photon diffusion analysis reveals that any delayed UPE in organism with a delay time >100ns cannot be addressed by the inherent temporal spread that realistic tissue scattering will cause. A slow stress-transfer phase is thus required to explain the delay time-scales of delayed UPE at a minimum of 8.5 µs as reported experimentally. The stress-transfer phase is hypothesized to carry the following types of responses: single or multiple 1st-order low-pass, single 2nd-order low-pass with various damping factors, and single 2nd-order band-pass with various damping factors. A single 1st–order low-pass response with a time-varying kinetic rate is also analyzed. The responses of these modeled pathways to bolus and step inputs demonstrate that a kinetic pattern other than the exact single-exponential one may have multiple causes.

Large volume bone defect regeneration is complex and demands time to complete. Several regeneration phases with unique characteristics including immune responses follow, overlap, and interdepend on each other and, if successful, lead to the regeneration of the organ bone's form and function. However, during traumatic, infectious, or neoplastic clinical cases, the intrinsic bone regeneration capacity may exceed, and surgical intervention is indicated. Scaffold-guided bone regeneration (SGBR) has recently shown efficacy in preclinical and clinical studies. To investigate different SGBR strategies over periods of up to 3 years we have established a well characterized large segmental tibial bone defect ovine model, for which we have developed and optimized immunohistochemistry (IHC) protocols. We present an overview of the immunohistochemical characterization of different experimental groups in which all ovine segmental defects were treated with a bone grafting technique combined with a three-dimensionally printed medical-grade polycaprolactone-tricalcium phosphate (mPCL-TCP) scaffold. The qualitative data set is based on osteoimmunological findings gained from IHC analyses of over &gt;350 sheep surgeries over the past two decades. Our systematic and standardized IHC protocols enabled us to gain further insight into the complex and long-drawn-out bone regeneration processes, which ultimately proved to be a critical element for successful translational research.

The relaxation process of lithium batteries caused by load variation is considered. It is shown that such processes have strong dependence on internal physical and chemical processes and battery technical conditions. Theoretical expressions of the relaxation process caused by a step-like load variation have been obtained for 1^st and 2^nd order equivalent electrical circuits. The experimental investigations show that the obtained models fit the real relaxation processes and the behavior of the identified parameters could be explained by specific features of physical and chemical processes within the lithium battery. It should be noted that the obtained results can be generalized for a different type of electrochemical power source. The proposed approach makes it possible to provide means for electrochemical power source characterization and diagnostic, the main advantages of which are good time localization of measurement procedures and inexpensive apparatus implementation.

The Double U-pipe ground heat exchanger, recognized for its straightforward process, cost-effectiveness, high heat exchange efficiency, and low thermal resistance, stands as the predominant ground heat exchanger type in today's shallow geothermal energy development and utilization. Recent years have seen significant research into the heat transfer influencing factors and heat exchange performance of Double U-pipe ground heat ex-changers via experimental testing methods. Yet, studies integrating numerical simulation with in-situ testing have been less frequent. Drawing on the cylindrical heat source model theory and the outcomes of regional in-situ thermal response tests, this paper develops a Double U-pipe ground heat transfer model by establishing physical, mathematical, and heat transfer geometric models. It assesses the impact of varying inlet temperatures, flow rates, and initial ground temperatures on heat exchange efficiency under heating conditions. The results validate the precision of the double U-pipe ground heat exchanger model based on in-situ testing. They show that enhancing the temperature differential between the inlet and initial temperatures, elevating the initial ground temperature, and moderately increasing the flow rate can boost the system's heat exchange efficiency.

Background: We aimed to create a model of radiological and pathological criteria able to predict the upgrade rate of low-grade ductal carcinoma in situ (DCIS) to invasive carcinoma, in patients undergoing vacuum-assisted breast biopsy (VABB) and subsequent surgical excision. Methods: 3100 VABBs were retrospectively reviewed among which we reported 295 low-grade DCIS who subsequently underwent surgery. The association between patients’ features and the upgrade rate to invasive breast cancer (IBC) was evaluated by univariate analysis. Finally, we developed a predictive multivariable model based on the features which were significantly associated with the univariate analysis outcome. Results: the upgrade rate to invasive carcinoma was 10.8 %. At univariate analysis, the risk of upgrade was significantly lower in the absence of post- biopsy residual lesion (p<0.001), age > 50 (p=0.029), and in presence of low-grade DCIS only in specimens with microcalcifications (p=0.002). According to the final multivariable model, the predicted probability of diagnostic underestimation for a patient with all the three favourable features selected at univariate analysis was 1% (95% CI: 0.3%-4%). Conclusions: An easy to use predictive model of radiological and pathological criteria is able to identify patients with low-grade carcinoma in situ with low risk of upstaging to infiltrating carcinomas.

In this paper, we introduce a control method for the linear quadratic tracking (LQT) problem with zero steady-state error. It is achieved by augmenting the original system with an additional state representing the integrated error between the reference and actual outputs. In its essence, it is a linear quadratic integral (LQI) control embedded in a general LQT control framework, with the reference trajectory generated by a linear exogenous system. During the simulative implementation for the specific real-world system Car-in-the-Loop (CiL) test bench, we assume that the 'real' system is completely known. Therefore, for the model-based control, we can have a perfect model identical to the 'real' system. It becomes clear that stable solutions can scarcely be achieved with controller designed with the perfect model of the 'real' system. Contrary, we show that a model learnt via Bayesian Optimization (BO) can facilitate a much bigger set of stable controllers. It exhibits an improved control performance. To the best of the authors' knowledge, this discovery is the first in the LQT related literature.

This paper proposes a methodology for multi-criteria calibration of a thermo-mechanical model for numerical simulation of welding in vacuum. A finite element model of a steel plate is created. Experimental and computational data are obtained. An inverse problem is formulated for the vector identification of five calibration parameters from the heat flow model. They are evaluated for adequacy with controlled accuracy according to four criteria. An optimization problem is solved using a two-step interactive procedure. The parameter space studying method (PSI) has been applied to the study of multidimensional regions by means of quasi-uniform sounding. A Pareto-optimal set is defined. It is used to determine reduced ranked Pareto subsets by -selection. Salukvadze optimum is also determined.

Developing short-term forecasting model for global atmospheric temperature and wind in the near space is crucial for understanding atmospheric dynamics and supporting human activities in this region. While numerical models have been extensively developed, deep learning techniques have recently shown promise in improving atmospheric forecasting accuracy. In this study, convolutional long short-term memory (ConvLSTM) and convolutional gated recurrent unit (ConvGRU) neural networks were applied to build for short-term global-scale forecasting model of atmospheric temperature and wind in the `near space based on the MERRA-2 reanalysis dataset from 2010-2022. The model results showed that the ConvGRU model outperforms the ConvLSTM model in the short-term forecast results. The ConvGRU model achieved a root mean square error in the first three hours of approximately 1.8 K for temperature predictions, and errors of 4.2 m/s and 3.8 m/s for eastward and northward wind predictions, respectively.

Background and Objective: Intimate relationships hold significant importance during emerging adulthood. This study aimed to investigate the critical determinants of perceived well-being in friendship relationships during emerging adulthood.Method: Using a quantitative approach, a sample of 726 undergraduate students from the Ferdowsi University of Mashhad were selected through convenience sampling. They completed the Interpersonal Behaviors Questionnaire (IBQ), the Compassionate and self-image goals scale (CSIGS), the Basic Need Satisfaction in Relationships Scale (BNS-RS), the Interpersonal Needs Questionnaire (INQ-10), Friendship Self-Regulation Questionnaire (SRQ-F), Interpersonal Behaviors Questionnaire-Self (IBQ-self), State Level Subjective Vitality Scale (SVS-SL), the Perceived Relationship Quality Component (PRQC), and the Basic Empathy Scale (BES). Data analysis was conducted using Partial Least Squares Structural Equation Modeling (PLS-SEM).Results: The results indicated that the critical determinants in predicting perceived well-being in friendship relationships were, in order, goals in friendship relationships, friendship self-regulation, perceived support of basic psychological needs by friends, satisfied basic psychological needs, frustrated psychological needs, and supporting the basic psychological needs of friends.Conclusion: The findings demonstrate that self-determination theory (SDT) provides a coherent framework for explaining perceived well-being in friendships.

To both survive and develop continuously, enterprises must overcome many kinds of competition and challenges. Cultivating employees' active and sustainable organizational citizenship behavior is important for enterprises to successfully cope with turbulence and uncertain events during their development. In this study, we investigated the development level of and factors influencing employees' organizational citizenship behavior in current organizations. By using the Belief in a Just World Scale, Organizational Citizenship Behavior Scale, and Interpersonal Intelligence Scale, we investigated 230 employees from 15 different enterprises. The results showed that belief in a just world, interpersonal intelligence, and organizational citizenship behavior were significantly positively correlated. Interpersonal intelligence played a moderating role between belief in a just world and organizational citizenship behavior; the organizational citizenship behavior of individuals with high interpersonal intelligence increased with the strengthening of the belief in a just world, and this increase was larger than that experienced by individuals with low interpersonal intelligence. This meant that under a certain level of belief in a just world, a high level of interpersonal intelligence was more conducive to promoting employees' sustainable organizational citizenship behavior.

Circulating tumor cells (CTCs) in the peripheral blood are the precursors to distant metastasis but the underlying mechanisms are poorly understood. This study aims at understanding the molecular features within CTCs in relation to their metastatic potential. Using in vitro CTC models, in which breast cancer cell lines are cultured in non-adherent conditions simulating the microenvironment in the blood stream, we found that suspension culture resulted in resistance to TNF-related apoptosis inducing ligand (TRAIL)-mediated cell death. Such a resistance was directly correlated with a reduction in surface and total levels of DR5 protein. In the non-adherent state, cells underwent rapid autophagic flux characterized by an accumulation of autophagosome organelles. Notably, DR5 was translocated to autophagosomes and underwent lysosomal degradation. Our data suggest that CTCs may evade TNF cytokine mediated immune surveillance through downregulation of DR expression. The data warrants further studies in cancer patients to find the status of DRs and other molecular features within primary CTCs in relation to disease progression or chemoresistance.

In this article, we analyse the determinants of Regulatory Quality-RQ for 193 countries in the period 2011-2020. We use a database from ESG-Environment Social Governance of the World Bank. We apply OLS, Panel Data with Fixed Effects and Panel Data with Random Effects. We found that the variables that have the most positive impact on RQ, among others, are “GHG Net Emission”, “Mean Drought Index”, and “Heat Index”. We also found that the variables that have the most negative impact on RQ are among others “Renewable Energy Consumption”, “Voice and Accountability” and “Rule of Law”. Furthermore, we have applied the k-Means algorithm optimized with the Elbow Method and we find the presence of five clusters. In adjunct, we confront eight machine learning algorithms to predict the value of RQ and we found that the best predictor is Polynomial Regression. The predictive level of RQ for the analysed countries is expected to diminish of -1,29%. In the end, we present a network analysis with the Euclidean distance and we found the presence of a structure of seven networks using augmented data.

Background &amp; Aim: Drug sustainability (DS) is a surrogate marker for treatment efficacy. We aimed to compare the DS of two main biologics used to treat moderate-to-severe ulcerative colitis (UC), infliximab (IFX) and vedolizumab (VDZ), in a real-world setting. Methods: We conducted a retrospective cohort study at a tertiary medical center in Israel. We included patients treated between Dec 1st, 2017, and May 1st, 2021, who were followed for up to 300 weeks. DS was defined as corticosteroid, surgical, and hospitalization-free treatment. Results: 217 patients with UC were included. VDZ had a significantly longer median DS of 265.6 weeks compared to IFX's 106.5 weeks (p=0.001) in treatment-naïve patients, even when adjusting for disease severity (HR 0.55 95 CI 0.3-0.98, p=0.042). In treatment-experienced patients, DS was comparable between IFX and VDZ (p=0.593). Conclusion: VDZ showed significantly longer DS in treatment-naïve patients with UC compared to IFX, also when adjusted for disease severity. There was no difference in DS between VDZ and IFX in treatment-experienced patients and patients switching from one drug to another. VDZ may be a suitable first-line treatment for biologic-naïve patients with moderate-to-severe UC.

Background: Cancer has been one of the most critical health problems during the past decades which require serious consideration, especially in developing countries. Methods: 80 parents of the children with different types of cancers were studied via both questionnaire and person-to-person interview after announcing their informed consent. Results: The highest delay in patients' initial referral was due to the following factors: lack of attention or ignoring the first symptoms, delay in referring to the physician, low economic status and even lack of family support for the patient. In addition, visiting several doctors after the initial diagnosis, uncertainty about the first proposed method, and high cost of treatment can be mentioned as the main causes of delays in the start of treatment. Conclusion: Education plays an important role in identifying the signs of cancer. In addition, proper relationship and cooperation between the health system and physicians as well as provision of adequate information to patients could lead to the long-term cooperation of these patients in continuing their treatment.

Recruitment is a fundamental aspect of Human Resource Management to drive organizational performance. Traditional recruitment processes, with manual stages, are time-consuming and inefficient. Artificial Intelligence (AI), which demonstrates its potential in various sectors such as healthcare, education and notable cases of ChatGPT, is currently reshaping recruitment by automating tasks to improve efficiency. However, in Thailand, where there is a growing demand for talents, the application of AI in recruitment remains relatively limited. This research focuses on human resources (HR) and recruitment professionals in Thailand, aiming to understand their perspectives on the integration of AI in recruitment. It extended the Unified Theory for Acceptance and Use of Technology (UTAUT) model, customized to suit the specific requirements of Thai recruitment practices. The study explores the factors influencing users' intention to adopt AI in recruitment. Survey questionnaire items were created based on prior literatures and refined with insights from HR and recruitment experts to ensure applicability in the context of recruitment in Thailand. A survey involving 364 HR and recruiting professionals in Bangkok metropolitan area supplied comprehensive responses. The research reveals that several factors, including Perceived Value, Perceived Autonomy, Effort Expectancy, and Facilitating Conditions, significantly impact the intention to adopt AI for recruitment. While Social Influence and Trust in AI Technology do not have a direct influence on intention, Social Influence directly affects Perceived Value. Trust in AI Technology positively influences Effort Expectancy. This study provides valuable benefits for HR and recruitment professionals, organizations and AI developers by offering insights into AI adoption and sustainability, enhancing recruitment processes and promoting the effective use of AI tools in this sector.

Recently, several research groups have reported on anomalous enhancement of the self-field critical currents, Ic(sf,T), at low temperatures in superconductor/Dirac-cone material/superconductor (S/DCM/S) junctions. Some papers attributed the enhancement to the low-energy Andreev bound states arising from winding of the electronic wave function around DCM. In this paper, Ic(sf,T) in S/DCM/S junctions have been analyzed by two approaches: modified Ambegaokar-Baratoff and ballistic Titov-Beenakker models. It is shown that the ballistic model is an inadequate tool to analyze experimental data from S/DCM/S junctions. The primary mechanism for limiting superconducting current in S/DCM/S junctions is different from the conventional view that the latter is the maximum value within the order parameter phase variation. Thus, there is a need to develop a new model for self-field critical currents in S/DCM/S systems.

Current article presents the study of psychological wellbeing of adolescents (n=168, age 15-17) gifted in math, humanities and sports and educated in advanced programs for gifted children. Theoretical framework of this study is eudemonic concept of psychological wellbeing by C. Ryff. Psychological wellbeing is measured with Ryff wellbeing scales in Russian adaptation by L.V. Zhukovskaya and E.G. Troshikhina. The study is aimed at understanding differences in psychological wellbeing of gifted teenagers connected to gender and type of giftedness. The results suggest that general wellbeing score did not differ for adolescents with different types of giftedness or of different genders. Separate components of psychological wellbeing, such as purpose in life and self-acceptance, are influenced by activity connected to the talent. Gender differences are subjected to age-specific trends of personal development in adolescence. Type of giftedness might reinforce these trends.

The temporo-spatial theory of consciousness postulates that the brain implements its own inner time and space for conscious processing of outside world. In line with this hypothesis, I present a mechanistic model of mutually connected processes that encode the inner space and time. The model is used to elaborate the binding mechanism between two sets of processes representing the inner space and time, respectively. Further, a stochastic version of the model is developed to investigate the interplay between the binding strength and noise. The spectral entropy is used to characterize the noise effects on the systems of processes when the binding strength is varied. The stochastic modeling results reveal that the spectral entropy values for strongly bound systems have similar entropy values for weakly bound or even decoupled systems. Thus, the analysis performed in this study allows to conclude that the binding mechanism is noise-resilient.

Abstract: The objective of these studies was to determine the dependence of the distribution of the microwave field into a grain layer and the efficiency of energy transfer from the magnetron into the grain layer, via a waveguide, on the moisture content. The subject of the research was a semicircular waveguide with slot radiators that supply a microwave field to the grain surrounding the waveguide. The change in the directional diagram of the microwave field in the longitudinal direction of the waveguide was studied using CST Microwave Studio 2019 software. It was found that the change in the moisture content of the processed grain leads to a significant change in both the radiation and total efficiency values of the waveguide. For instance, the radiation efficiency of the waveguide decreases by 15.1% (from 68.729 dB to 58.294 dB) when the moisture content of the processed grain increases from 14% to 26%. The total radiation efficiency also decreases (from 11.27 dB to 21.7 dB). In this case, not only the value of the radiation efficiency but also the shape of its dependence on the magnetron radiation frequency change. Data were obtained on the change in the Q-factor for resonators in which grain layers are processed, depending on the variation in grain moisture content.

With Internet of Things (IoT) gaining presence throughout different industries a lot of new technologies have been introduced to support this undertaking. Implications on one such technology, wireless systems allowed for the use of different communication methods to achieve the goal of transferring data reliably, with more cost efficiency and over longer distances. Anywhere from a single house with only a few IoT devices such as a smart light bulb or a smart thermostat connected to the network, all the way to a complex system that can control power grids throughout countries, IoT has been becoming a necessity in everyday lives. This paper presents an overview of the devices, systems and wireless technologies used in different IoT architectures (Healthcare, Vehicular Networks, Mining, Learning, Energy, Smart Cities, Behaviors and Decision Making), their upbringings and challenges to this date and some foreseen in the future.

The numerous biological activities of phenothiazine and sulphonamide derivatives, especially their antibacterial qualities, have attracted so much interest. In this study, the synthesis and characterization of phenothiazine-3-sulphonamide derivatives and evaluation their antimicrobial activity against the following pathogenic microorganisms is reported. Two gram-positive bacteria; (Staphylococcus aureus, and Streptococcus pyogenes), two gram-negative bacteria; (Escherichia coli, and Salmonella typhi) as well as one fungus (Aspergillus fumigatus) were used while ciprofloxacin, gentamycin and ketoconazole served as standard drugs. The synthesis of the derivatives was achieved through a base catalyzed the reaction of 4-chloroaniline with 1-naphthylamine to form 1-(naphthalen-1-yl) benzene-1,4-diamine. This intermediate was then treated with sulphur and iodine to yield the phenothiazine derivative while subsequent treatment of the phenothiazine compound with sulphonyl chlorides gave the final products. The synthesized compounds were characterized via proton nuclear magnetic resonance (1HNMR), carbon-13 nuclear magnetic resonance (13C NMR) and Fourier-transform infrared (FTIR) spectroscopic techniques. The minimum inhibitory concentration (MIC) of each compound was then determined using the agar well diffusion method. To predict the binding energies and patterns of the synthesized compounds with target proteins of the above mentioned microorganisms, molecular docking simulations were run using Autodock Vina software (version 4.2). The spectra data of the compounds for FTIR, 1H NMR and 13C NMR (δ) spectral data were consistent with the assigned structures of the synthesized compounds. The binding energies (kcal/mol) for in silico antimicrobial studies were in the range -5.1 to -7.6 kcal/mol. The MIC values were in the range -3.5 to 1.0 mg/L. The results of the in vitro test revealed that the synthesized compounds exhibits promising antimicrobial activity, and showed excellent bactericidal and fungicidal activities. The results obtained showed that the synthesized compounds possess drug-like properties and are good starting materials for drug production.

Background: Redo mitral valve surgery is the standard of care for failed mitral bioprostheses or recurrence of mitral regurgitation after repair. Nonetheless, catheterbased valve-in-valve (ViV) or valve-in-ring (ViR)-procedures increasingly become viable alternatives in high risk subpopula-tions. Despite reported good initial results, only little is known about longer-term outcomes. The present series report long-term outcomes of transcatheter mitral ViV- and ViR-procedures. Methods: All consecutive patients (n=54) undergoing transcatheter mitral ViV- or ViR-procedures for failed bioprostheses or recurring regurgitation after mitral repair were retrospectively en-rolled in the time period between 2011 and 2021. The mean age was 76.5 ± 6.5 years, and 30 (55.6%) of the patients were male. The procedures were done using a commercially available balloon-expandable transcatheter heart valve. Clinical and echocardiographic follow-up data were obtained out of the hospital’s database and analyzed. Follow-up reached up to 9.9 years with a total of 164.3 patient-years. Results: A total 25 patients received a ViV- and 29 patients a ViR-procedure. Both groups were at high surgical risk with an STS-PROM of 5.9 ± 3.7 % in ViV- and 8.7 ± 9.0% in ViR-patients, respectively (p<0.01). The procedures itself were mainly unevent-ful with no intraoperative deaths and a low conversion rate (n=2/54; 3.7%). VARC-2 procedural success was low (ViV 20.0% and ViR 10.3%; p=0.45), which was either driven by high rates of transvalvular pressure gradients “>5mmHg” (ViV 92.0% and ViR 27.6%; p<0.01) or residual regurgitation “>trace” (ViV 28.0% and ViR 82.7%; p<0.01). ICU-stay was prolonged in both groups (ViV 3.8 ± 6.8 days and ViR 4.3 ± 6.3 days; p=0.96) with acceptable hospital stay (ViV 9.9 ± 5.9 days and ViR 13.5 ± 8.0 days; p=0.13). Despite 30-days mortality was acceptable (ViV 4.0% and ViR 6.9%; p=1.00), the mean posthospital survival time was disappointingly low (ViV 3.9 ± 2.6 years and ViR 2.3 ± 2.7 years; p<0.01). Overall survival I the entire group was 33.3%.Cardiac reasons for death were frequent in both groups (ViV 38.5% and ViR 52.2%). Cox-regression analysis identified ViR-procedures as a predictor of mortality (HR 2.36, CI 1.19 - 4.67, p=0.01). Conclusions: Despite acceptable immediate outcomes in this high-risk subpopulation, long-terms results are discouraging. Transvalvular pressure gradients as well as residual regurgitations remained drawbacks in this real-world population. The indication for catheterbased mitral ViV- or ViR-procedures thoughtfully must be made in consideration of conventional redo-surgery or conservative treatment.

In an effort to discover an effective and selective antitumour agent, synthesis and anti-cancer potential of 4-(pyridin-4-yl)-6-(thiophen-2-yl)pyrimidin-2(1H)-one (SK-25), which has been reported earlier by us with significant cytotoxicity towards MiaPaCa-2 malignant cells, with an IC₅₀ value of 1.95 μM and was found to instigate apoptosis. In the present study, the antitumour efficacy of SK-25 was investigated on Ehrlich ascites tumour (solid), Sarcoma 180 (solid) tumour and Ehrlich ascites carcinoma. The compound was found to inhibit tumour development by 94.71% in Ehrlich ascites carcinoma (EAC), 59.06% in Ehrlich tumour (ET, solid) and 45.68% in Sarcoma-180 (solid) at 30 mg/kg dose. Additionally, SK-25 was established to be non-toxic at a maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. Computer-based predictions also show that the compounds could have an interesting DMPK profile. The current study provides insight for further investigation of the antitumour potential of the molecule.

We propose a model for gravity based on the gravitational polarization of space. With this model, we can relate the density parameters within the Friedmann model, and show that dark matter is bound mass formed from massive dipoles set up within the vacuum surrounding ordinary matter. Aggregate matter induces a gravitational field within the surrounding space, which reinforces the original field. Dark energy, on the other hand, is the energy density associated with gravitational fields both for ordinary matter, and bound, or induced dipole matter. At high CBR temperatures, the cosmic susceptibility, induced by ordinary matter vanishes, as it is a smeared or average value for the cosmos as a whole. Even though gravitational dipoles do exist, no large scale alignment or ordering is possible. Our model assumes that space, i.e., the vacuum, is filled with a vast assembly (sea) of positive and negative mass particles having Planck mass, called planckions, which is based on extensive work by Winterberg. These original particles form a very stiff two component superfluid, where positive and negative mass species neutralize one another already at the submicroscopic level, leading to zero net mass, zero net gravitational pressure, and zero net entropy, for the undisturbed medium. It is theorized that the gravitational dipoles form from such material positive and negative particles, and moreover, this causes an intrinsic polarization of the vacuum for the universe as a whole. We calculate that in the present epoch, the smeared or average susceptibility of the cosmos equals, , and the overall resulting polarization equals, . Moreover, due to all the ordinary mass in the universe, made up of quarks and leptons, we calculate a net gravitational field having magnitude, . This smeared or average value permeates all of space, and can be deduced by any observer, irrespective of location within the universe. This net gravitational field is forced upon us by Gauss’s law, and although technically a surface gravitational field, it is argued that this surface, smeared value holds point for point in the observable universe. A complete theory of gravitational polarization is presented. In contrast to electrostatics, gravistatics leads to anti-screening of the original source field, increasing the original value, , to, , where is the induced or polarized field. In the present epoch, this leads to a bound mass, , where is the sum of all ordinary source matter in the universe, and equals the relative permittivity. A new radius, and new mass, for the observable universe is dictated by the density parameters in Friedmann's equation, and Gauss’s law. These lead to the very precise values, , and, , respectively, somewhat larger than current less accurate estimates.

Keywords: Artificial Intelligence in Implantology; AI in Dental Implantology; Machine Learning in Dental Implantology; Deep Learning in Implant Dentistry; Robotics in Dental Implantology; AI-Based Implant Planning.

In this paper, we discuss major issues of mathematics teaching and learning in Nepal. The issues coming from theories such as social and radical constructivism suggest that teachers are not trained to use such approach in teaching mathematics, and there is a lack of teaching aids and materials and technological tools. The issues related to social aspects are gender issues, language issues, social justice issues, and issues related to the achievement gap. The cultural issues are related to the diversity of language and ethnicity. The issues related to political aspects are equity and access, economic status, pedagogical choice, and professional organizations and unions. The issues related to technology include the technological skills, use of technology, and affordance. Finally, we suggest that all the stakeholders should pay attention to resolving these issues by improving the curriculum, training teachers, resourcing the classroom with locally made and new technological tools.

The Particle-In-Cell (PIC) method has been developed in order to investigate microscopic phenomena, and with the advances of computing power, newly developed codes have been used for several fields such as astrophysical, magnetospheric, and solar plasmas. PIC applications have grown extensively with large computing powers available on supercomputers such as Pleiades and Blue Waters in the US. For astrophysical plasma research PIC methods have been utilized for several topics such as reconnection, pulsar dynamics, non-relativistic shocks, relativistic shocks, relativistic jets, etc. PIC simulations of relativistic jets have been reviewed with the emphasis on the physics involved in the simulations. This review summarizes PIC simulations, starting with the Weibel instability in slab models of jets, and then focuses on global jet evolution in helical magnetic field geometry. In particular we address kinetic Kelvin-Helmholtz instabilities and mushroom instabilities.

Engineering of drug nanocarriers combining fine-tuned mucoadhesive/mucopenetrating properties is currently being investigated to ensure more efficient mucosal drug delivery. Aiming to improve the transmucosal delivery of hydrophobic drugs, we designed a novel kind nanogel produced by the self-assembly of amphiphilic chitosan graft copolymers ionotropically crosslinked with sodium tripolyphosphate. In this work, we synthesized for the first time chitosan-g-poly(methyl methacrylate) nanoparticles thiolated by the conjugation of N-acetyl cysteine. First, we confirmed that both non-crosslinked and crosslinked nanoparticles in the 0.05-0.1% w/v concentration range display very good cell compatibility in two cell lines that are relevant to oral delivery, Caco2 cells that mimic the intestinal epithelium and HT29-MTX cells that produce mucin. Then, we evaluated the effect of crosslinking, nanoparticle concentration and thiolation on the permeability in vitro utilizing monolayers of (i) Caco2 and (ii) Caco2:HT29-MTX cells (9:1 cell number ratio). Results confirmed that the ability of the nanoparticles to cross Caco2 monolayer was affected by the crosslinking. In addition, thiolated nanoparticles interact more strongly with mucin, resulting in a decrease of the apparent permeability coefficient (Papp) compared to the pristine nanoparticles. Moreover, for all the nanoparticles, higher concentration resulted in lower Papp suggesting indicating that the transport pathways could undergo saturation.

In this article, I estimate the value of “Individual Using Internet”-IUI in the context of Environmental, Social and Governance-ESG database of the World Bank. I use data from 193 countries for the period 2011-2020. I found that among others the value of IUI is positively associated to “Methane Emissions” and “People Using Safely Managed Sanitation Services” and negatively associated among others to “Fossil Fuel Energy Consumption” and “Renewable Energy Consumption”. I apply the k-Means algorithm for the clusterization optimized with the Elbow Method and we find the presence of three clusters. Finally, I confront eight machine-learning algorithms to predict the future value of IUI. I found that the best predictive algorithm is Linear Regression and that the value of IUI is expected to decrease on average of 0.30% for the analysed countries.

Physics behind collimated highly directional nature of lasers, and factors that keep the seven coloured waves that form white light together during their journey from Sun to Earth, in the face of the natural disruptive forces, is not fully understood. Energy levels were measured, in terms of alterations in induced current and voltage, in beams from a red laser, white LED light and the Sunlight before and during their disruption by diffusers (frosted glass for the lasers) and diffractors (diffraction grating for the white light) using a photovoltaic solar cell panel attached to a digital multimeter. Results show that disruption of the beams results in release of extra energy named as ‘Latent Light Binding’ Energy’. It is hypothesized that the ‘binding’ energy keeps laser waves firmly bound together both end-on and side-on enabling laser beams to travel long distances in collimated manner. Likewise, the 7 coloured waves that constitute white light are kept together, probably side-on, in their journey from the Sun to the Earth. The observation that diffraction of sunbeam is associated with increased power generation provides a new lead to improve harnessing of solar energy, where, currently, the focus is mainly on improving efficiency of photovoltaic cell.

Leishmaniasis is a vector-borne parasitic infection caused by the bite of female Phlebotomine sandflies. World Health Organization (WHO) estimates 100,000 cases to be reported annually on a global scale, moreover, 13 million people were infected between 2010 and 2015 worldwide. Treatment of leishmaniasis by conventional synthetic compounds is met by challenges pertaining to adverse effects which call for the discovery of newer anti-leishmanial molecules. This study was performed to evaluate the effect and modes of action of a sesquiterpene alcoholic molecule Farnesol on Leishmania major, the causative agent of Zoonotic Cutaneous leishmaniasis. The cytotoxic effect of Farnesol against L. major promastigotes, amastigotes and macrophages was assessed by MTT test and counting. The IC50 on promastigotes by Farnesol on L. major was evaluated by flow cytometry. In the findings, Promastigotes were reduced at 167 µM/mL & the mean numbers of L. major amastigotes in macrophages were significantly decreased in exposure to Farnesol at 172 µM/ml. In addition, Farnesol demonstrated no cytotoxicity on macrophages as the IC50 value was 945 µM/ml; it induced significant apoptosis dose-dependent on L. major promastigotes. In silico protein-ligand binding analyses indicated the effect of Farnesol in perturbation of the ergosterol synthesis pathway of Leishmania with attributes suggesting inhibition of Lanosterol-α-demethylase, the terminal enzyme of ergosterol synthesis machinery. Findings from flow cytometry reveal the role of farnesol in apoptosis-induced killing in promastigotes. Farnesol was effective at very lower concentrations when compared to Paromomycin. Further studies are crucial to evaluate the therapeutic potentials of Farnesol alone and in combination with other conventional drugs using clinical settings.

The pore-throat radius of shale oil reservoir is extremely small, and it is difficult to accurately obtain the absolute permeability and oil-water two-phase relative permeability of actual oil reservoir through conventional core experiments. However, these parameters are very important for reservoir numerical simulation. In this paper, a method for characterizing flow parameters based on pore network model that considers differential pressure flow and diffusion flow is proposed. Firstly, a digital core was reconstructed using focused ion beam scanning electron microscopy (FIB-SEM) from the Gulong shale reservoir in the Songliao Basin, China, and a pore network model was extracted. Secondly, quasi-static single-phase flow and two-phase flow equations considering diffusion were established in the pore network model. Finally, pore throat parameters, absolute permeability, and oil-water two-phase permeability curves were calculated, respectively. The results show that the pore throat distribution of Gulong shale reservoir is mainly concentrated in the nanometer scale, the mean pore radius is 87 nm, the mean throat radius is 41 nm, and the mean coordination number is 3.97; The calculated permeability considering diffusion is 0.000124mD, which is approximately twice the permeability calculated without considering diffusion; The irreducible water saturation of the Gulong shale reservoir is approximately 0.26, and the residual oil saturation is approximately 0.73. The method proposed in this paper can provide an important approach for characterizing the flow parameters of similar shale oil reservoirs.

We estimate the value of Research and Development Expenditures as a percentage of GDP-RDE in the context of Environmental, Social and Governance-ESG model. We use the ESG World Bank database. We analyze data from193 countries in the period 2011-2020. We apply a set of econometric techniques i.e. Pooled Ordinary Least Squares-OLS, Panel Data with Random Effects, Panel Data with Fixed Effects, Weighted Least Squares-WLS. We found that the level of RDE is positively associated, among others, to “Nitrous Oxide Emissions” and “Scientific and Technical Journal Articles”, and negatively associated, among others to “Heat Index 35”, “Maximum 5-day Rainfall”. Furthermore, we perform a cluster analysis with the application of the k-Means algorithm optimized with the Elbow Method. The results show the presence of four clusters. Finally, we confront eight different machine-learning algorithms to predict the future value of RDE. We find that Linear Regression is the best predictive algorithms. RDE is expected to growth on average of 0.07% for the analysed countries.

Influenza virus strain A/South Africa/3626/2013 (H1N1)pdm09 (SA-WT) is a non-mouse-adapted model strain, which has naturally high pathogenic properties for mice. It has been suggested that the high pathogenicity of this strain for mice could be due to the three strain-specific substitutions in the polymerase complex (Q687R in PB1, N102T in PB2, and E358E/K heterogeneity also in PB2). To evaluate the role of these replacements, SA-WT was passaged five times in mouse lungs, and the genome of the mouse-adapted version of the SA-WT strain (SA-M5) was sequenced. SA-M5 lost E358E/K heterogeneity and retained E358, which is the prevalent amino acid at this position among H1N1pdm09 strains. Besides, in the hemagglutinin of SA-M5, two heterogeneous substitutions (G155G/E and S190S/R) were identified. Both viruses, SA-M5 and SA-WT, were compared for their toxicity, ability to replicate, pathogenicity, and immunogenicity for mice. In mice infected with SA-M5 or SA-WT strains, toxicity, virus titer in pulmonary homogenates, and mouse survival did not differ significantly. Contrarily, an increase in the immunogenicity of SA-M5 compared to SA-WT was observed. This increase could be due to the substitutions G155G/E and S190S/R in the HA of SA-M5. The prospects for using SA-M5 in studying the immunogenicity mechanisms were also discussed.

Nowadays, according to spectacular improvement in health care and biomedical level, a tremendous amount of data is recorded by hospitals. In addition, the most effective approach to reduce disease mortality is to diagnose it as soon as possible. As a result, data mining by applying machine learning in the field of diseases provides good opportunities to examine the hidden patterns of this collection. An exact forecast of the mortality after heart surgery will cause Successful medical treatment and fewer costs. This research wants to recommend a new stacking predictive model after utilizing the random forest feature importance method to foresee the mortality after heart surgery on a highly unbalanced dataset by using the most practical features. To solve the unbalanced data problem, a combination of the SVM-SMOTE over-sampling algorithm and the Edited-Nearest-Neighbor under-sampling algorithm is used. This research compares the introduced model with some other machine learning classifiers to ensure efficiency through shuffle hold-out and 10-fold cross-validation strategies. In order to validate the performance of the implemented machine learning methods in this research, both shuffle hold-out, and 10-fold cross-validation results indicated that our model had the highest efficiency compared to the other models. Furthermore, the Friedman statistical test is applied to survey the differences between models. The result demonstrates that the introduced stacking model reached the most accurate predicting performance after Logistic Regression.

This article explores the relationship between convex functions defined on integers ($\mathbb{Z}$) and their extension to real numbers ($\mathbb{R}$). We introduce key definitions and investigate the hypothesis that there exists a unique convex curve within this family of functions, leading to a proof by contradiction. Our findings highlight the preservation of convexity as functions transition from integers to real numbers.

Among the alternatives pointed out as able to make livestock a more efficient activity and reduce its environmental impact, the use of feeds with high digestibility and the use of non-conventional fodder species can be highlighted. Tithonia diversifolia (Hemsl.) A. Gray (TD) has already gained attention as a feed for ruminants. Nonetheless, there has been little discussion about the impacts of this plant on the rumen dynamics that lead to better animal performance. The aim of this study was to assess how increasing levels of TD could affect ruminal microbial biomass synthesis, degradability, and in vitro gas production (IVGP) of diets. Four diets were evaluated: a control diet (TD0: 400 g kg-1 soybean meal and corn grain, and 600 g kg-1 Tifton 85 hay (Cynodon spp)) and three increasing levels of TD (TD9: 90, TD27: 270, and TD45: 450 g kg-1 – dry matter basis) as a replacement for dietary roughage. A 96-hour IVGP assay was carried out and five incubation times (2, 4, 10, 24, and 96 hours) were used for degradability determination. Gas produced, methane (CH4), degradability of organic matter (IVDOM), short-chained fatty acid (SCFA) production, partitioning factor (PF), and microbial biomass (MB) were evaluated among treatments. There was no significant effect (P&gt;0.05) between TD inclusion and IVGP at most incubation times; only at 6 hours of incubation did gas production increase linearly with TD inclusion (R2=0.19; P&lt;0.05). TD inclusion had no effects on CH4. IVDOM increased linearly with TD inclusion at 6 and 10 hours, with TD45 being more degradable than the control diet at 6 hours only. There was a positive linear relationship (R2=0.20; P&lt;0.05) between TD inclusion and PF. TD45 had significantly higher PF values than the control. MB also increased linearly (R2=0.30; P&lt;0.05) with TD inclusion, and all diets with TD had significantly more MB than the control diet. The inclusion of TD at the levels used in this work was revealed to have a positive impact on microbial protein synthesis, which could be related to the higher microbial efficiency of increased substrate quality.