The type of implant at the fracture site has effects not only from biological perspective but also from mechanical perspective in fracture healing. Biodegradable implants such as magnesium (Mg) based alloys have shown faster secondary bone healing properties as compared to bioinert implants such as titanium (Ti). The general reasoning behind this is the benefit of Mg from biocompatibility perspectives. We study the effect of Ti and Mg as base materials for implants with their different mechanical properties. The focus of our work is on the displacements at the fracture site of the tibia and their influence on the stimulus for bone healing. We have found that in comparison to Ti, Mg implants have minimal stress shielding problem, only which led to better mechanical stimulus at the fracture site.

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.

Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson´s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the FDA, only a very small number is truly selective for one of the DR subtypes. Additionally, most of them show promiscuous activity at related G-protein coupled receptors, thus suffering from diverse side-effect profiles. Multiple studies have shown that combined in silico / in vitro approaches are a valuable contribution to drug discovery processes. They can also be applied to divulge the mechanisms behind ligand selectivity. In this study, novel DR ligands were investigated in vitro to assess binding affinities at different DR subtypes. Thus, nine D2R/D3R-selective ligands (micro- to nanomolar binding affinities, D3R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D3R activity (KI = 2.3 nM) with 263.7-fold D2R/D3R selectivity. Subsequently, ligand selectivity was rationalized in silico based on ligand interaction with a secondary binding pocket, supporting selectivity data determined in vitro. The developed workflow and identified ligands could aid in the further understanding of structural motifs responsible for DR subtype selectivity, thus, benefitting drug development in D2R/D3R-associated pathologies like PD.

The massive amount of human biological, imaging and clinical data produced by multiple and diverse sources, necessitates integrative modeling approaches able to summarize all this information into answers to specific clinical questions. In this paper, we present a hypermodeling scheme able to combine models of diverse cancer aspects regardless of their underlying method or scale. Describing tissue-scale cancer cell proliferation, biomechanical tumor growth, nutrient transport, genomic-scale aberrant cancer cell metabolism, and cell signaling pathways that regulate the cellular response to therapy, the hypermodel integrates mutation, miRNA expression, imaging, and clinical data. The constituting hypomodels as well as their orchestration and links are described. Two specific cancer types, Wilms tumor (nephroblastoma) and non-small cell lung cancer, are addressed as proof of concept study cases. Personalized simulations over the actual anatomy of a patient have been carried out. The hypermodel has also applied to predict tumor control after radiotherapy and the relationship between tumor proliferative activity and response to neoadjuvant chemotherapy. Our innovative hypermodel holds promise as a digital twin based clinical decision support system and the core of future in silico trial platforms, although additional retrospective adaptation and validation is necessary.

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.

Acute lymphoblastic leukemia (ALL) is the most common cancer among children worldwide, characterized by an overproduction of undifferentiated lymphoblasts in the bone marrow. The treatment of choice for this disease is the enzyme L-asparaginase (ASNase) from bacterial sources. ASNase hydrolyzes circulating L-asparagine in plasma, leading to starvation of leukemic cells. The ASNase formulations of E. coli and E. chrysanthemi present notorious adverse effects, especially the immunogenicity they generate, which undermines both their effectiveness as drugs and patient safety. In this study, we developed a humanized chimeric enzyme from E. coli L-asparaginase, which would reduce the immunological problems associated with current L-asparaginase therapy. For these, the immunogenic epitopes of E. coli L-asparaginase (PDB: 3ECA) were determined and replaced with those of the less immunogenic Homo sapiens asparaginase (PDB:4O0H). The structures were modeled using the Pymol software and the chimeric enzyme was modeled using the SWISS MODEL service. A humanized chimeric enzyme with four subunits similar to the template structure was obtained, and the presence of asparaginase enzymatic activity was predicted by protein-ligand docking.

In plants and animals, endogenous biological molecules, termed damage-associated molecular patterns (DAMPs) or alarmins, are released by damaged, stressed or dying cells following abiotic stress such as radiation and drought stress. In turn, a cascade of downstream signaling events is initiated leading to the up-regulation of defense-related genes. In the present study, in an effort to investigate the conservation status of the molecular mechanisms implicated in the danger signaling, thorough in silico phylogenetic and structural analyses of the effector biomolecules were performed in taxonomically diverse plant species. On the basis of our results, the defense mechanisms appear to be largely conserved within the plant kingdom. Of note is our finding that the sequence and/or function of several components of these mechanisms were found to be conserved in animals, as well.

The vastness of chemical-space constrains traditional drug-discovery methods to the organic laws that are guiding the chemistry involved in filtering through candidates. Leveraging computing with machine-learning to intelligently generate compounds that meet a wide range of objectives can bring significant gains in time and effort needed to filter through a broad range of candidates. This paper details how the use of Generative-Adversarial-Networks, novel machine learning techniques to format the training dataset and the use of quantum computing offer new ways to expedite drug-discovery.

Chemical exposures from diverse sources merge on a limited number of molecular pathways described as toxicity pathways. Changes in the same set of molecular pathways in different cell and tissue types may generate seemingly unrelated health conditions. Today, no approaches are available to predict in an unbiased way sensitivities of different disease states and their combinations to multichemical exposures across the exposome. We propose an inductive in-silico workflow where sensitivities of genes to chemical exposures are identified based on the overlap of existing genomic datasets, and data on sensitivities of individual genes is further used to sequentially derive predictions on sensitivities of molecular pathways, disease states, and groups of disease states (syndromes). Our analysis predicts that conditions representing the most significant public health problems are among the most sensitive to cumulative chemical exposures. These conditions include six leading types of cancer in the world (prostatic, breast, stomach, lung, colorectal neoplasms, and hepatocellular carcinoma), obesity, type 2 diabetes, non-alcoholic fatty liver disease, autistic disorder, Alzheimer's disease, hypertension, heart failure, brain and myocardial ischemia, and myocardial infarction. Overall, our predictions suggest that environmental risk factors may be underestimated for the most significant public health problems.

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.

Background: Currently, limited number of therapeutic options are available to treat Diabetes mellitus, and to find a potential candidate, laboratory work takes time and also needs animal studies. So, the aim of this study was to determine the efficacy of some natural phytocompounds with the aid of molecular docking, bioinformatics and in silico drug design approaches. Method: Two proteins (Human CYP3A4 linked to metformin and Human dipeptidyl peptidase-IV) were selected and molecular docking studies were conducted using Pymol, AutoDock Vina, PyRx, and Discovery Studio. Different important pharmacokinetic parameters like ADME and toxicity data were obtained from online databases SwissADME and pkCSM program. Results: It was found that human dipeptidyl peptidase-IV (PDB ID: 4A5S) has exhibited a maximal affinity of -9.7 Kcal/mol for bryonolic acid and hesperidin, but only -6.7 kcal/mol for metformin hydrochloride. Similarly, the highest affinity of hesperidin for human CYP3A4 bound to metformin (PDB ID: 5G5J) is -10.7 Kcal/mol compared to metformin hydrochlor (-6.3 Kcal/mol). Besides, all the compounds have been documented outstanding ADMET profile, and accepted by drug-likeness or Lipinski rule. Conclusions: The present study suggested that these compounds can be further investigated in vitro and in vivo to establish them as lead compounds against Diabetes mellitus..

Sugarcane mosaic virus (SCMV) is a (genus, Potyvirus; family, Potyviridae) is a widespread, deleterious, and the most damaging pathogen of sugarcane ((Saccharum officinarum L. and Saccharum spp.) which causes a substantial barrier to producing high sugarcane earning. Sugarcane mosaic disease (SCMD) is caused by, single or compound infection of SCMV, disseminated by the several aphid vectors in a non-persistent manner. SCMV has flexuous filamentous particle of 700-750 nm long, which encapsidated a positive-sense, single-stranded RNA molecule of 9575 nucleotides. RNA interference (RNAi)-mediated antiviral innate immunity is an evolutionary conserved, key biological process in eukaryotes and has evolved as an antiviral defence system to interfere with viral genomes for controlling infections in plants. The current study aims to analyze sugarcane (Saccharum officinarum L. and Saccharum spp.) locus-derived microRNAs (sof-miRNAs/ssp-miRNAs) with predicted potential for targeting the SCMV +ssRNA-encoded mRNAs, using a predictive approach that involves five algorithms. The ultimate goal of this research is to mobilize the in silico- predicted endogenous sof-miRNAs/ssp-miRNAs to experimentally trigger the catalytic RNAi pathway and generate sugarcane cultivars to evaluate the potential antiviral resistance surveillance ability and capacity for SCMV. Experimentally validated mature sugarcane (S. officinarum, 2n = 8X = 80) and (S. spp., 2n = 100-120) sof-miRNA/ssp-miRNA sequences (n = 28) were downloaded from the miRBase database and aligned with the SCMV genome (KY548506). Among the 28 targeting mature locus-derived sof-miRNAs/ssp-miRNAs evaluated, one sugarcane miRNA homolog, sof-miR159c, was identified to have a predicted miRNA binding site, at nucleotide position 3847 of the SCMV genome targeting CI ORF. To verify the accuracy of the target prediction accuracy and to determine, whether the sugarcane sof-miRNA/ssp-miRNA could bind the predicted SCMV mRNA target(s), we constructed an integrated Circos plot. A genome-wide in-silico-predicted miRNA-mediated target gene regulatory network has implicated to validate interactions necessary to warrant in vivo analysis. The current work provides valuable computational evidence for the generation of SCMV-resistant sugarcane cultivars.

Metabolic enzymes are often targeted for drug development programs of metabolic diseases such as diabetes and its complications. Many secondary metabolites isolated from natural products have shown therapeutic action against these enzymes. However, some commercially available synthetic drugs have shown unfriendly impacts with various side effects. Thus, this research has focused on a comprehensive study of secondary metabolites showing better inhibitory activities towards metabolic enzymes such as α-amylase, α-glucosidase, aldose reductase, and lipase. Further receptor-based virtual screening was performed against the various secondary metabolites database designed in-silico. Using Gold combined with subsequent post-docking analyses, the score was obtained as methyl xestospongic ester (Gold score 65.83), 2,″4″-O-diacetylquercitrin (Gold score 65.15), kaempferol-3-O-neohesperidoside (Gold score 53.37) and isosalvianolic acid C methyl ester (Gold score 53.44) for lipase, aldol reductase, α-amylase, and α-glucosidase, respectively. Besides, vitexin and isovitexin for α-amylase; N-trans-Caffeoyl-tyramin for α-glucosidase; purpurolide F and schaftoside for lipase; acteoside and orientin for aldose reductase could be potential drugs for respective enzymes based on in-silico analyses, supported by experimental IC₅₀ values reported. They could bind to the competitive sites of the various targets of metabolic enzymes, and finally, toxicity analysis using ProTox-II was also performed.

Natural products comprise a rich reservoir for innovative drug leads and are a constant source of bioactive compounds. To find pharmacological targets for new or already known natural products using modern computer-aided methods is a current endeavor in drug discovery. Nature’s treasures, however, could be used more effectively. Yet, reliable pipelines for large scale target prediction of natural products are still rare. We have developed an in silico workflow consisting of four independent, stand-alone target prediction tools and evaluated its performance on dihydrochalcones (DHCs) – a well-known class of natural products. Thereby, we revealed four previously unreported protein targets for DHCs, namely 5-lipoxygenase, cyclooxygenase-1, 17β- hydroxysteroid dehydrogenase 3, and aldo-keto reductase 1C3. Moreover, we provide a thorough strategy on how to perform computational target prediction and guidance on using the respective tools.

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was isolated in 2012 and is well known to cause the respiratory syndrome. The orf1ab gene is known to mediate MERS-CoV replication. In this study, we have discussed the in silico prediction of potential siRNAs targeting MERS-CoV-orf1ab gene for antiviral therapeutics. To identify the potential siRNAs, various factors were considered. We have excluded the siRNAs with off-target effects and potential binding with human mRNAs. By using available softwares, total twenty-one functional, off-target reduced potential siRNA were selected from four hundred and sixty-two siRNAs based on greater potency and specificity. We have tested only seven siRNAs initially to evaluate their performance by reverse transfection approach by lipofectamine mediated delivery in Vero cells. The evaluation results showed no cytotoxicity at various concentrations of siRNAs used. The results obtained in this study provided preliminary information about the cytotoxicity which will help us to further evaluate siRNAs in other cell cultures to find out the replication inhibition efficiency of MERS-CoV. Finally, it is concluded that the in silico prediction and designing resulted in filtration and selection of potential siRNAs with high accuracy, efficiency, and strength which can be further utilized for the development of oligonucleotide-based therapeutics.

Sugarcane mosaic virus (SCMV) is a deleterious pathogen which causes widespread Sugarcane mosaic disease (SCMD) and is classified in the genus Potyvirus (Potyviridae), disseminated by the aphid vector. RNA interference (RNAi)-mediated antiviral innate immunity is a key biological process and antiviral defence system to interfere with viral genomes for controlling plant pathogens. The current study aims to analyze sugarcane (Saccharum officinarum L. and Saccharum spp.) locus-derived microRNAs (sof-miRNAs/ssp-miRNAs) with predicted potential for targeting the SCMV +ssRNA-encoded mRNAs, using ‘five algorithms’ approach. The ultimate goal in this research is to mobilize the in silico endogenous predicted sof-miRNAs/ssp-miRNAs to trigger RNAi catalytic pathway experimentally and generate sugarcane cultivars for evaluating potential antiviral resistance monitoring capability and capacity for SCMV. Experimentally validated mature sugarcane (S. officinarum, 2n = 8X = 80) and (S. spp., 2n = 100-120) sof-miRNAs/ssp-miRNAs (n = 28) were acquired for alignment with the SCMV genome. Of the 28 targeting mature locus-derived sof-miRNAs/ssp-miRNAs investigated, one sugarcane miRNA homolog, sof-miR159c, was concluded to localize potential binding site at genomic nucleotide site 3847 targeting CI ORF of SCMV. In order to validate target prediction accuracy, whether the sugarcane sof-miRNA/ssp-miRNA might bind predicted SCMV mRNA target(s), we created an integrated Circos plot. Genome-wide in-silico-predicted miRNA-mediated target gene regulatory network validated interactions that warrant in vivo analysis. The current work provides valuable evidence and biological material for generating SCMV-resistant sugarcane varieties.

Apple chlorotic leaf spot virus (ACLSV) is a widespread, deleterious and the most damaging pathogen of fruit tree plants including domesticated apple (Malus domestica) ―a great threat to apple production worldwide. The positive-sense single-stranded RNA genome of ACLSV (7.5 Kbp) encodes three proteins: RNA polymerase (Rep), movement protein (MP) and coat protein (CP). RNA interference (RNAi)-mediated antiviral innate immunity is a key sequence-specific biological phenomenon in eukaryotes to control plant viruses. The aim of this study was to analyze apple (M.domestica) locus-derived microRNAs (mdm-miRNAs) with predicted potential for targeting the ACLSV +ssRNA-encoded mRNAs, using ‘four algorithms’ approach. The ultimate goal in this research is to mobilize the in silico endogenous predicted mdm-miRNAs to trigger RNAi catalytic pathway experimentally and generate apple tree varieties for evaluating potential antiviral resistance monitoring capability and capacity for ACLSV. Experimentally validated mature apple (M.domestica, 2n = 2X = 34) mdm-miRNAs (n = 322) were acquired from miRBase database and tested for alignment with the ACLSV genome. Of the 322 targeting mature locus-derived mdm-miRNAs investigated, nine apple mdm-miRNA homologs (mdm-miR395k, mdm-miR5225c and mdm-miR7121 (a, b, c, d, e, f, g, h) were predicted by all ‘four algorithms’. Only fifty eight mdm-miRNAs were predicted consensus binding sites by union of consensus between two algorithms. The miRanda, RNA22, TAPIR algorithms predicted binding of mdm-miR395k at unique nucleotide position 4691, as the most effectively interacting mdm-miRNAs in targeting the ORF1 sequence. In order to validate target prediction accuracy, whether the apple mdm-miRNAs might bind predicted ACLSV mRNA target(s), we created an integrated Circos plot. Genome-wide in-silico-predicted miRNA-mediated target gene regulatory network validated interactions that warrant in vivo analysis. The current work provides valuable evidence and biological material for generating ACLSV-resistant apple varieties.

To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine derivatives 7a-l have been designed and synthesized via cyclocondensation reactions of pyrazolo-enaminone 5 with a series of arylidene malononitriles; compound 5 was obtained from 5-amino-4-cyanopyrazole (3). The structures of the target compounds 7a-l were investigated by spectral techniques and elemental analysis (IR, UV-Vis, 1H NMR, 13C NMR and ESI-MS). All compounds were evaluated for their in vitro cytotoxicity employing a panel of different human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells. It has been found that the conjugate 7e was the most active towards many cell lines with EC50 values ranging between 9.1 and 13.5 µM, respectively. Moreover, in silico docking studies of 7e with six anticancer drug targets, i.e. DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX also was performed, in order to gain some insights into their putative mode of binding interaction and to estimate the free binding energy of this bioactive molecule.

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.

The tumour-associated isoenzymes, hCA IX and hCA XII catalyze the hydration of carbon dioxide to bicarbonate and protons. These isoforms are highly overexpressed in many types of cancer, where they contribute for the acidification of the tumor environment promoting the tumor cell invasion and metastasis. In this work, in order to identify novel dual hCA IX and XII inhibitors, virtual screening techniques and biological assays were combined. A structure based virtual screening towards hCA IX and XII was performed using a database of approximately 26000 natural compounds. The best shared hits were submitted to a thermodynamic analysis and 3 promising best hits were identified and evaluated in terms of their hCA IX and XII inhibitor activity. In vitro biological assays are in line with the theoretical studies and revealed that Syringin, Lithospermic acid, and (-)- Dehydrodiconiferyl alcohol behave as good hCA IX and hCA XII dual inhibitors.

Aims: In late December 2019, early reports predicted the onset of a potential Coronavirus outbreak in china, given the estimate of a reproduction number for the 2019 Novel Coronavirus (COVID-19). Because of high ability of transmission and widespread prevalence, the mortality of COVID-19 infection is growing fast worldwide. Absent of an anti-COVID-19 has put scientists on the urge to repurpose already approved therapeutics or to find new active compounds against coronavirus. Here in this study, a set of computational approaches were performed in order to repurpose antivirals for dual inhibition of the frontier proteases involved in virus replication, papain-like protease (PLpro; corresponding to nsp3) and a main protease (Mpro), 3C‑like protease (3CLpro; corresponding to nsp5). Materials and Methods: In this regard, a rational virtual screening procedure including exhaustive docking techniques was performed for a database of 160 antiviral agents over 3CLpro and PLpro active sites of SARS-CoV-2. The compounds binding energies and interaction modes over 3CLpro and PLpro active sites were analyzed and ranked with the aid of free Gibbs binding energy. The most potent compounds, based on our filtering process, are then proposed as dual inhibitors of SARSC-CoV-2 proteases. Key findings: Accordingly, seven antiviral agents including two FDA approved (Nelfinavir, Valaganciclovir) and five investigational compounds (Merimepodib, Inarigivir, Remdesivir, Taribavirine and TAS106-106) are proposed as potential dual inhibitors of the enzymes necessary for RNA replication in which Remdesivir as well as Inagrivir have the highest binding affinity for both of the active sites. Significance: The mentioned drug proposed to inhibit both PLpro and 3CLpro enzymes with the aim of finding dual inhibitors of SARSC-CoV-2 proteases.

The main inhibitory neurotransmitter in the mammalian brain is 4-aminobutyric acid (GABA). Phthalimide acts as a sodium channel antagonist, one of the finest targets for treating epilepsy is the sodium channel and JNK kinase activity is inhibited to treat epilepsy. a novel compound with multiple targets of action for the treatment of epilepsy also anti-oxidant activity has been designed. The compounds are designed in two series aldehydes and aniline. Docking of all the designed compounds has been done with the suitable protein GABA-AT, sodium channel, JNK protein, and anti-oxidant from protein bank. QSAR was done for constructing many linear regression models. In combination with the developed Docking and QSAR outcomes, ADMET has been performed for the active compounds. The result shows that 11 of the compounds have excellent binding energy in docking with all the receptors and also have good QSAR results and follow the ADMET. The structural understanding of human GABA-AT inhibition was obtained from molecular dynamics simulation studies for compound no. 11 at 5 nanoseconds. Synthesis and pharmacological activity also suggest that the designed compound no.11 be considered the best Novel Compound.

In CNS drug discovery, estimation of brain exposure of lead compounds is critical for their optimization. Compounds need to cross the blood-brain barrier (BBB) to reach the pharmacological targets in the CNS. The BBB is a complex system involving passive and active mechanisms of transport and efflux transporters such as P-glycoproteins (P-gp) and breast cancer resistance protein (BCRP), which play an essential role in CNS penetration of small molecules. Several in vivo, in vitro and in silico methods are available to estimate human brain penetration. Preclinical species are used as in vivo models to understand the unbound brain exposure by deriving the Kp,uu parameter, the brain/plasma ratio of exposure corrected with the plasma and brain free fraction. MDCK-mdr1 (Madin Darby canine kidney cells transfected with the MDR1 gene encoding for the human P-gp) assay is the most commonly used in vitro assay to estimate compound permeability and human efflux. The in silico methods to predict brain exposure, such as CNS MPO, CNS BBB scores and various Machine Learning models, help save costs and speed up compound discovery and optimization at all stages. These methods enable the screening of virtual compounds and building of a CNS penetrable compounds library as well as optimization of lead molecules for CNS penetration. Therefore, it is crucial to understand these methods' reliability and ability to predict CNS penetration. We review the in silico, in vitro and in vivo data and their correlation with each other and assess published in silico approaches to predict the BBB penetrability of compounds.

Cervical cancer is a significant global health concern, with human papillomavirus (HPV) infection being a crucial risk factor. Photodynamic therapy (PDT) is an attractive, minimally invasive treatment for HPV-related cervical lesions, which uses photosensitizers and light to selectively de-stroy abnormal cells. We aim to provide an overview of the various sorts of dyes that are utilized in PDT for decreasing the incidence and mortality of cervical cancer. Besides, the article discusses ongoing clinical trials for PDT in low-grade squamous intraepithelial neoplasia (LSIL) and high-grade squamous intraepithelial lesions (HSIL), as well as preclinical approaches for PDT in cervical cancer using various dyes. Moreover, it highlights potential dyes for PDT, examine them in in-silico condition, their pros and cons and also the solutions for enhancing their anticancer com-patibility. We also display that PDT is a promising therapeutic strategy for the diagnosis and treatment of HPV-associated cervical lesions. Moreover, it shows that using different classes of dyes improves the anticancer effects of PDT. Finally, among all dyes which are used in PDT, Fullerene demonstrated high tendency to over expressed receptors in cervical cancer cells and seems to be a proper candidate for be used in PDT more than before, but further research is necessary to assess its long-term efficacy and safety.

Zinc, being a part of many proteins and enzymes, plays an important role in the vital processes of the body. Racemic α-lipoic acid (LA) has a wide range of biological activities: antioxidant, antidiabetic, anticancer, and it is also used in diseases such as Parkinson's and Alzheimer's. Nowadays, the synthesis and structural studies of new zinc complexes with biologically active compounds are of great importance for drug discovery. This work shows the studies carried out on the synthesis, structure, identification, also biological activity using in silico methods of a complex compound based on LA and zinc. A complex compound of zinc with LA (ZnLA) was synthesized in the presence of LA and zinc acetate in ethanol. The identification of ZnLA by (FT-IR, XRD and TGA-DTA), also DFT calculations at the B3LYP/def2-TZVPP level of theory was performed. The molecular docking investigation involved docking ZnLA with two different protein receptors such us Glycogen phosphorylase (2GPA) and Kv potassium channel beta subunit (1ZSX) using CB-Dock 2 server and Auto-Dock Vina program to determine the mechanism of action and biological activity. This study reveals potential ligand-protein interactions at the atomic level and suggests that the treatment of diabetes (non-insulin dependent) with ZnLA.

Single nucleotide polymorphisms (SNP) are associated with diseases and drug response variabilities in humans. Elucidating the damaging and disease-associated SNPs using wet-laboratory approaches can be challenging and resource-demanding due to the large number of SNPs in the human genome. Due to the growth in the field of computational biology and bioinformatics, algorithms have been developed to help screen and filter out the most deleterious SNPs that are worth considering for wet-laboratory studies. Here we review the existing in-silico based methods used to predict and characterize the effects of SNPs on protein structure and function. This cutting-edge approach will facilitate the search for novel therapeutics, help understand the etiology of diseases and fast-track the personalized medicine agenda.

The current globally dominant SARS-CoV-2 variants are showing immune escape and reduced susceptibility to antiviral drugs. Therefore, agencies responsible for drug evaluation and regula-tion such as the FDA and EMA are revising their emergency authorization use of several COVID-19 neutralizing antibodies. These NAbs proved to be unlikely effective against new variants espe-cially Omicron descendants and several pharmaceutical companies are pursuing the development of more potent neutralizing antibodies. To address the issue of using in silico prediction for the rapid assessment of anti-SARS-CoV-2 MAbs neutralization power, we used a computational method we developed previously, to evaluate 10 SARS-CoV-2 antibodies propensity to neutralize the new Omicron’s subvariants Eris (EG.5) and Pirola (BA.2.86) based on comparative binding affinity and previous experimental and clinical observations. Nine of these MAbs were once granted emergency use authorization, and one is currently under clinical investigation. The rapid, cost-effective in silico evaluation provided reliable predictions consistent with published clinical and experimental data. Furthermore, our data showed new potential therapeutic MAbs combi-nation that could be effective for the treatment countermeasure of the new Omicron’s subvariants Eris (EG.5) and Pirola (BA.2.86).

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.

An abdominal aortic aneurysm (AAA) is usually asymptomatic until rupture, which is associated with extremely high mortality. Consequently, early detection of AAAs is of paramount importance in reducing mortality; however, most AAAs are detected by medical imaging incidentally. The aim of this study was to investigate the feasibility of machine learning-based pulse wave (PW) analysis for the early detection of AAAs using a database of in silico PWs. PWs in the large systemic arteries were simulated using one-dimensional blood flow modelling. A database of in silico PWs representative of subjects (aged 55, 65 and 75 years) with different AAA sizes was created by varying the AAA-related parameters with major impacts on PWs – identified by parameter sensitivity analysis – in an existing database of in silico PWs representative of subjects without AAA. Then, a machine learning architecture for early detection of AAAs was proposed, which was trained and tested using the new in silico PW database. The parameter sensitivity analysis revealed that the AAA maximum diameter and stiffness of the large systemic arteries were the dominant AAA-related biophysical properties that significantly influence the PW. The simulated PW indexes extracted from the database showed that the PW was not only influenced by the presence of an AAA but was also significantly affected by multiple cardiovascular parameters that compromised the detection of AAAs by using individual PW indexes. Alternatively, the trained machine learning model performed well in classifying normal and AAA conditions using digital photoplethysmogram PWs from the database. These findings suggest that machine learning-based PW analysis is a promising approach for AAA screening using PW signals acquired by wearable devices.

Conventional chemotherapy for colorectal cancer (CRC) gives only a small increase in patient survival, since it is often diagnosed in late stages, when tumor has disseminated to other organs. Besides, it is common to observe that malignant cells acquire tumor escape mechanisms which leads to therapy resistance. Considering these facts, the discovery of new molecules with therapeutic potential has become an invaluable tool in chemoprevention. In this context, we previously evaluated two hybrids (SAC-CAFA-MET and SAC-CAFA-PENT) which exhibited selective cytotoxicity against SW480, with better results than the conventional chemotherapeutic agent (5-fluorouracil; 5-FU). Here, we investigated a little deeper in the possible mechanism of these molecules to identify potential therapeutic alternatives for the treatment of CRC. Both compounds induced cell damage and reduced ROS formation. Further evaluations showed that SAC-CAFA-MET induces cell death independent from caspases and p53, but probably mediated by the negative regulation of the proapoptotic Bcl-2. In addition, the lack of activation of caspase 8 and the positive regulation of caspase 3 induced by SAC-CAFA-PENT suggest this compound acts through an apoptotic mechanism, probably initiated by intrinsic pathway. Besides, the down regulation of IL-6 by SAC-CAFA-PENT suggests it also induces a significant anti-inflammatory process. In addition, docking studies would suggest caspase-3 modulation as the primary mechanism by which hybrids elicits apoptosis in human colorectal adenocarcinoma SW480. Meanwhile, DFT calculations suggest that hybrids would produce effects in modulation of ROS in SW480 cells via hydrogen atom transfer pathway (HAT). Finally, both, SAC-CAFA-MET and SAC-CAFA-PENT displayed a favorable pharmacokinetic profile. The current work highlights the potential of the lead compounds SAC-CAFA-MET and SAC-CAFA-PENT as potential agents for colorectal cancer chemoprevention.

COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, TMPRSS2, and AP2-associated protein kinase 1. In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of drug candidates to target receptors, providing insight into their potential efficacy. However, it is crucial to consider both the advantages and limitations of these studies and to complement them with experimental validation to ensure the efficacy and safety of identified drug candidates.

This study empirically analyzes the effectiveness of resource optimization utilizing artificial intelligence (AI) within cloud computing environments. It compares systems that have been transitioned from a Monolithic structure to Microservices Architecture (MSA) with those adopting a simple Rehost strategy, to validate the operational efficiency of two systems whose resource efficiency has been enhanced compared to traditional legacy systems. The research is based on systems that determined resource efficiency post-cloud migration using APM tools. It points out the limitations of traditional heuristic operation methods in resource optimization, which lead to issues such as application performance degradation, resource over-allocation, and increased operational costs. This study aims to overcome the conventional resource optimization standards that depended on the average peak usage of CPU and memory infrastructure, by introducing AI-based optimization tools, and applying on-premise standards to cloud and container environments to achieve resource optimization. The paper emphasizes the importance of resource optimization through AI-based automation tools, exploring the possibilities of resolving real-world application performance issues in cloud environments, reducing unnecessary resource usage costs, and cutting down on labor risks and operational expenses. Through this, it presents strategic directions on how AI technology can offer financial and operational advantages in managing cloud resources.

Knowledge of permafrost’s ice and unfrozen water content is critical for predicting the permafrost behavior during ice–water–ice transition. This is especially relevant when ice and permafrost are melting in many regions under the influence of global warming. It is well-known that only a part of the formation's pore water turns into ice at 0 ^oC. After the further lowering the temperature, the water phase transition continues, but at gradually decreasing rates. Thus, the porous space is filled with ice and unfrozen water. The laboratory data show that frozen formations' mechanical, thermal, and rheological properties strongly depend on the moisture content. Hence, porosity and temperature are essential parameters of permafrost. In this paper, it is shown how, and by combining research in three fields: (1) geophysical exploration, (2) numerical modeling, and (3) temperature logging, it is possible to estimate in-situ the porosity of permafrost. To demonstrate the procedure, five examples of numerical modeling (where all input parameters are specified) are given. This investigation is the first attempt to analyze the permafrost’s porosity in situ quantitively.

Electrical remodelling as a result of the homeodomain transcription factor 2 (Pitx2)‐dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to Class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action potential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax) and conduction velocity (CV), and decreased AP duration (APD) and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that quinidine and disopyramide may be more effective against Pitx2-induced AF than propafenone by prolonging WL.

We statistically investigate the Coronavirus Disease 19 (hereinafter Covid-19) epidemics, which is particularly invasive in Italy. We show that the high apparent mortality (or Case Fatality Ratio, CFR) observed in Italy, as compared with other countries, is likely biased by a strong underestimation of infected cases. To give a more realistic estimate of the mortality of Covid-19, we use the most recent estimates of the IFR (Infection Fatality Ratio) of epidemic, based on the minimum observed CFR, and furthermore analyse data obtained from the ship Diamond Princess, a good representation of a ‘laboratory’ case-study from an isolated system in which all the people have been tested. From such analyses we derive more realistic estimates of the real extension of the infection, as well as more accurate indicators of how fast the infection propagates. We then point out from the various explanations proposed, the dominant factors causing such an abnormal seriousness of the disease in Italy. Finally, we use the deceased data, the only ones estimated to be reliable enough, to predict the total number of infected people and the interval of time when the infection in Italy could stop.

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.

Fall detection systems play a crucial role in addressing the significant health concern of elderly falls, a leading cause of health deterioration and mortality. As the aging population grows and life expectancy increases, the development of accessible tools becomes vital for predicting and preventing falls, offering a practical and widely applicable solution in contrast to costly and expertise-dependent assessment tools. In contrast, due to the formidable challenges encountered, a comprehensive investigation into the comparative performance of standard ML models within this field still needs to be explored. This paper proposes a standard pipeline for pre-processing, training, and evaluating ML models for fall detection on the SisFall dataset. We conducted extensive experiments to evaluate the performance of various ML models for fall detection. The results validate the efficiency of the deep model in identifying the time windows in which a fall occurred. Among the deep models, the architecture, including a combination of convolutional neural networks and fully connected layers, outperforms the others by macro-averaged Precision, macro-averaged Recall, and macro-averaged F1-Score of 87.03\%, 86.83\%, and 86.93\%, respectively.

Lack of shock absorption capability of conventional steel bollards causes significant vehicle damage and consequently high repair costs. This research studies a solution to reduce vehicle damage by inserting PLA honeycomb structures. A honeycomb-inserted bollard was designed based on numerical simulations using LS-DYNA, which yielded the bollard designed for actual vehicle-bollard collision experiments. Simulation efforts were focused on calculating the acceleration characteristics when a vehicle collides with steel and honeycomb-inserted bollards. Compared to the simulated steel bollards, 20 MPa yield-strength honeycomb-inserted bollard showed 0.017s delay in the maximum acceleration occurrence time, reduction of the maximum acceleration to 37.4% of that of steel bollards, and 13.1% reduction in the B-pillar maximum acceleration. Actual vehicle-bollard collision experiments, with a gyro-sensor installed at the test vehicle front bumper frame, also proved improved shock absorption characteristics of the honeycomb-inserted bollards. An experiment with honeycomb-inserted bollard showed 0.783s delay in the maximum acceleration occurrence time, a significant delay when compared to steel bollards. The maximum acceleration measured by the gyro-sensor was 0.35m/s2 when the simulation predicted it to be 0.388 m/s2, proving the similarity in the simulations and experiments. Thus, this study of shock absorption characteristics promised reduced damage to vehicles and lower repair cost.

We present here a five hours experimentation of a didactical path about the electromagnetic induction addressed to students of the last year of an Italian scientific high school and oriented to better understand the physical origin of the induced electromotive force. The expression of the induced electromotive force as the sum of the term linked to the time variation of the magnetic field and of the motional one has been obtained in a detailed way, still suitable for presentation at high school. Many examples have been proposed to the students in order to clarify the conceptual physical knots. The students’ responses to a 6-questions multiple choice questionnaire have been analyzed. It emerged that our approach is concretely feasible although we find the well-known difficulties in calculating flux and circulation of a vector field. Furthermore, it emerged that an integral approach to the problem masks the understanding of the nature of the forces acting locally on the charges. Hence our proposal of a “redefinition” of the induced electric field in terms of the magnetic vector potential is also presented.

A sedentary lifestyle associated with unregulated diets rich in high-calorie foods have contributed to the great prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) latterly, with up to 60% in high-risk population and 25% in the general population. The absence of specific pharmacological strategies for this syndrome represents one of the major problems in the management of MASLD patients. Lifestyle interventions and adherence to a healthy diet are the main cornerstones of current therapies. The identification of nutraceuticals useful in the treatment of MASLD appears to be one of the most promising strategies for the development of new effective and safe treatments for this disease. The onion, one of the most widely studied foods in the field of nutraceuticals, serves as an inexhaustible reservoir of potent compounds with various beneficial effects. The following preliminary study analyses, mediating in silico studies, the iteration of a library of typical onion compounds with 3-hydroxy-3-methylglutaryl-coenzyme A reductase, Liver receptors X α and β as well as Peroxisome proliferator-activated receptors α and γ. In this study fort the first time promising smart molecules from the onion that could have a beneficial action in MASLD patients were identified.

The microstructure of Al-5Fe-1.5Er alloy was characterized and analyzed by using XRD, SEM, TEM and EDS. The effect of microstructure on the behavior of crack initiation and propagation was investigated by in situ tensile testing. Results show that the microstructure consists of α-Al matrix, Al₃Fe, Al₄Er, eutectic phase Al₃Fe + Al₄Er, while the 1.5 wt.% Er was added in Al-5Fe alloy. The twin structure of the Al₃Fe phase was observed, and the twin plane is {001}. Moreover, a continuous concave and convex interface structure of the Al₄Er has been found. Al₃Fe is in the form of a sheet with a clear gap inside.In situ tensile tests of the alloy at room temperature show that the crack initiation occured mainly in the Al₃Fe phase, and that the crack propagation modes include intergranular and transgranular expansion. Crack transgranular expansion is due to the strong binding ability between Al₄Er phases and surrounding organization, and the continuous concave and convex interface structure of the Al₄Er provides a significant meshing effect on the matrix and eutectic structure.

Based on the geochemical analysis of the volcanic material from the sediment core AMK-340, central zone of the Reykjanes Ridge, we could detect two ash-bearing sediment units accumulated during the Termination I. They correlate to the Ash Zone I in the North Atlantic Late Quaternary sediments having an age of 12170-12840, within the Younger Dryas cold chronozone, and 13600-14540 years, within and Bølling-Allerød warm chronozone. The ash of the Younger Dryas unit is presented mostly by the mafic and persilicic material originated from the Icelandic volcanoes; Vedde Ash is presented in one sediment sample from this unit. The ash of the Bølling-Allerød unit is presented mostly by the mafic shards which are related to the basalts of the rift zone on the Reykjanes Ridge, having presumably the local origin. A detection of Vedde Ash helped to specify the timing of the previously reconstructed paleoceanographic changes for the Termination I in the point of study: a significant warming in the area could occur as early as 300 years prior to the end of the conventional Younger Dryas cold chronozone.

This study assesses the impact of globalization on female participation in the labor force (FPLF). The increased globalization in the last several decades has created various economic opportunities for enterprises and individuals worldwide at an unprecedented rate. As a result, it has helped improve the quality of life for many men and women. In this process, the issue of women’s economic participation has been a critical topic for discussion worldwide. In that context, the objective of the paper is to determine if FPLF is influenced by a country’s participation in foreign markets through foreign direct investment (FDI) – a proxy for globalization. The paper uses a panel dataset obtained from the World Bank’s World Development Indicators database for 99 countries from 2001 to 2018. We then use system Generalized Method of Moments (system GMM) to estimate a dynamic panel model with appropriate specification tests. The results show that the positive effects of FDI on FPLF are more robust for low- and middle-income countries than high-income countries. We also find that results may be sensitive to outlier observations. Our results explain the seemingly inconclusive results within existing literatures and suggest that low- and middle-income countries should particularly focus on sectors that generate FDI as they stand to yield the greatest benefits with regards to female economic empowerment.

This work focuses on the study of the microstructure, hardening and stiffening effect caused by the secondary phases formed in titanium matrices. These secondary phases were originated from reactions between the matrix and boron particles added in the starting mixtures of the composites. Not only was the composite composition studied as an influencing factor in the behaviour of the composites, but also different operational temperatures. Three volume percentages of boron content were tested (0.9, 2.5 and 5 vol % of amorphous boron). The manufacturing process used to produce the composites was inductive hot pressing, which operational temperatures were between 1000 °C to 1300 °C. Specimens showed optimal densification. Moreover, microstructural study revealed the formation of TiB in various shapes and proportions. Mechanical testing confirmed that the secondary phases had a positive influence on the properties of the composites. In general, adding boron particles increased the hardness and stiffness of the composites; however rising temperatures resulted in greater increases in stiffness than in hardness.

Here, we report on ZnO nanoparticles (NPs) generated by nanosecond pulsed laser (Nd:YAG, 1064 nm) through ablation of metallic Zn target in water and air and their comparative analysis as potential nanomaterials for biomedical applications. The prepared nanomaterials were carefully characterized in terms of their structure, composition, morphology and defects. It was found that in addition to the main wurtzite ZnO phase, which is conventionally prepared and reported by others, the sample laser-generated in air also contained some amount of monoclinic zinc hydroxynitrate. Both nanomaterials were then used to modify model wound dressings based on biodegradable poly-L-lactic acid. The as-prepared model dressings were tested as biomedical materials with bactericidal properties towards S. aureus and E. coli strains. The advantages of the NPs prepared in air over their counterparts generated in water found in this work are discussed.

Environmental DNA (eDNA) sampling has emerged as a powerful approach for monitoring biodiversity in the context of diverse terrestrial and aquatic ecosystems, and has broad potential for both environmental surveys and species management. eDNA studies focusing on plant and animal species have capitalized on analytical methodologies developed originally for metagenomic studies of microorganisms, and on technological improvements in sample collection. However, while eDNA studies have proliferated rapidly, efforts to standardize sampling and analytical methods are still nascent. Critically, fundamental data concerning the distribution and persistence of eDNA in different ecological contexts are lacking, complicating both confidence in species detection and comparability between studies. We propose that key deficits could be addressed by using well-designed synthetic DNA standards or tracers, which are widely used in fields ranging from medical diagnostics to hydrology. In-field application of a standardized mixture of barcoded synthetic DNA fragments of varying lengths and concentrations that are recovered concommitantly with eDNA sampling should provide critical yet missing data on environmental DNA distribution and turnover, as well as an internal molecular standard to enhance both species detection and comparability between eDNA studies.

With permafrost degenerating caused by climate change, water accumulation increases in permafrost regions during last decades. Water accumulation will deteriorate existing status of engineering in cold regions. Water accumulation can make a thermal effect on permafrost under construction, even result in failure of the subgrade. Moreover, the thermal effect is related to water temperature. However, temperature variation of water accumulation is complex, and its influence factors include air temperature, environment, scope of water accumulation and so on. In order to make analysis of the damage mechanism of water accumulation on permafrost, it is necessary to explore the internal temperature change of water accumulation. This paper proposes a review about temperature calculation method of water accumulation in cold environment. The thermal calculation method between air and water boundary of water accumulation is summarized. Water temperature change of water accumulation with various type is analyzed. The thermal calculation considering phase transformation in water accumulation is discussed, and heat transfer from the bottom of water accumulation to the underlying soil is further studied. Finally, the key factors which are advantageous to make research about the thermal effect of water accumulation in permafrost is proposed to optimize calculation method.

The growing impact of Artificial Intelligence (AI) on Humanity is unavoidable, and therefore, “AI literacy” is extremely important. In the field of education – AI in education (AIED) – this technology is having a huge impact on the educational community and on the education system itself. The present study seeks to assess the level of AI literacy of teachers at Portalegre Polytechnic University (PPU), aiming to identify gaps, find the main opportunities for innovation and development and seek the degree of relationship between the dimensions of AI literacy, as well as identifying the predictive variables in this matter. As a measuring instrument, a validated questionnaire based on three dimensions (AI Literacy, AI Self-Efficacy and AI Self-Management) was applied to a sample of 75 teachers in the various schools of PPU. This revealed an average level of AI literacy (3.28), highlighting that 62.4% of responses are at levels 3 and 4 (based on a Likert scale from 1 to 5). The results also demonstrate that the first dimension is highly significant for the total dimensions, i.e., for AI Literacy, and no factor characterizing the sample is a predictor, but finding a below-average result in the Learning factor indicates a pressing need to focus on developing these skills.

The silanol activity and trace metal detection methods for chemically bonded silica gels were evaluated in silico. Test compounds with large molecular sizes may demonstrate negative results because of the possibility of indirect hydrogen bonding via short alkyl groups or siloxane of the silica gels. This hypothesis was based on the observation of weak hydrogen bonding energy values similar to those observed in the study of the alkyl group effect on the hydrogen bonding of alkanols. Consequently, smaller molecules may be a better choice for the analysis of bonded-phase quality.

This study describes a comparative in vitro study of the toxicity behavior of zinc oxide (ZnO) nanoparticles and micro-sized particles. The study aimed to understand the impact of particle size on ZnO toxicity by characterizing the particles in different media, including cell culture media, human plasma, and protein solutions (bovine serum albumin and fibrinogen). The study used various techniques such as atomic force microscopy (AFM), transmission electron microscopy (TEM), and dynamic light scattering (DLS) to characterize the particles and their interactions with proteins. Hemolytic activity, coagulation time, and cell viability assays were used to assess ZnO toxicity. The results highlight the complex interactions between ZnO NPs and biological systems, including their aggregation behavior, hemolytic activity, protein corona formation, coagulation effects, and cytotoxicity. Moreover, the study indicates that ZnO nanoparticles are not more toxic than micro-sized particles, and the 50 nm particles resulted in general the least toxic. Furthermore, the study found that at low concentrations, no acute toxicity was observed. Overall, this study provides important insights into the toxicity behavior of ZnO particles and highlights that no direct relationship between nanometer size and toxicity can be directly attributed.

This observational pilot study aimed to investigate continuous glucose monitoring (CGM) metrics in older Japanese patients with type 2 diabetes mellitus (T2DM) using a continuous glucose monitoring system (FreeStyle Libre Pro) for CGM during the first tirzepatide administration and compared the glycemic control measures before and after the treatment. The four patients re-ported a mean age of 79.5 years (standard deviation [SD]: 5.8), mean body mass index of 24.63 kg/m2 (SD: 4.7), and mean glycated hemoglobin level of 9.1% (SD: 2.1). After tirzepatide treatment, the mean of time in range, time above range, and time below range changed from 53.2% to 78.9% (p = 0.041), 45.8% to 19.7% (p = 0.038), and 1.0% to 1.5% (p = 0.206), respectively. Improved hy-perglycemia reduced the oral glucose medication in two cases and decreased the frequency of insulin injections in two cases. All cases demonstrated the CGM index improvement during short-term observation despite some differences. Future studies need to investigate the long-term impact on functional prognosis, safety, and tolerability, especially in nonobese older Asian pa-tients, to elucidate the potential benefits of tirzepatide. However, tirzepatide-associated robust glycemic improvement may simplify and reduce diabetes treatment-associated complication in older patients with T2DM.

The social vulnerability approach (SV) has set up that social inequalities and disadvantages have gone beyond monetary poverty in the last years, since the process is built at different scales. In its objectives, the SV multidimensional measurement is contemplated as a priority tool to monitor the compliance of the first goal – eliminate poverty in all its forms. Therefore, the objective of this research is to calculate the SV of the fishing communities of the Gulf of Ulloa (GU), Mexico by macro-markers to subsequently contrast them with field micro-data, and finally perform a behavior scenario, considering the current public policies restrictive to fishing in such areas. The results showed significant differences depending on the type of information used, obtaining a contingency coefficient of 83.42%, which indicates that the calculus depends strongly on the data used and suggesting that macro-data may be masking the true SV values in the area, in such a way they could be severely underestimated. Even though the context at micro-scale is not the only one, SV should be calculated to analyze the fishing communities since coastal fishery represents almost the total livelihood of the inhabitants. Nevertheless, these communities confront numerous local and global threats, and these pressures on SV put their livelihoods, well-being, food security and traditional lifestyle at risk. Therefore, the role of researching human dimensions and governance is not only basic but also urgent to turn to sustainable socioeconomic management.

The extrusion of food for human and animal consumption is a unit operation that includes mixing, shearing and force to the materials related to the rheological properties of the materials in the extruder. The present work aims to study the rheological behavior of an extruded fish diet incorporating hydrolyzed protein flour processed by extrusion. The measurement was carried out online with a slit die rheometer, defining the rheological models and parameters that fit the process. During the extrusion process, the raw materials used were hydrolyzed protein meal, fish meal and cassava starch. For the results, the evaluated treatments were adjusted to the Power Law, where an increase in the shear rate decreases the viscosity of the material, corresponding to a pseudoplastic behavior. The incorporation of hydrolyzed protein flour presented a significant effect on the value of n and Klp, increasing the viscosity with the increase in the percentage of inclusion of HPH. The models obtained for the prediction of the viscosity are adjusted to the changes in shear rate, temperature and humidity of the system.

Buildings use 30-40 % of all energy resources and are thus their main consumers in modern society. Moreover, buildings require a vast amount of different raw materials. During the last two decades, several green building certifications have been created in order to consider social, economic and environmental aspects of sustainability of buildings. One of the most famous and widely used of these certifications is Leadership in Energy and Environmental Design (LEED). So far, the use of LEED has concentrated in the US and other developed countries. One reason that restricts the use of this point-based system certification in developing countries is the limited data about its costs. In this study, the extra cost of the certification process will be evaluated besides the changes needed in the design of the building to reach the points required by LEED. At the first stage, the number of points the case study earns in its current format (Scenario 1) were found out, then the cost difference of getting either the Certified (Scenario 2) or Silver (Scenario 3) level LEED certification for the building was studied. It was found that besides some technical considerations, filling the criteria of the Certified and Silver level increases the total costs of construction by 3.4% and 5.9%. Further improvement of the building’s energy efficiency would enable the attainment of a higher-level certification. The results of the study could help to promote the use of green building certifications in Western Asia.

Background : Probiotics are composed of microorganisms that have positive effects on health when consumed in prescribed quantities. Lately, studies have attempted to establish this role of probiotics in enhancing health. Aim : The aim of this study was to compare the antifungal activity of 3 different probiotics against Candida albicans.Methodology :This was an in-vitro study. 3 types of commercially available probiotics - Bifilac, Pre pro HS and VSL-3 were cultured separately with Candida albicans and were placed under incubation. The maximum zone of inhibition was recorded for each of the probiotic solutions.Results : In this study, it was found that among the three probiotic products, Bifilac exhibited a maximum zone of inhibition of 13mm at concentration of 100µL against C. albicans, while Pre pro HS and VSL-3 showed zone of inhibition of 11mm at concentrations of 50µL and 100µL, respectively.Conclusion : Within the limits of the present study, This study could prove that probiotics can be considered as an alternative and safe treatment option for treatment of Oral candidiasis infections.

Metal and alloy toughening was the core and long-term research direction in materials filed. As grain size had bimodal distribution, micro/nano-structured alloys presented excellent comprehensive mechanical properties, and this had become one of the research hotspots and developing trends in the field of nanotechnology. In-situ tensile test was a direct and effective method to study the deformation mechanism of materials, which revealed the multiple mechanisms responding to feature grain sizes and provided reliable experimental means and research technique. Research on development of in-situ technique and its applications in mechanical properties was reviewed in this paper according to the recent advances on the modern mechanical properties for high strength and high plasticity alloy at home and abroad. The disadvantages of the present study of preparation methods and investigation techniques for high-performance alloy had been concluded. Finally, the development prospects of high strength and high plasticity alloy materials were analyzed.

Irrigation and debridement using an irrigation solution is a fundamental step during the surgi-cal treatment of both acute and chronic periprosthetic joint infection (PJI). However, there is no consensus on the optimal solution, nor is there sufficient evidence on optimal irrigation time and combination of solutions. Therefore, it is necessary to determine which solution or combi-nation of solutions is most efficacious against biofilm, as well as the optimal irrigation time. We conducted an experimental in vitro model by inoculating stainless steel discs with ATCC strains of methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, Pseudomonas aeru-ginosa, and a clinical strain of Staphylococcus epidermidis. The discs were all irrigated with com-monly used antiseptic solutions (10% and 3% povidone iodine, hydrogen peroxide, 3% acetic ac-id, and Bactisure™) for 1 min, 3 min, and 5 min and their combinations for 9 min (3 min each) vs. sterile saline as a positive control. We evaluated the reduction in biofilm based on colony form-ing unit (cfu) counts and, in combination assays, also based on cell viability and scanning elec-tron microscopy. All antiseptics alone reduced more than 90% of cfu counts after 1 min of irriga-tion; the worst results were for hydrogen peroxide and 3% acetic acid. When solutions were combined, the best results were observed for all those starting with acetic acid, in terms of both reduction of log cfu/ml counts and viable cells. We consider that a combination of antiseptic so-lutions, particularly that comprising the sequence acetic acid+povidone iodine+hydrogen per-oxide, would be the best option for chemical debridement during PJI surgery.

3D-printed aluminium alloy fabrications made by selective laser melting (SLM) offer a promising route for the production of small series of custom-designed heat exchangers with complex geometry and shape and miniature size. Alloy composition and printing parameters need to be optimized to mitigate fabrication defects (pores and microcracks) and enhance the part performance. The deformation response needs to be studied with adequate characterization techniques at relevant dimensional scale capturing the peculiarities of micro-mechanical behavior relevant to the particular article and specimen dimensions. Purposefully designed Al-Si-Mg 3D-printable RS-333 alloy was investigated with a number of microscopy techniques including in situ mechanical testing with a Deben Microtest 1 kN stage integrated and synchronized with Tescan Vega3 SEM to acquire high resolution image datasets for Digital Image Correlation (DIC) analysis. Dog bone specimens were 3D-printed in different orientation of gauge zone cross-section with respect to the fast laser beam scanning and growth directions. This corresponds to varying local conditions of metal solidification and cooling. Specimens show variation in mechanical properties, namely, Young’s modulus (65…78 GPa), yield stress (80–150 MPa), ultimate tensile strength (115–225 MPa) and elongation at break (0,75–1,4 %). Furthermore, the failure localization and character was altered with the change of gauge cross-section orientation. DIC analysis allowed correct strain evaluation that overcame the load frame compliance effect and helped to identify the unevenness of deformation distribution (plasticity waves) that ultimately resulted in exceptionally high strain localization near the ultimate failure crack position.

Lean is one of the systematic approach to achieve higher value for organizations through eliminate non-value-added activities. It is an integrated set of tools, techniques, and principles designed to optimize cost, quality and delivery while improving safety. In Vietnam, industry waste management and treatment has become serious issue. The aim of this research is to present the effective of Lean application for industrial wastes collecting and delivery improvement. Through a case study, this paper showed the way of Lean tools and principles applied for wastes management and treatment such as Value Stream Mapping, Pull system, Visual Control, and Andon.... to get benefit on both economic and environment. In addition, the results introduced a good experience for Vietnamese enterprises in cost saving and sustainable development in waste management.

This study analyzes tree diversity and its ecological importance value in silvopastoral systems in the Sumaco Biosphere Reserve (SBR), Ecuador, along an altitudinal gradient of 400-2000 masl. Twenty-six plots distributed in low (400-700 masl), medium (701-1600 masl) and high (1601-2000 masl) zones were used. The Shannon index and the Importance Value Index (IVI), based on abundance, dominance and relative frequency, were estimated. The results show variations in the diameter structure of the trees, influenced by factors such as settlement history and pasture management. The lower and middle zones showed higher tree density and diversity, linked to regeneration and the presence of nearby forests. Species of high commercial value, such as Cedrela odorata and Jacaranda copaia, were common, reflecting knowledge of the local timber market. In the lower and middle zones, the 10 most important species accounted for more than 70% of the trees, and up to 96% in the upper zone, indicating the need for further research on abundance factors and promotion of diversification in pastures. A total of 51 tree species were identified, mostly native, 64.7% are classified by the IUCN as "Least Concern", 31.4% as "Not Evaluated", and 3.9% as "Vulnerable", specifically highlighting Cedrela odorata and Cedrela Montana. The study concludes with policy recommendations related to the importance of trees in silvopastoral systems for the conservation of species and the livelihoods of local communities, highlighting the need for responsible management of Amazonian pasturelands.

Shut-in after fracturing is generally adopted for wells in shale oil reservoirs, and imbibition occurring in matrix nanopores has been proven as an effective way to improve recovery. In this research, the molecular dynamics (MD) simulation was used to investigate the effects of wettability and pressure on nanopores imbibition during shut-in for a typical shale reservoir Jimsar. The results indicate that the microscopic advancement mechanism of the imbibition front is the competitive adsorption between “interfacial water molecules” at the imbibition front and “adsorbed oil molecules” on the pore wall. The essence of spontaneous imbibition involves the adsorption and aggregation of water molecules onto the hydroxyl groups on the pore wall. The flow characteristics of shale oil suggest that the overall push of the injected water to the oil phase is the main reason for the displacement of adsorbed oil molecules. Thus, shale oil especially the heavy hydrocarbon component in the adsorbed layer tends to slip on the walls. However, the weak slip ability of heavy components on the wall surface is an important reason that restricts the displacement efficiency of shale oil during spontaneous imbibition. The effectiveness of spontaneous imbibition is strongly dependent on the hydrophilicity of the matrix pore's wall. The better hydrophilicity of the matrix pore's wall facilitates higher levels of adsorption and accumulation of water molecules on the pore wall and requires less time for “interfacial water molecules” to compete with adsorbed oil molecules. During the forced imbibition process, the pressure difference acts on both the bulk oil and the boundary adsorption oil, but mainly on the bulk oil, which leads to the occurrence of wetting hysteresis. Meanwhile, shale oil still existing in the pore always maintains a good stratified adsorption structure. Because of the wetting hysteresis phenomenon, as the pressure difference increases, the imbibition effect gradually increases, but the actual capillary pressure gradually decreases and there is a loss in the imbibition velocity relative to the theoretical value. Simultaneously, the decline in hydrophilicity further weakens the synergistic effect of pressure difference because of the more pronounced wetting hysteresis. Thus, selecting an appropriate well pressure enables cost savings and maximizes the utilization of the formation's natural power for EOR.

There is still little research on psychological wellbeing, life satisfaction and reported problems in preadolescents and adolescents under therapy for leukaemia, and also little research comparing them with their healthy peers. The present study aims to analyse the life satisfaction, hope, psychological wellbeing and reported problems’ intensity in patients aged 8-18 during the first year of therapy, to identify those more at risk and to compare their reports with matched healthy peers. After the parental written consent signature, a battery of self-reported questionnaires was administered during hospitalisation or day hospital admissions post 6 months and post 12 months from the diagnosis. Younger patients (aged 8–13 years) were more at risk than older ones in their problems’ intensity and psychological symptoms; females and Acute Myeloid Leukaemia patients reported lower current life satisfaction perceptions; hope was associated with lower depression symptoms and mood problems. Healthy peers have a better perception of current life, but reported a lower hope score, more anxiety symptoms and more cognitive problems than patients. The first 6 months were more critical for patients’ psychological health. The clinical aim was to identify the patients more at risk in order to prepare ad hoc psychological interventions.

Pruning is an important part in controlling the branching, good fruit size, and prodctivity of fruit trees. and consequently, ‘Valencia’ orange trees were grown many years ago, the trees were suffering from a decline in productivity in the newly reclaimed lands after certain years of plantation. This study elucidated the effect of pruning severity on growth, yield and fruit quality of ‘Valencia’ orange trees. Four levels of pruning were applied on 35 years old ‘Valencia’ orange trees as follows: T1: Control (un-pruned), T2: Light pruning ( 25% of main branches were removed); T3: Moderate pruning (50% of main branches were removed) and T4: Heavy pruning: 75% of main branches were removed. The treatments were done in February 15th (for each season). The results indicated that pruning severity increased vegetative growth paraments such as shoot length and leaf area and decreased canopy volume of Valencia orange trees in comparison to control. Maximum yield was gained from 75% followed by 50% and 25% pruning severity treatment. The pruning treatments improve in fruit weight, size, firmness, juice content, TSS%, TSS/acid ratio and vitamin C content. In addition, pruning produced an increasing in fruit yield per tree as well as yield increasing %. Hence, it might be concluded that pruning at different severity applied in February can be used effectively on ‘Valencia’ orange trees to improve vegetative growth, fruit physical and chemical properties. Besides, increasing fruit yield by nearly 20% in comparison to control.

The concept of collecting data of people using a domestic space is not novel. However, the methods and processes used to decipher this raw data and transform it into useful and appropriate information (i.e., sequence, duration, and timing derived from domestic activities) have been challenging and the focus of many research groups. But how are the results of the decoded transposition received, interpreted and used by the various professionals (e.g., occupational therapists and architects) who consume the information? This paper describes the inclusive evaluation process undertaken, which involved architects, engineers and end-users (not the occupant, but the care team managing the occupant). Finally, our study evidence the importance of making accessible to a multidisciplinary audience spatial, temporal and sequential aspects derived from people's domestic routines. Shedding light on how a systematic approach to collecting, processing and mapping low-level sensor data into higher forms and representations can be a valuable source of knowledge for improving the domestic living experience.

The diamagnetic levitation technique can be applied to non-destructive testing for identifying cracks and defects in magnetic materials. Pyrolytic graphite is a material that can be leveraged in micromachines due to its no-power diamagnetic levitation on a permanent magnet (PM) array. However, the damping force applied to pyrolytic graphite prevents it from maintaining con-tinuous motion along the PM array. This paper investigates the in-plane motion and damping characteristics of pyrolytic graphite sheets on the PM array. The centroid of pyrolytic graphite will maintain a stable levitation when positioned on the intersecting point of the PM array. Fur-thermore, the in-plane motion of two different pyrolytic graphite sizes - PG10 (10×10×0.5mm3) and PG20 (20×20×0.5mm3) - has revealed that the in-plane forces applied to them are approximately 61.4μN and 28.2μN, respectively. The smaller sheet has a shorter oscillation time while oscillating before it stabilizes. The damping ratio of the oscillation was between 0.1-0.2. The in-plane force and the stable time of pyrolytic graphite are related to its size ratio in comparison with the PM. This relationship is believed to promote stability, as the force acting on the graphite sheet will be distributed over a larger area when the sheet size increases. During the fixed-axis rotation process, the study found that the friction coefficient and friction force decreased as the rotational speed decreased. The diamagnetic levitation of pyrolytic diamagnetic levitation is also unable to maintain long-term axial rotation. Finally, friction force was tested using PG10 during fixed-axis rotation above a circular PM array. The results showed that the order of the friction coefficient is 10-3, and the friction force is about 0.8μN, decreasing with graphite rotation speed. We hope this technique will be used in crack detection, magnetic detection and other micromachine.

The analysis presented is based on actual GHU energy demand. The special feature of this load is the existence of strong daily fluctuations in energy consumption, especially during the summer months. This study presents a methodology for managing such loads with the main objective of maximizing the operating efficiency of MG.

Human displacement is on the rise globally, and the increase in the burden of tuberculosis (TB) is also attributed to migrations worldwide. A significant number of such displacement occur in regions with considerably higher areas of TB burden. Displacements may delay in TB diagnosis and treatment, which possibly will lead to TB transmission among healthy individuals. In this study, we assessed the association of existing determinants after a protracted internal displacement of people with the delay in TB diagnosis and treatment outcomes. A cross-sectional study was conducted on internally displaced TB patients registered at selected health facilities in three urban districts of Pakistan from March 2019 to February 2020. The univariate and multivariate logistic regression model was used to assess the delay in diagnosis and treatment outcomes. IDPs with delay in initiation of treatment beyond 30 days were at high possibility of unsuccessful TB treatment outcomes (adjusted odds ratio AOR,2.60; 95% CI 1.06-6.40). Analysis of factors that affect health seeker behavior and timely treatment showed a significant association (p<0.05) in-between age group 55-65 years (AOR, 2.66; 95% CI 1.00-7.07), female patients (AOR, 2.42; 95% CI 1.21-4.81), visited non-formal health provider (AOR, 8.81; 95% CI 3.99-19.46), self-medication (AOR, 2.72; 95 % CI 1.37-5.37), poor knowledge of TB (AOR, 11.39; 95% CI 3.31-39.1), and perceived stigma (AOR, 8.81; 95% CI 3.99-19.4). Prolong delay in treatment was associated with unfavorable treatment outcomes among IDPs, more specifically. As migrants and IDPs are more likely to experience an interruption in care due to overall exclusion from social and health care services. Therefore, it is imperative to understand the barriers in providing public health care services, particularly in preventing and treating TB.

Fiber coupling efficiency is one of the key technical indicators of atmospheric laser communication, which directly affects the communication system BER. According to the optical fiber coupling efficiency model, the optical fiber coupling model under atmospheric slant link is established, and the relationship between wavelength, zenith angle, receiving aperture, altitude and coupling efficiency is studied through numerical simulation. Based on the principle of adaptive optics turbulence correction, the relationship between fiber coupling efficiency and adaptive optics order is established. A fast method for estimating the coupling efficiency based on Strehl ratio is proposed. According to the principle of laser communication system, the semi-physical simulation experimental system of atmospheric slant-range channel coupling efficiency is constructed, and the coupling efficiency test and analysis are completed.

Background: Early rehabilitation is an important strategy for the treatment of severe diseases. The study aimed to assess the efficacy of early rehabilitation of patients with mild-to-moderate COVID-19. Methods: The retrospective single-center study with propensity score matching. Results: 180 patients (54 (44 - 62.3) yo) divided into three equal groups: 1 - physical exercises; 2 - physical exercises and chest massage in an electrostatic field; 3 - no rehabilitation. The length of stay (LOS) in the hospital in group 1 was 14 (11-15) days, group 2 - 13 (11-15) days, group 3 - 15 (13-18) days, p=0.0026. Physical exercises for patients with CT-1 improved the quality of life, assessed by the EQ-5D questionnaire, by reducing the level of anxiety and depression. The Hazard Ratio (HR) for desaturation (<93%) was 2.34 (95% Confidence Interval (CI) 1.18-4.63) for group 2, p=0.001. The HR for C-reactive protein level above 50 mg/l in patients with CT-2 was 2.33 (95% CI 1.56-3.47), p=0.0001. Conclusions: Rehabilitation programs are safe for СOVID-19-patients; reduce hospital LOS; improve the quality of life. Continuous monitoring of a patient's condition during rehabilitation is essential. ClinicalTrials.gov ID: NCT0580836

The current regeneration mode of public space in the old city of Guangzhou is ineffective, thus necessitating supplementation with a more systematic methodology. The “plug-in design” targets sustainable regeneration while preserving the overall urban texture and context, i.e., has little impact on the spatial qualities of the old city. The ultimate goal is to activate the public space of the old city of Guangzhou point-to-area through the insertion of various plug-ins. In this study, the methodology is applied to Xudi Gaodi Street, the core area of the old city of Guangzhou, to explore its effects on sustainability. The internal public space is isolated and supplied with rigid and flexible plug-ins from multiple dimensions, which not only improves the spatial environment but also injects new urban formats. This work provides a specific solution for regeneration in Guangzhou’s old city while enhancing empirical knowledge of the plug-in design to support urban regeneration theory and further practical development.

Halloysite and kaolinite are dioctahedral TO phyllosilicates that drive the interest of scientists for formulating environmental friendly materials, and consequently in the field of ceramics. The main scope of this study was the understanding of the texture evolution upon the dehydroxylation reaction and the influence of the presence of halloysite. In situ synchrotron (002) and (111) poles figures were recorded on the DiffAbs beamline at SOLEIL Synchrotron, from room temperature to 1000°C, on kaolinite and/or halloysite-rich samples shaped by tape casting. Commercial kaolins and halloysite provided by Imerys company were used. The samples were labeled KRG100, KCS100, H100, KRG50H50 and KRG59H50 in relation with the wt. % of kaolin (KRG, KCS) or halloysite (H) clays. In samples KCS100 and KRG100, a strong texture was observed until in situ annealing at 700°C, with respect to the c-axis of kaolinite. One the contrary, the texture with respect to the c-axis of halloysite for the sample H100 was weak whatever the temperature was. Moreover, this weak texture disappeared before the complete dehydroxylation of halloysite. This is due to the opening of some halloysite tubes. When considering the samples KRG50H50 and KCS50H50, a significant texture was observed with the c-axis preferentially oriented perpendicular to the sample surface . The presence of kaolinite platelets predominated onto the alignment of halloysites tubes. Furthermore, it was noted that the halloysite influenced the (002) diffracted intensity into the temperature range 20 °C and 400 °C. Above 400°C, the behavior obtained for the (002) reflection in samples KRG50H50 and KCS50H50 was similar to the behavior noticed for pure kaolins KRG100 and KCS100 respectively. The dehydroxylation temperature range appeared to be relevant with combined effect of kaolinite and halloysite transformations arising from KRG100 or KCS100 and H100 samples. Therefore, the onset point of dehydroxylation is 550 °C ± 25 °C for KRG100, KCS100 KRG50H50 and KCS50H50. For the pure halloysite H100 sample, the dehydroxylation starts at lower temperature 475°C. It was also noted that during the dehydroxylation of kaolinite, the characteristic portion of ring related to the diffracted intensity of the (111) reflection located at χ = 45 ° tended to disappear above 550 °C and led to the formation of a new transitory phase with a (111) reflection with perpendicular alignment to the c-axis. Indeed, an epitaxial relationship with the (111) kaolinite reflection could be assumed. Further X-ray scattering experiments allowed highlighting the effective offset temperature of the dehydroxylation, which was identified as close to 720 °C. The metakaolinite obtained undergone structural transformation to another transitory phase at 1000°C.

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.

Aims: To report on the clinico-pathological features of a series of 12 intra-oral mucoepidermoid carcinomas showing exclusive intra-cystic growth. Methods and methods: All mucoepidermoid carcinomas diagnosed in the period 1990-2012 were retrieved, the original histological preparations were reviewed to confirm the diagnosis, and from selected cases, showing exclusive intra-cystic neoplastic component, additional sections were cut at 3 subsequent 200m intervals and stained with Hematoxylin-Eosin, PAS and Alcian Blue, to possibly identify tumor invasion of the adjacent tissues, which could have been overlooked in the original histological preparations. Also, pertinent findings collected from the clinical charts and follow-up data were analyzed. Results: We identified 14 intraoral mucoepidermoid carcinomas treated by conservative surgery and with a minimum follow up of 5 years. The neosplasm were located in the hard palate (9 cases), the soft palate (2), the cheeck (2) and the retromolar trigone (1). In all instances histological examination was revealed the presence of a single cystic space, containing clusters of columnar, intermediate, epidermoid, clear and mucous-producing cells, the latter exhibiting distinct intra-cytoplasmic mucin production, as confirmed by PAS and Alcian Blue stains. The cysts were entirely circumscribed by fibrous connective tissue and no solid areas or infiltrating tumour clusters were detected. Conservative surgical resection was performed in all cases and no recurrences or nodal metastases were observed during the follow up period. Conclusions: Mucoepidermoid carcinomas showing prominent (>20%) intra-cystic proliferation currently are considered low-grade tumours. In addition, we also unveil the possibility that mucoepidermoid carcinomas, at least in their early growth phase, may display an exclusive intra-cystic fashion and might be considered as in situ carcinomas, unable to infiltrate adjacent tissues or metastasize.

Acid in-situ leaching (ISL) is a common approach to the recovery of uranium in the subsurface. As some toxic and harmful substances might be produced by the chemical reactions among the injected sulphuric acid, the groundwater, and the porous media during leaching processes, the pollution control of the mining plan for ISL is important. In this study, a three-dimensional reactive transport modeling (3DRTM) was applied to decide the pollution control mining plan, considering the partial penetration through wellbore in confined aquifer and complex chemical reactions between main minerals. Based on the 3DRTM, different pumping ratio and non-uniform injection schemes were compared. The results show that the preferential pollution control mining plan is non-uniform injection ratio equal 0.1. By analyzing the characteristics of water table and streamline, it is concluded that the scheme has a strong hydraulic capture effect. In this scheme, the concentration of UO22+, H+, SO42- obtained by 3DRTM is lower. The inner well injection rate is 194.09 m3/d, the outer well injection rate is 158.89 m3/d, and the pumping rate is 264.00 m3/d. A reasonable suggestion is to adopt non-uniform injection mining mode in ISL.

Objective: The stability of the flight phase in ski jumping is crucial for athletes' performance and safety. This study aims to investigate the influence of unfavorable conditions on aerodynamic characteristics and flight stability through computational fluid dynamics (CFD) numerical simulations. Methods: The ski jumper and the skis are considered as a multi-body system. A detailed three-dimensional (3D) model of this multi-body system under a commonly observed posture during flight is established. The partially averaged Navier-Stokes (PANS) turbulence model is employed, and CFD simulations are conducted to predict the aerodynamic characteristics of the multi-body system under lateral environmental wind and asymmetric postures during flight phase. The conditions of asymmetric postures include yaw rotation and roll rotation. Results: (1) Lateral environmental wind generated yaw force, yaw moment, and roll moment, which influenced the lift, drag, and pitch moment of the athlete. These forces and moments were relatively small at lower wind speeds (less than 3 m/s) and became more significant at higher wind speeds (greater than 4.5 m/s). (2) Under the influence of yaw rotation or roll rotation, the multi-body system exhibited noticeable yaw force, yaw moment, and roll moment, all showing a monotonic increasing trend. Moreover, they had a significant impact on the lift, drag, and pitch moment of the multi-body system. Conclusion: (1) The influence of unfavorable conditions is complex, resulting in significant yaw force, yaw moment, and roll moment on the multi-body system. The adverse effects of roll rotation were generally greater than those of yaw rotation. (2) The multi-body system exhibited self-stabilizing tendencies in yaw and roll. This phenomenon can provide a solution to maintain flight stability by employing appropriate yaw or (and) roll rotation angles, effectively compensating for or even eliminating the adverse effects of lateral environmental wind. (3) Understanding the mechanisms of how unfavorable conditions affect the aerodynamic characteristics and stability during flight in ski jumping can provide valuable assistance for real-time prediction and decision-making during competitions, as well as scientific guidance for training athletes stable flight control and techniques and improving their sport performance.

Cariogenic oral biofilms cause a considerable amount of recurrent dental caries around composite restorations every year, resulting in unprosperous oral health status and expensive restorative treatment for many patients. Quaternary ammonium monomers that can be copolymerized with the current dental resin systems have been increasingly explored for modulation of dental plaque biofilm growth over dental composite surfaces. Here, we investigated the effect of bis(2-methacryloyloxyethyl) dimethylammonium bromide (QADM), against human overlying mature oral biofilms grown intra-orally in human participants for 7 and 14 days, for the first time. Seventeen volunteers wore palatal devices containing composite specimens containing 10% by mass of QADM or a control composite without QADM. After 7 and 14 days, the adherent biofilms were collected for determination of bacterial counts via colony-forming unit (CFU) counts. The biofilm viability, chronological changes, and percentage coverage were also determined by live/dead staining. QADM composites caused a significant inhibition of S. mutans biofilm formation for up to seven days. No difference in the CFU values were found for the 14-day period. Our findings suggest that (1) QADM composite was successful in inhibiting 1-3 day biofilms in the oral environment in vivo; (2) QADM significantly reduced the portion of S.mutans group in a time course where patients at high risk of caries would develop initial enamel carious lesions; and (3) stronger antibiofilm activity is required for the control of mature long-term cariogenic biofilms. These results provide a perspective on the value of integrating bioactive restorative materials with traditional caries management approaches into clinical practice. Contact-killing strategies via dental materials aiming to prevent or at least reduce high numbers of cariogenic bacteria seem to be a promising approach in patients at high risk of recurrence of dental caries around composites.

Legumes develop root nodules that harbour endosymbiotic bacteria, rhizobia. These rhizobia convert nitrogen to ammonia by biological nitrogen fixation. A thorough understanding of the biological nitrogen fixation in legumes and its regulation is key to develop sustainable agriculture. It is well known that plant hormones affect nodule formation; however, most studies are limited to model legumes due to their suitability for in vitro, plate-based assays. Specifically, it is almost impossible to measure the effects of exogenous hormones or other additives during nodule development in crop legumes such as soybean as they have huge root system in soil. To circumvent this issue, the present research develops suitable media and growth conditions for efficient nodule development under in vitro, soil free conditions in an important legume crop, soybean. Moreover, we also evaluate the effects of all major phytohormones during soybean nodulation under identical conditions. This versatile, inexpensive, scalable and simple protocol provides several advantages over previously established methods. It is extremely time-and resource-efficient, does not require special training or equipment, and produces highly reproducible results. The approach is expandable to other large legumes as well as for other exogenous additives.

Mutations, especially those at the protein-protein interaction (PPI) interface, have been associated with various diseases. Meanwhile, though de novo mutations (DNMs) have been proven important in neuropsychiatric disorders, such as developmental delay (DD), the relationship between PPI interface DMNs and DD has not been well studied. Here we curated developmental delay DNM datasets from the PsyMuKB database and showed that DD patients showed a higher rate and deleteriousness in DNM missense on the PPI interface than sibling control. Next, we identified 302 DD-related PsychiPPIs, defined as PPI harboring a statistically significant number of DNM missenses at their interface, and 42 DD candidate genes from PsychiPPI. We then observed that PsychiPPIs preferentially affected hub proteins in the human protein interactome network. When analyzing DD candidate genes using gene ontology and gene spatio-expression, we found that PsychiPPI genes carrying PPI interface mutations, such as FGFR3 and ALOX5, were enriched in development-related pathways and the development of the neocortex, and cerebellar cortex, suggesting their potential involvement in the etiology of DD. Our results demonstrated that DD patients carried an excess burden of PPI-truncating DNM, which could be used to efficiently search for disease-related genes and mutations in large-scale sequencing studies. In conclusion, our comprehensive study indicated the significant role of PPI interface DNMs in developmental delay pathogenicity.

Sanctuaries devoted to Asclepius were established and operated for almost a thousand years in various Greek and Roman cities throughout the Mediterranean region. The Asclepieion sanctuary in Lenta (formerly known as Ancient Lebena) in Crete was famous for receiving water from a sacred spring. In the Ancient Lebena, Levinaion was a famous centre for hydrotherapy, physiotherapy and a psychiatric hospital. In the present paper, we aim to assess the hydrochemical status of this sacred spring that holds a prominent position in archaeological and historical studies. The main objectives of this study are: Initially, to present supervisory evidence (archaeological, geological, hydrochemical) of an area that was a water resource management model for many centuries, carrying out therapeutic work. The second objective is to present and compare hydrochemical data in the last century, i.e. from 1915 to 2021. The third objective is to highlight and warn of an incipient saltwater intrusion in the area along the Lentas coast. The fourth objective is to propose an alternative and sustainable form of water resources management in the region that requires the study and rational utilization of the sporadic small water springs in the region. Our study focuses on a basic hydrochemical analysis of spring and borehole water in the remains of Levinaion in the Lentas region and their comparison with spare historical data of the sacred spring water, aiming to interpret the impact of the changes in the spring water resources that occurred in the last decades due to urban modernization. Our results highlight (i) visible fluctuations in chemical composition of borehole water samples, (ii) a neutral to alkaline pH in borehole waters, and an alkaline pH in spring waters, (iii) un-detectable arsenic of Lentas borehole water, unlike historical data of Lentas spring water, (iv) low values of dissolved radon of Lentas borehole water and spring water of Kefalovrysa, and (v) a timeless constant and hypothermic nature of the water of both sacred spring and borehole of Lenta, but also of Kefalovrysa spring. The recorded historical data, i.e. from 1915 to 1957, due to the absence of substantial anthropogenic activity in the area, can be used as reference values (natural background levels, NBLs) for the Lentas area. Our findings emerge with the need to bring again the flowing spring water of the sacred spring of Lentas in its original form through sustainable management and re-discover its beneficial therapeutical effects.

Efficient thermal management of modern electronics requires the use of thin films with highly anisotropic thermal conductivity. Such films enable the effective dissipation of excess heat along one direction while simultaneously providing thermal insulation along the perpendicular direction. In this study, we investigate the thermal conductivity of bilayer graphene (BLG) sheets using non-equilibrium molecular dynamics, examining both in-plane and cross-plane thermal conductivities. The in-plane thermal conductivity of 10 nm × 10 nm BLG with zigzag and armchair edges at room temperature is found to be around 204 W/m.K and 124 W/m.K, respectively. The in-plane thermal conductivity of BLG increases with sheet length. For all sizes, BLG with a zigzag edge exhibits higher thermal conductivity than that of the armchair edge, with this difference becoming more pronounced as the lengths of the sheets increase. In addition, increasing temperature from 300 K to 600 K decreases the in-plane thermal conductivity of a 10 nm× 10 nm zigzag BLG by about 34%. Similarly, the application of a 12.5% tensile strain induces a 51% reduction in its thermal conductivity compared to the strain-free values. Armchair configurations exhibit similar responses to variations in temperature and strain, but with less sensitivity. Furthermore, the cross-plane thermal conductivity of BLG at 300 K is estimated to be 0.05 W/m·K, significantly lower than the in-plane results by approximately four orders of magnitude. The cross-plane thermal conductance of BLG decreases with increasing temperatures, specifically, at 600 K, its value is almost 16% of that observed at 300 K.

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.

Mycotoxins are secondary metabolites produced by filamentous fungi associated to a variety of acute and chronic foodborne diseases. Current toxicology studies mainly rely on monolayer cell cultures and animal models, which are undeniably affected by several limitations. To bridge the gap between the current in vitro toxicology approach and the in vivo predictivity of the data, we here investigated the cytotoxic effects induced by the mycotoxins sterigmatocystin (STE), ochratoxin A (OTA) and patulin (PAT) on different 2D and 3D cell cultures. We focused on human tumours (neuroblastoma SH-SY5Y cells, and epithelial breast cancer MDA-MB-213 cells) and healthy cells (bone marrow derived mesenchymal stem cells, BM-MSC, and umbilical vein endothelial cells, HUVECs). Cytotoxicity of STE, OTA, and PAT was determined after 24, 48 and 72 h of exposure by ATP assay in both culture models. 3D spheroids morphology was also analysed using the MATLAB-based open-source software AnaSP. Our results highlighted how each cell line and different culture models showed specific sensitivities, reinforcing the importance of using more complex models for toxicology studies and a multiple cell line approach for an improved and more comprehensive risk assessment.

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.

Among the many Lysosomal Storage Disorders (LSDs) that would benefit from the establish-ment of novel cell models, either patient-derived or genetically engineered, is Mucopolysaccha-ridosis type II (MPS II). In fact, even though a specific therapeutic approach does exist for this disorder (Enzyme Replacement Therapy, ERT, with recombinant human IDS) and haematopoiet-ic stem cell transplantation (HSCT) may also hold promise whenever the disorder is diagnosed soon enough, both approaches have their own drawbacks. Here we present our results on the establishment and characterization of two MPS II pa-tient-derived stem cell line(s) from deciduous baby teeth. To the best of our knowledge, this is the first time a stem cell population is isolated from LSD patient samples obtained from the oral cavity. Taking into account our results on the molecular and biochemical characterization of those cells and our first insights on their subcellular MPS phenotype, we consider these cells will be a valuable tool for both pathophysiological assessments and drugs screenings. Ultimately, we believe patient-derived dental pulp stem cells (DPSC) may represent a feasible alternative to induced pluripotent stem cells (iPSC) in many labs with standard cell culture con-ditions and limited (human and economic) resources.

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.

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.

Objective: To describe the methodology used and the results found in the implementation of Lean in Emergencies in the Emergency sector of the Hospital de Clínicas of the Federal University of Uberlândia (HC-UFU), verifying the difficulties and particularities that involved the process, as well as the result obtained. Material and methods: For the comparison between the periods before (T1), contemporary (T2) and after (T3) the implementation of Lean, hospital data were used , and the indicators corresponding to 10 variables were analyzed: Male Hospitalization and Female Hospitalization; High Male and High Female; Male Transfer and Female Transfer, Male Death <24h and Female Death <24h; Male Death >24h and Female Death >24h and general occupancy rate. All raw data related to the 36 months of evaluation were provided by the HC-UFU Statistics sector in spreadsheets without identifying patients. The indicators were compared to each other in the three analyzed periods, with the study directed as follows: Previous stage - Pre -intervention (T1): considered between the months of April 2017 to March 2018, completing 12 months before the implementation of Lean; Intra-intervention stage - contemporary (T2): considered between the months of April 2018 to March 2019, in a total of 12 months which was the implementation period; Post-Intervention Stage (T3): later: considered between the months of April 2019 to March 2020, completing 12 months after the implementation of Lean. The Lean in Emergencies scores (NEDOCS and LOS) were only recorded during the period that the implementation team was able to record and were used only to demonstrate trend over time. Comparison of the indicators with those found in other hospital units that also implemented Lean was carried out based on bibliographical research. Results and Discussion: The analysis of the behavior of the indicators did not demonstrate effectiveness related to the implementation of the system in the emergency sector. The failure to obtain better indicators can be attributed to discontinuity in monitoring the project, the lack of involvement of the clinical staff and alignment with the needs of the staff training academy, the difficulty of understanding the project by local and regional public entities. geographical location where the hospital is located, and by users of the health system who were not properly informed about the development of the project. These aspects should be considered in future management projects that may be implemented in the hospital. Despite the result of the implementation of Lean in the emergency sector not having reached the expected goals, the attempt showed windows of opportunity for future action on points that can improve the hospital management process and that should be tested in the next experiences. Conclusion: The methodology followed for the implementation of Lean in Emergencies in the emergency sector of the hospital did not produce improvement in hospital indicators.

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.

The research is focusing on analyzing the concentrations of particulate matter (PM) next to a highly congested road section, with 39,900 as a maximum number of vehicles per 24 h, in the vicinity of Timisoara, Romania. Concentrations have been measured in multiple episodes using two different measurement methods, gravimetric and dynamic light scattering, showing a disperse range of PM concentrations. Presence of metal particles in the samples have been analyzed using an electron microscope. Additionally, impact on human health is described by evaluating results for inhalable, thoracic, and alveolar sized particles.

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.

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.

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.

Objective: This study investigated the effect of the hierarchical medical system under the national health insurance program on resident’s healthcare-seeking behavior in Taiwan. Background: Healthcare authorities in Taiwan initiated the allowance reduction of outpatient visits at regional hospitals and higher hierarchical hospitals from 2018. The ultimate goal is to implement a hierarchical medical system and provide the residents accessible as well as consistent medical services. Methods: This research was conducted through the questionnaire survey method and data were collected between August and December 2018 from the records of subjects who had recently sought medical attention. A total of 1,340 valid questionnaires were returned. Results: Regarding the effect on healthcare-seeking behavior, the following factors were significant: being aged between 40 to 49 (p＜.1), subjects with an educational background of junior high school (p＜.05), those who were not aware of the policy (p＜.001), and an awareness about both the hierarchical medical system and the policy to reduce outpatient visits to large hospitals (p＜.001). Conclusion: The public should be made aware about the hierarchical medical system to improve healthcare.

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.

Oxalate, a compound produced by many edible plants and as a terminal metabolite in the liver of mammals, is a toxin that has a detrimental role to human health. Humans and other mam-mals do produce the enzymatic machinery to degrade oxalate. However, numerous oxa-late-degrading bacteria reside in the mammalian gut and thus provide an important function for hosts. The current review focuses on the environmental factors that influence the efficacy of pro-biotic oxalate-degrading bacteria, relative to oxalate metabolism. We describe the mechanism of oxalate catabolism and its consumption by obligate and facultative anaerobic oxalate-degrading bacteria, in both in vitro and in vivo environments. We also explore the environmental variables that impact oxalate degradation. Studies on single species degrade oxalate have not shown a strong impact on oxalate metabolism especially in high oxalate conditions such as consumption of foods high in oxalate (such as coffee and chocolate for humans or halogeton in animal feed). Considering effective variables which enhance oxalate degradation could be used in application of effective probiotic as a therapeutic tool in individuals with hyperoxaluria. This study indicates probiotics can be considered a good source of naturally occurring oxalate degrading agent in human colon

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.

Objectives: The study aimed to uncover the percentages of battered women in Jordan, its causes, forms, and relationship to several social factors. Methodology: The study was conducted on a random, targeted sample of (1308) women based on social sample survey method and electronic questionnaire tool for data collection, the Descriptive statistical method and chi-square test were used to examine statistically significant differences. Results: The study found that the percentage of battered women reached 17.1% during Corona pandemic in 2020, and the increase in men's violence against women during this period of was in large and medium degrees according to the sample. Husbands were the most practicing violence against their wives at 37.5%, followed by fathers against daughters at 28.6%, and brothers against sisters at 26.8%. The causes of male violence are due to social factors represented by male domination culture, interference by family and relatives, and economic factors represented by the high cost of living, low household income and poverty. The most common forms of violence are verbal, physical, and psychological. The study found that women in southern Jordan, who are poorer and less educated, and who live in a large family, are the most abused. The study recommended activating family and community service and reform offices, solving problems of deteriorating economic situation and individual poverty, and enlightening community awareness of the dangers of domestic violence.