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

In the world's first pig-to-human cardiac xenotransplant, the elevated levels of porcine cytomeg-alovirus (PCMV) are considered key factors contributing to patient mortality. This has renewed attention to PCMV, a virus widely prevalent in pigs. Currently, there are no effective drugs or vaccines targeting PCMV, and its high detection difficulty poses challenges for prevention and control research. In this study, antiviral small hairpin RNA (shRNA) was selected and inserted into the Rosa26 and miR-17-92 loci of pigs via a CRISPR/Cas9-mediated knock-in strategy. Further in vitro viral challenge experiments demonstrated that these genetically edited pig cells could effec-tively limit PCMV replication. Through this process, we constructed a PCMV-infected cell model, validated partial viral interference sites, enhanced gene knock-in efficiency, performed gene editing at two different gene loci, and ultimately demonstrated that RNA interference (RNAi) technology combined with CRISPR/Cas9 has the potential to generate pig cells with enhanced antiviral infec-tion capabilities. This opens up possibilities for the future production of pig populations with anti-viral functionalities.

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

Acute and chronic respiratory diseases impose a significant economic and health burden. Distal small airway assessment requires invasive procedures such as a bronchoscopy and bronchoalveolar lavage. The Particles in Exhaled Air (PExA) device provides a non-invasive means of assessing small airways; it captures distal airway particles sized around 0.5-7m and contains particles of respiratory tract lining fluid (RTLF) that originate during airway closure and opening. The PExA device can measure particle count and mass according to particle size. Subsequent capture of particles in a thin membrane enables application of various analytical methods to assess a broad range of biomolecules including phospholipids, proteins, inflammatory profile, and other metabolites to characterise inflammation and diseases processes such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, lung cancer, and more recently acute infections such as COVID-19. PExA analysis provides a promising alternative to traditional investigative methods in the assessment, diagnosis, and management of respiratory conditions. By evaluating specific biomarkers in the RTLF associated with airway inflammation, PExA may offer a more accurate and comprehensive understanding of the molecular-level changes in the small airways of patients with acute and chronic lung diseases.

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.

Infections caused by KPC-producing K. pneumoniae continue to pose a significant clinical challenge due to emerging resistance to new antimicrobials. We investigated the association between two drugs whose roles have been repurposed against multidrug-resistant bacteria: fosfomycin and temocillin. Temocillin exhibits unusual stability against KPC enzymes, while fosfomycin acts as a potent “synergizer”. We conducted in vitro antimicrobial activity studies on 100 clinical isolates of KPC-producing K. pneumoniae using a combination of fosfomycin and temocillin. The results demonstrated synergistic activity in 91% of the isolates. Subsequently, we assessed the effect on Galleria mellonella larvae using 5 different KPC-Kp isolates. The addition of fosfomycin to temocillin increased larvae survival from 73 to 97% (+Δ 32%; isolate 1), from 93 to 100% (+Δ 7%; isolate 2), from 63 to 86% (+Δ 36%; isolate 3), from 63 to 90% (+Δ 42%; isolate 4), and from 93 to 97% (+Δ 4%; isolate 10), respectively. Among the temocillin-resistant KPC-producing K. pneumoniae isolates (24 isolates), the addition of fosfomycin reduced temocillin MIC values below the resistance breakpoint in all isolated except one. Temocillin combined with fosfomycin emerges as a promising combination against KPC-producing K. pneumoniae, warranting further clinical evaluation.

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

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

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

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

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

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

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

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

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

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

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

In this review we look at the developments in the field of artificial intelligence (A.I) and their current impact as well as future implications in the field of cardiology, we as physicians and cardiologists have tried to put our perspective on the rapidly evolving field, In light of the fact that many of the healthcare workers and professionals across the world still find the concept of A.I quite complicated, elusive and somewhat paradoxical, we have tried to simplify the concept of artificial intelligence and make it easy for everyone to understand from all walks of life. The Databases utilized for our review are PubMed, PubMed Central, Google Scholar. The Keywords used for our Data Search are “Artificial Intelligence”, “A.I Cardiology”, “A.I in Cardiovascular Medicine”, “Machine Learning in Cardiology”. We screened all relevant since inception till March 25th and included 44 relevant articles after careful consideration into our paper. We have discussed the implementation of and scope of artificial intelligence across a broad spectrum of applications including cardiovascular imaging and diagnostics like electrocardiograms, echocardiograms, cardiac CT/MRIs to novel cardiac monitoring devices, CRISPR gene editing in cardiology and implementation of artificial intelligence in the field of Cardiovascular Bioprinting. This is the initial review in a series of reviews regarding A.I in Cardiology.

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

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

Endovascular therapy (EVT) has revolutionized the management of acute ischaemic strokes with large vessel occlusion, with emerging evidence suggesting its benefit also in large infarct core volume strokes. In the last 2 years, 4 randomised controlled trials have been published on this topic - RES-CUE-Japan-LIMIT, ANGEL-ASPECT, SELECT2 and TENSION, with overall results showing that EVT improves functional and neurological outcomes compared to medical management alone. This review seeks to summarise the recent evidence presented by these 4 trials and highlight some of the limitations of our current understanding on this topic.

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.

While obesity is recognized as a key global public health issue, there has been no research to date on the perceptions of care for people with this condition held by individuals in positions of organizational power. The aim of this study was therefore to describe the perceptions and experiences of clinical leaders and managers of providing care to inpatients with obesity at a metropolitan public health service. This study applied an interpretative phenomenological analysis (IPA) approach to qualitative research, conducting interviews with 17 participants. Their perceptions of care for inpatients with obesity encompassed both their personal understanding as an individual, and their observations about the organizational, patient and carer perspectives. Three overall themes were identified: 1) The problem of inpatients with obesity, 2) Inpatients with obesity as sources of risk and 3) Personal and professional perceptions of inpatients with obesity. While clinical leaders and managers were aware of potential impact of stigma and weight bias on the care given to this cohort, elements of implicit bias, stereotyping, ‘othering’ and ambivalence were frequently present in the data. Ongoing efforts to improve care for patients with obesity must therefore include efforts to address perceptions and attitudes at all organisational levels of the workforce.

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

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

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

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

The dominant view of cleaning compulsion as a dimension of OCD is that it is motivated by contamination anxiety. However, in daily life, much cleaning is undertaken as part of tidying one’s home. Such cleaning as well as the other tidying chores may equally assume obsessive-compulsive proportions. However, empirical interest in this phenomenon has remained sparse so far. This article aims to increase awareness of this ill-acknowledged symptom cluster among OCD researchers and to invite them to investigate it. After the introduction, clinical evidence for this OCD dimension is dealt with. Next, empirical studies with OCD inventories, which contain items referring to compulsive tidying, are discussed. Two of these made use of an OCD-inventory, devised by the present author. These also provide the data for the main investigation to be discussed in this paper. In that latter study, six OCD-item clusters, among which tidying compulsion, are predicted. These predictions are tested by evaluating and comparing the item-cluster correlations of all six clusters. These also offer a basis to optimize the clusters toward more homogeneous and distinct ones. By comparing predicted with final clusters, the items can be qualified as either hits, false positives, or false negatives. This output provides the details for revising the predictions, but also allows for calculating the values of two global “goodness-of-fit” measures for each predicted cluster. Though the results do not completely endorse the predicted composition of part of the clusters in the second sample, tidying compulsion is doing rather well. To determine the incidence of tidying compulsion based on the cluster scores, decisions had to be made about what constitute a cluster score, how its gravity can be estimated, and what should be the cut-off per cluster to divide the sample into clinical and subclinical cases on each cluster. If these ‒ unavoidably arbitrary ‒ decisions are accepted, both samples show an incidence of tidying compulsion of around 25%. After a brief critical evaluation of all discussed studies, it is concluded that the evidence presented, though modest, is solid enough to warrant further research into tidying compulsion.

Museums are called to respond to contemporary challenges and contribute to the formation of more progressive societies. One of the major challenges of our time is climate change and museums could construct cocreated narratives around climate and implement targeted actions for the audiences through their sensorial and affective experiences. More specifically, Geology and Palaeontology museums are repositories of knowledge on geoheritage and geoconservation, recognized for their scientific, pedagogical, cultural and recreational values. The educational potential of geological and paleontological exhibits could be used in informal education activities regarding the climate emergency. Taking the above into consideration, this study focuses on both the creation and evaluation of an educational program for the Natural History Museum of Arsakeio Campus at Psychicko.

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.

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

We aimed to investigate the clinical results following poor-quality embryo transfer and the parameters to foresee the prognosis. In this study, 2123 cycles that had day 3 and day 5 single-fresh embryo with a poor-quality embryo transfers and a good-quality embryo transfers were compared. The cycles according to transfer day were evaluated by conducting a subgroup analysis. The correlation between all the obtained demographic characteristics, controlled ovarian stimulation parameters and cycle results were analysed. Clinical pregnancy was established in 53 patients that underwent transfer in the poor-quality embryo group (14.9%). Of these patients, 36 had live birth (live birth rate per clinical pregnancy 67.9%). In cleavage-stage embryos, live birth rates per clinical pregnancy were higher in poor-quality blastocyst transfer. When analysing the factors affecting live births in poor-quality embryo group, as the total gonadotropin dose increases, the probability of live birth decreases, as in the probability of hCG positivity. In conclusion; although the probability of pregnant is low, when clinical pregnancy is established, there is a high chance of having a live birth after poor-quality embryo transfers. This could be regarded as an acceptable option in cycles when only poor-quality embryos were available.

Parkinson's Disease (PD) is a neurodegenerative disorder that affects the motor system of the human body. Currently, the available treatments are limited and often have undesirable side effects. In this context, the aim of this study was to develop a novel combinational formulation of Apomorphine and Quetiapine and evaluate its efficacy in a rat model of PD. The formulation was prepared using the solvent evaporation technique and characterized for its physicochemical properties. The in-vitro drug release was evaluated using the Franz diffusion cell method, and the pharmacokinetics of the combination was studied in rats. The behavioural and biochemical parameters were evaluated in the rats using the Rotarod, pole test, and biochemical assays. The results showed that the developed formulation had satisfactory physicochemical properties and exhibited sustained drug release. The pharmacokinetic studies showed that the combination exhibited a longer residence time than the individual drugs. The behavioural and biochemical parameters showed that the combination was effective in improving motor function and reducing oxidative stress. In conclusion, the developed Apomorphine and Quetiapine combination formulation showed promising results in improving motor function and reducing oxidative stress in rat model of PD. Further studies are required to evaluate the safety and efficacy of the developed formulation in humans.

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

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

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.

With the development of organizational biology and forced from the EU Cosmetic Regulation (EU/1223/2009) with the complete ban of animal testing for cosmetic purposes, 3D skin models have been widely developed due to their similar physiological structure and metabolic function to native human tissue. 3D skin models for in vitro cosmetic evaluation are still promising alternative methods for evaluating phototoxicity, corrosivity and irritation. These models have been used for early screening and later validation of toxicity and efficacy evaluation by many well-known cosmetic companies. 3D skin models have become an important tool in cosmetic evaluation research. This article reviews the development of 3D skin models and their application in cosmetic evaluation. An outlook on the current application and future technological development directions in the cosmetic field is also presented.

In this work, we designed a MEMS device which allows simultaneous direct measurement of mechanical properties during deformation under external stress and characterization of the evolution of microstructure of nanomaterials within a transmission electron microscope. This MEMS device makes it easy to establish the correlation between microstructure and mechanical properties of nanomaterials. The device uses piezoresistive sensors to qualitatively measure the force and displacement of nanomaterials, e.g., in wire and thin plate forms. The device has a theoretical displacement resolution of 0.19 nm and a force resolution of 2.1 μN. The device has a theoretical displacement range limit of 2.74 μm and a load range limit of 27.75 mN.

The building envelope has the most significant contribution in the reduction of the building energy consumption. Application of new, alternative and improved materials and systems has an important impact on the buildings performances. This paper is focused on the thermal transmittance, as an indicator of the thermal conductance of the construction element. It includes comparisons of the U-values, calculated by software, with those measured in situ on three representative façade walls. The walls have been constructed with the new wall system Fragmat NZ-1, a new product in Macedonian buildings. This research provides basic information on the thermal transmittance of the system. The results of the analysis show that the in situ measuring is a useful tool in validation of the precision of analytically calculated values, since it was difficult to obtain precise results from the analytical calculations only, especially when the layers are with non-uniform thickness.

Fever control is essential in patients with severe traumatic brain injury (TBI). The efficacy of therapeutic hypothermia (TH) in severe TBI has been investigated over the last few decades; however, in contrast to experimental studies showing benefits, no evidence of efficacy has been demonstrated in clinical practice. In this review, the mechanisms and history of hypothermia were briefly outlined, while the results of major randomized controlled trials (RCTs) and meta-analyses investigating TH for adult TBI are introduced and discussed. The retrieved meta-analyses showed conflicting results, with a limited number of studies indicating benefits of TH. Some studies have shown benefits of long-term TH compared with short-term TH. Although TH is effective at lowering elevated intracranial pressure (ICP), reduced ICP does not lead to favorable outcomes. Low-quality RCTs overestimated the benefits of TH, while high-quality RCTs showed no difference or worse outcomes with TH. RCTs assessing standardized TH quality demonstrated the benefits of TH. As TBI has heterogeneous and complicated pathologies, applying a uniform treatment may not be ideal. A meta-analysis of young patients who underwent early cooling and hematoma removal showed better TH results. TH should not be abandoned, and its optimal should be advocated on an individual basis.

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

Bovine mastitis is the most impacting disease of dairy industry, and it is characterized by a complexity of causal agents, which have revealed a geographical variation among regions and countries. The mastitis-related pathogens have been traditionally classified as contagious or environmental, based on habits of the microorganisms and transmission routes. In addition, the severity of mammary infections has been associated with the virulence of the pathogens, and immune and nutritional status of the hosts. Considering this scenario, we investigated the etiological nature, clinical severity scores, and days in milk (DIM) data in 4,273 clinical cases of bovine mastitis among ten large-dairy farms located in the Southeast region of Brazil. Streptococcus dysgalactiae (283/4,273=6.6%), Escherichia coli (190/4,273=4.4%), Prototheca spp. (112/4,273=2.6%), and Streptococcus uberis (95/4,273=2.2%) were the predominant pathogens isolated, all from the environmental origin. Among 4,273 clinical cases, clinical gravity score was available in 43.8% (1,871/4,273) animals. From these, 69.8% (1,306/1,871), 27.3% (510/1,871) and 2.9% (55/1,871) were scored as mild, moderate, and severe, respectively. Most of isolation of pathogens were observed in the first 100 days in milk, and their clinical severity scored as mild (3,612/4,273=84.5%). Our results contribute to the etiological identification, clinical severity scoring, and milking aspects of bovine clinical mastitis in dairy farms with a history of clinical mammary infections.

The FDA has concluded that a biosimilar candidate capable of demonstrating pharmacodynamic biomarkers in a healthy subject need not be tested for clinical efficacy in patients, regardless of if the biomarker correlates with clinical response. Since monoclonal antibodies (mAbs) do not trig-ger pharmacodynamic response, they can be substituted with robust functional disqualifying them for this waiver that can be overcome by allowing comparison of functional properties that eventually result in clinical response. This suggestion is based on the FDA's preference for more sensitive testing methods. However, clinical efficacy testing in patients is the least sensitive method, as confirmed by statistical modeling, a fact that regulatory agencies need to admit. In this paper, I present a logical and rational argument to establish the biosimilarity of products that do not have pharmacodynamic biomarkers based on their orthogonally proven functional bio-similarity. This understanding will significantly lower the development cost of biosimilars, a goal that the FDA outlined in all its guidance. Keywords: biosimilarity 1; biosimilars 2; pharmacodynamic biomarkers 3; monoclonal antibodies 4; FDA 5; clinical efficacy testing in healthy subjects 6; clinical efficacy testing in patients 7; functional assays 8; receptor binding 9.

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.

Laser in situ keratomileusis (LASIK) is the gold standard in the surgical correction of refractive errors on the cornea. It entails the creation of a superficial hinged corneal flap by a femtosecond laser, ablation of the underlying stromal bed by an excimer laser, and reposition of the flap. The corneal flap can be build in a 2-dimension (2D) fashion with tapered edges, or in a 3-dimension (3D) fashion, with angled sidecut. The latter reduces the risk of flap dislocation and infiltration of epithelial cells. This retrospective study compares with optical coherence tomography 3D and 2D flaps, and respective intra- and early post-operative complications. Four hundred consecutive eyes were included, 200 for each group. In the 3D group, the mean edge angle was 92°. The procedure was in average 5.2 seconds slower in the 3D group (p=0). Non visually significant flap folds were found in 13 eyes of the 2D group and in 7 eyes of the 3D group (p= 0.17). An intracorneal opaque bubble layer induced by laser photodisruption was more commonly observed in the 3D group (9 eyes vs. 2; p=0.03). In conclusion, the creation of a LASIK flap by a 3D-femtosecond laser cut was safe and effective.

Urinary tract diseases are common in cats, and often require surgical reconstruction. Here, to explore the possibility of urinary tract reconstruction in cats using in-vivo tissue architecture (iBTA), biosheets fabricated using iBTA technology were implanted into the feline bladder and the regeneration process was histologically evaluated. The biosheets were prepared by embedding molds into the dorsal subcutaneous pouches of six cats for 2 months. A section of the bladder wall was removed, and the biosheets were sutured to the excision site. After 1 and 3 months of implantation, the biosheets were harvested and evaluated histologically. Implantable biosheets were formed with a success rate of 67%. There were no major complications following implantation, including tissue rejection, severe inflammation, or infection. Urinary incontinence was also not observed. Histological evaluation revealed the bladder lumen was almost entirely covered by urothelium after 1 month, with myofibroblast infiltration into the biosheets. After 3 months, the urothelium became multilayered, and mature myocytes and nerve fibers were observed at the implantation site. In conclusion, this study showed that tissue reconstruction using iBTA can be applied to cats, and that biosheets have the potential to be useful in both the structural and functional regeneration of the feline urinary tract.

Background Coronary artery disease (CAD) is a widely recognized cardiovascular disease that is considered the leading cause of death worldwide, affecting people on a global scale. Percutaneous coronary intervention (PCI), which involves procedures such as balloon angioplasty or stenting, plays an important role in opening blocked arteries and minimizing damage to the cardiac muscle. While the use of drug-eluting stents (DESs) has significantly reduced the occurrence of coronary restenosis, the problem of in-stent restenosis (ISR) continues to pose a significant clinical challenge. Gaining a deeper understanding of the clinical predictors associated with ISR is vital for early detection and appropriate treatment. Hence, this study aimed to evaluate the clinical predictors of ISR specifically in Taiwanese patients. Methods We conducted a single-center, retrospective case-control study, enrolling 517 CAD patients undergoing previous coronary stenting and stable angina with positive stress test or acute coronary syndrome (ACS) during follow-up between January 2019 and December 2022 at National Taiwan University Hospital. The patients were categorized into two groups: the ISR group, consisting of individuals who received drug-coated balloon (DCB) treatment (n=177), and the non-ISR group, comprising patients who did not receive DCB treatment (n=340). To gather relevant data, we meticulously reviewed the medical records and analyzed the findings from coronary angiography to assess the clinical characteristics of the patients. Results Patients with three-vessel disease (3VD) exhibited a higher prevalence of underlying diseases and were more likely to be taking aspirin and clopidogrel. Moreover, our analysis revealed that age (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00 - 1.04, p = 0.037) and the presence of 3VD (adjusted odds ratio [aOR] 2.15, 95% confidence interval [CI] 1.03 - 4.46, p = 0.039) were significantly associated with an increased risk of coronary ISR. Conclusions Older age and 3VD were the independent predictors of coronary ISR in CAD patients receiving coronary stent implantation.

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

Ensuring access to water, sanitation, and hygiene (WASH) facilities, coupled with behavior change education in schools, is fundamental for fostering a conducive learning environment and promoting principles of inclusion, dignity, and equality. This study focuses on 12 primary schools in Anápolis, Brazil, encompassing 4,394 students and 248 teachers. WASH assessments were conducted through a questionnaire, observation of water and sanitation facilities and structures, and microbiological analysis. Over the period 2018 to 2020, the proportion of schools with safely managed drinking water surged from 42% to 92%. However, sanitation conditions in the schools were categorized as a basic level, with hygiene services rated as limited in 92% of the schools due to the absence of soap. While this study reveals that Anápolis schools generally align with WASH guidelines for basic/advanced drinking water services, there is a crucial need for enhancements in both hardware and software facilities to address sanitation and hygiene challenges.

In recent experimental studies, we reported the aggravating effects of Asian sand dust (ASD) on male reproductive function in mice. However, the effects of fetal ASD exposure on male reproductive function have not been investigated. The present study investigated the effects of fetal ASD exposure on reproductive function in male offspring. Using pregnant CD-1 mice, ASD was administered intratracheally on days 7 and 14 of gestation, and the reproductive function of male offspring was determined at 5, 10, and 15 weeks after birth. The secondary sex ratio was significantly lower in the fetal ASD-exposed mice than in the controls. Histologic examination showed partial vacuolation of seminiferous tubules in immature mice. Moreover, daily sperm production (DSP) was significantly less in the fetal ASD-exposed mice than in the controls. DSP in the fetal ASD-exposed mice was approximately 10% less than the controls at both 5 and 10 weeks. However, both the histologic changes and the DSP decrease were reversed as the mice matured. These findings suggest that ASD exposure affects both the fetal development and the reproductive function of male offspring. In the future, it will be necessary to clarify the onset mechanisms of ASD-induced male fetus death and male reproductive disorders.

Detecting cracks in teeth is a clinical challenge. Patients may complain of diffuse pain on chewing, pain, at times, on temperature change and pain that occurs episodically. Common diagnostic tools such as radiographs and visual examination may not detect cracks. This case report shows how PTR-LUM in The Canary System can detect cracks in teeth not seen with other devices. In this clinical situation, the crack involved a portion of the mesial and distal surfaces of a mandibular second molar.

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.

Background: Open AI developed ChatGPT, a language model based on the GPT architecture, designed for text-based communication. Trained on diverse internet texts, ChatGPT generates contextually appropriate responses using machine learning. It understands input through analysis and context interpretation, generating coherent and contextually relevant responses. Interaction is possible through messaging platforms. Materials and Methods: In November 2023, we utilized ChatGPT 3.5, the default version at that time, to answer questions from the Italian National Residency Program Admission Tests (SSMs) of 2021, 2022, and 2023. The questions cover clinical, diagnostic, analytical, therapeutic, and epidemiological scenarios, sometimes accompanied by images. The study compared ChatGPT's answers to the official corrections on the Italian Ministry of University and Research (MUR) website. The scoring method used for evaluation was 1 point for correct answers, 0 points for unanswered questions, and -0.25 points for incorrect answers, reflecting the SSM test scoring system. Results: In summary, ChatGPT was tested with a total of 420 questions, 140 for each test. It achieved an overall accuracy of 80.48%, providing correct answers for 338 questions and incorrect answers for 82 questions. When faced with questions containing both text and images, it answered 55% correctly and 45% incorrectly. The model's performance varied over time, with an 82.14% accuracy rate in 2021 and 2022 (115 correct out of 140) and a 77.14% accuracy rate in 2023 (108 correct out of 140). Applying thisscoring method to the SSM test, ChatGPT would have scored 105 points in 2021 and 2022, and 100 points in 2023. Conclusions: ChatGPT has exhibited above-average performance in the last three SSM tests, highlighting its robust capability to interpret clinical scenarios and offer precise diagnostic and therapeutic guidance. Despite this, some limitations persist, notably the software's inability to interpret non-textual information.

To improve efficacy and safety of sunscreen emulsions, UV‐filter skin permeation could be kept as low as possible by reducing UV‐filter content or changing emulsion composition. In this work, different lipid phase ratio (12, 14 and 16% w/w) were assessed for their ability to affect the technological and sensory properties of O/W emulsions in which bemotrizinol (BMTZ), a broad spectrum sunscreen agent, was incorporated free or loaded into nanostructured lipid nanocarriers (NLC) to reduce its release from the vehicle and, hence, its skin permeation. The following technological properties were evaluated in vitro by suitable methodologies: spreadability, viscosity, pH, occlusion factor, BMTZ release, sun protection factor (SPF). Sensory attributes were assessed by trained panelists in three different phases: before/during pick‐up, rub‐in, after application. Raising the lipid phase ratio led to an increase of viscosity and to a corresponding drop of spreadability while the incorporation of BMTZ‐loaded NLC determined a decrease of occlusion factor and an increase of SPF. No BMTZ release was observed from all emulsions. Sensory attributes were mainly affected by lipid phase ratio. These results suggest that lipid phase ratio and BMTZ incorporation into NLC could contribute to determine technological and sensory properties of O/W emulsions.

Oilseed plants of the Brassicaceae plant family are cultivated for food, feed and industrial purposes on large-scale in Europe. This review gives an overview of current market-oriented applications of new genomic techniques (NGTs) in relevant Brassicaceae oilseed crops based on a literature survey. In this respect, changes in oil quality, yield, growth and resistance to biotic and abiotic stress are goals in oilseed rape (B. napus) and camelina (C. sativa). Environmental risk assessment scenarios are developed for specific NGT applications in Brassicaceae oilseed crops with either a changed oil composition or with fitness related traits. In case of a changed oil composition an increase or decrease of polyunsaturated fatty acids (PUFA) demonstrates risks for health and survival of pollinators. In case of fitness related traits other risks were identified, i. e. an increased risk of spread and persistence of NGT plants. Furthermore, there are indications for potential disturbance of interactions with the environment, involving signalling pathways and reaction to stress conditions. It is shown that for a comprehensive risk assessment the technological potential of NGTs, the plants’ biology and the scale of releases have to be considered in combination. Therefore, the release of NGT plants into the environment for agricultural purposes will require risk assessment and monitoring of single traits as well as of combinatorial and long-term cumulative effects. In addition, risk management should develop concepts and measures to control and potentially restrict the scale of releases. This is especially relevant for NGT Brassicaceae in Europe which is a centre of diversity of this plant family.

This paper proposes an innovative mechatronic piezo-actuated module to control vibrations in modern machine tools. Vibrations represent one of the main issues that compromise seriously the quality of the workpiece. The active vibration control (AVC) device is composed by a host part integrated with sensors and actuators synchronized by a regulator, able to make a self-assessment and adjust to the environmental alteration. This study presents the mechatronic model based on the kinematic and dynamic analysis of the AVC device. To ensure a real time performance, a H2-LQG controller has been developed and validated by simulations involving machine tool, PZT actuator and controller models. The Hardware-in-the-loop (HIL) architecture is adopted to control and attenuate the vibrations. A set of experimental tests has been performed to validate the AVC module on a commercial machine tool. The feasibility of the real time vibration damping is demonstrated and the simulation accuracy is evaluated.

In this paper, a proof similar to the Pusey-Barrett-Rudolph (PBR) theorem is given to prove that time in quantum theory is not epistemic but has ontological reality. For this, we first discuss how time can be encoded as an intrinsic property of a quantum system. We prepare a quantum state containing time as an intrinsic property and show by a PBR-type proof that time cannot be an epistemic notion. In fact, the PBR theorem implies an ontic notion of time. Indeed, if the quantum state is a physical property, then quantum state reduction is a physical process involving information destruction. In this case, quantum probabilities are intrinsic probabilities without epistemic origin, and they generate a genuinely new sequence of events. This novelty introduced by quantum probabilities can be interpreted as time.

Abstract: The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational workflow using scRNA-Seq data to assess cellular metabolism during viral infection. With this workflow we predicted the capacity of cells to sustain SARS-CoV-2 virion production in patients and found a tissue-wide induction of metabolic pathways that support viral replication. Expanding our analysis to influenza A and dengue viruses, we identified metabolic targets and inhibitors for potential broad-45 spectrum antiviral treatment. These targets were highly enriched for known interaction partners of all analyzed viruses. Indeed, phenformin, an NADH:ubiquinone oxidoreductase inhibitor, suppressed SARS-CoV-2 and dengue virus replication. Atpenin A5, blocking succinate dehydrogenase, inhibited SARS-CoV-2, dengue virus, respiratory syncytial virus, and influenza A with high selectivity indices. In vivo, phenformin showed antiviral activity against SARS-CoV-2 in a Syrian hamster model. Our work establishes host metabolism as druggable for broad-spectrum antiviral strategies, providing invaluable tools for pandemic preparedness.

Human Activity Recognition (HAR) technology enables continuous behavior monitoring, particularly valuable in healthcare. This study investigates the viability of using an ear-worn motion sensor for classifying daily activities, including lying, sitting/standing, walking, ascending stairs, descending stairs, and running. Fifty healthy participants (between 20 and 47 years old) engaged in these activities while under monitoring. Various machine learning algorithms, ranging from interpretable shallow models to state-of-the-art deep learning approaches designed for HAR, were employed for classification. Results demonstrate the ear sensor's efficacy, with deep learning models achieving 98% accuracy rate of classification. The obtained classification models are agnostic regarding which ear the sensor is worn and robust against moderate variations in sensor orientation (e.g., due to differences in auricle anatomy), meaning no initial calibration of the sensor orientation is required. The study underscores the ear's efficacy as a suitable site for monitoring human daily activity and suggests its potential for combining HAR with in-ear vital signs monitoring. This approach offers a practical method for comprehensive health monitoring by integrating sensors in a single anatomical location. This integration facilitates individualized health assessments, with potential applications in tele-monitoring, personalized health insights, and optimizing athletic training regimes.

The feeling of beauty is one of the positive human feelings. In architecture and design, it is associated with forms appropriate to their purpose. The usefulness of products to meet needs is also important. They are well received by users. The task of designers is to achieve perfection in their work. The rational design and use of artificial living environments are expressions of concern for natural resources (sustainable environment). These issues are addressed, i.e., by an interdisciplinary initiative of the New European Bauhaus. The aim of the paper is to expand knowledge about beauty and utility. They are important when choosing mass-produced goods. The article uses research methods: interpretive research, analyses, comparisons, logical argumentation, etc. Experimental qualitative research using a checklist was used. The results expand the knowledge on the selected topic and research scope of the research of the paper. The survey can be used to rationally evaluate architecture, interiors, and design facilities. It can be helpful for various aesthetic and functional strategies dedicated to different users. The paper demonstrates the role of beauty and functionality in the built environment. They are analyzed in the context of social and technical conditions, as well as contemporary sustainable design

We are currently facing a potential ‘polycrisis’, a critical inflection point that requires a whole-of-society response aimed at building collective foresight and preparedness for short-, medium-, and long-term risks. The role of higher education institutions and social stakeholders is decisive to make an impact. This paper depicts the alignment of academia, governance, and industry with the aim to challenge, inspire, and encourage universities to go beyond commodified courses and mere employability, enhance student growth and bind macro-scale measures that lead to a sustainable future. A modest teaching innovation project has served as a transforming lever, with the private sector joining in, to create a platform that reaches more than 50 000 undergraduate students and teaching staff. The resulting structure, rooted in the University’s strategic plan, has served to channel local and regional initiatives, establish effective partnerships with broad social members, raise awareness and promote actions to advance in the pursuit of Sustainable Development Goals. Chronology, materials and methodology, together with a description of the different courses, programmes and actions are provided. The paper concludes with some recommendations for future research, policy and cooperation among stakeholders. Research methodology posted on clinicaltrials.gov under ID NCT04392869, NCT05598944, and NCT05775978.

We are currently facing a potential ‘polycrisis’, a critical inflection point that requires a whole-of-society response aimed at building collective foresight and preparedness for short-, medium-, and long-term risks. The role of higher education institutions and social stakeholders is decisive to make an impact. This paper depicts the alignment of academia, governance, and industry with the aim to challenge, inspire, and encourage universities to go beyond commodified courses and mere employability, enhance student growth and bind macro-scale measures that lead to a sustainable future. A modest teaching innovation project has served as a transforming lever, with the private sector joining in, to create a platform that reaches more than 50 000 undergraduate students and teaching staff. The resulting structure, rooted in the University’s strategic plan, has served to channel local and regional initiatives, establish effective partnerships with broad social members, raise awareness and promote actions to advance in the pursuit of Sustainable Development Goals. Chronology, materials and methodology, together with a description of the different courses, programmes and actions are provided. The paper concludes with some recommendations for future research, policy and cooperation among stakeholders. Research methodology posted on clinicaltrials.gov under ID NCT04392869, NCT05598944, and NCT05775978.

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

Panel data of our interest consist of a moderate number of panels, while the panels contain a small number of observations. An estimator of common breaks in panel means without a boundary issue for this kind of scenario is proposed. In particular, the novel estimator is able to detect a common break point even when the change happens immediately after the first time point or just before the last observation period. Another advantage of the elaborated change point estimator is that it results in the last observation in situations with no structural breaks. The consistency of the change point estimator in panel data is established. The results are illustrated through a simulation study. As a by-product of the developed estimation technique, a theoretical utilization for correlation structure estimation, hypothesis testing, and bootstrapping in panel data is demonstrated. A practical application to non-life insurance is presented as well.

The rapid expansion of transcriptomics from increased affordability of next-generation sequencing (NGS) technologies generates rocketing amounts of gene expression data across biology and medicine, and notably in cancer research. Concomitantly, many bioinformatics tools were developed to streamline gene expression analysis and quantification. We tested the concordance of NGS RNA sequencing (RNA-seq) analysis outcomes between the two predominant programs for reads alignment, HISAT2 and STAR, and the two most popular programs for quantifying gene expression in NGS experiments, edgeR and DESeq2, using RNA-seq data from a series of breast cancer progression specimens, which include histologically confirmed normal, early neoplasia, ductal carcinoma in situ and infiltrating ductal carcinoma samples microdissected from formalin fixed, paraffin embedded (FFPE) breast tissue blocks. We identified significant differences in aligners’ performance: HISAT2 was prone to misalign reads to retrogene genomic loci, STAR generated more precise alignments, especially for early neoplasia samples. edgeR and DESeq2 produced similar lists of differentially expressed genes in stage comparisons, with edgeR producing more conservative, though shorter, lists of genes. Albeit, Gene Ontology (GO) enrichment analysis revealed no skewness in significant GO categories identified among differentially expressed genes by edgeR vs DESeq2. As transcriptome analysis of archived FFPE samples becomes a vanguard of precision medicine, identification and fine-tuning of bioinformatics tools becomes critical for clinical research. Our results indicate that STAR and edgeR are well-suited tools for differential gene expression analysis from FFPE samples.

The application of space robotic manipulators and heightened autonomy for ios represents a paramount pursuit for leading space agencies, given the substantial threat posed by space debris to operational satellites and forthcoming space endeavors. This work presents a guidance algorithm based on drl to solve for the space manipulator path-planning during the motion synchronization phase with the mission target. The goal is the trajectory generation and control of a spacecraft equipped with a 7-dof robotic manipulator, such that its end effector remains stationary with respect to the target point of capture. The ppo drl algorithm is used to optimize the manipulator’s guidance law, and the autonomous agent generates the desired joints rates of the robotic arm, which are then integrated and passed to a model-based feedback linearization controller. The agent is first trained to optimize its guidance policy and then tested extensively to validate the results against a simulated environment representing the motion synchronization scenario of an ios mission.

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.

The study was conducted to evaluate the agronomic performance, forage yield, and nutritive values of Desho grass varieties under supplementary irrigation at Dambi Dollo University experimental site, Western Ethiopia. Three Desho grass varieties (Areka /DZF#590, Kindu kosha-1/DZF #591, and Kulumsa /DZF #592) were arranged in randomized complete block design (RCBD) with three replications. The CROPWAT 8.0 model, local climate data, forage data, and soil data were used to determine Desho grass water requirements and irrigation schedules. The agronomic parameters, yield, chemical composition, and in vitro digestibility of the feed samples at standardization cut were determined following the standard procedures. The results showed significant differences (p

An adequate representation of the water infiltration process in the soil allows improving the efficiency in application and the uniformity in surface irrigation. The Green and Ampt model has shown a good representation of the process, and researchers from the United States Department of Agriculture (USDA) determined the values of their parameters for soils of that country, which are shown in tables or through functional relationships and this information is used as reference in several parts of the world, although there is no certainty that they are representative of the soils in Mexico. In this study, the parameters of the Green & Ampt equation were determined and evaluated in some soils of agricultural importance in Mexico. The parameters were obtained in four ways: one of them applied a methodology adapted from Brooks and Corey to quantify the wetting front capillary pressure head and used an permeameter under constant hydraulic head to determine the saturated hydraulic conductivity, and the other three consisted in taking them from three studies reported by the USDA. The values of the parameters suggested in Mexico drastically underestimated the results with relative errors (RE) in a range of -49.0 to -94.0% and the most representative were those obtained with the methodology proposed in this research with RE of -15.0 to 6.0%.

In the area of dental healthcare services, where patients and professionals deal with multiple auditory stimuli, this cross-sectional study reports on the intricate dynamics of sound preferences, noise obstacles, and the profound impact of music on anxiety reduction within dental office set-tings. The sample comprises of 134 dental patients, primarily females (56.7%), with varying age groups, education levels, and therapy durations in the university clinics of the department of Dentistry, National and Kapodistrian University of Athens and four private dental offices at the metropolitan area of Athens, Greece. Notably, 92.5% of the participants report no hearing loss, and 56.7% exhibit some level of noise sensitivity. The study reveals a moderate to good perceived health status (M=3.84, SD=0.95) among participants, with low perceived noise disturbance in university dental clinics. Preferences for instrumental music, foreign pop, and classical music are prominent during waiting times. Potential irritations include impersonal treatment (44%) and staff behavior (41.8%). Music player usage within the settings of the dental clinic involves radios (49.3%) and headphones (41.0%). Correlations and predictors indicate associations between health status, music preferences, and noise disturbances. More specifically, visiting the university dental clinics (β = .300, p = .005) as well as younger age (β = .300, p = .034) were significant predictors of better perceived health status. Clearer perception of external sounds while using the music player (β = .190, p = .039) was a significant predictor of better perceived health status, while poorer health was predicted by the preference of Greek folk songs (β = -.200, p = .030). Also, the use of smartphones for playing music was related to poorer health (β = -.370, p < .001). Following, younger age (β = -.270, p = .015), lower education (β = -.210, p = .035), higher noise sensitivity (β = .190, p = .027), as well as feelings of anxiety and nervousness due to ambient noise from people and machines (β = .510, p = .027) were significant predictors of noise disturbance from machines. Also, visiting private clinics (β = .240, p = .018), preferences of specific playlist (β = .310, p = .012), no music (β = .280, p = .016) and use of smartphones to play music (β = .230, p = .029) were significant predictors of noise disturbance from patients or staff. Finally, the preference of listening to a specific playlist was related to better health status (r = .190, p < .05). Findings aim to optimize eco-soundscapes in dental offices, con-tributing to enhanced patient well-being. The research underscores the potential of music inter-ventions to alleviate dental anxiety and improve the overall dental experience and quality care.

Introduction: Chronic wounds caused by diabetes or lower-extremity artery disease are intractable because the wound healing mechanism is no longer effective due to the poor environment of the wound bed. Biosheet obtained using in-body tissue architecture (iBTA) is a collagen-based membranous tissue that is created within the body and autologously contains various growth factors and somatic stem cells including pluripotent stem cells. When applied to a wound, granulation formation can be promoted and even epithelialization may be achieved. Hearin, we report our clinical treatment experience with seven cases of intractable diabetic foot ulcers. Cases: From 46- to 93-year-old 7 patients had large foot ulcers including heel area, which was failed to heal with standard wound treatment. Methods: Two or four Biosheet-forming molds were implanted subcutaneously in the chest or abdomen, and after 3 to 6 weeks, the molds were removed. Biosheets that formed inside the mold were obtained and applied directly to the wound surface. Results: In all cases, there were no problems with the mold embedding and removal procedures, and Biosheets were formed without any infection or inflammation during the implantation period. The Biosheets were simply applied to the wounds, and in all cases, they adhered within one week, did not fall of, and became integrated with the wound surface Complete wound closure was achieved within 8 weeks in two cases and within 5 months in two cases. One patient was lost due to infective endocarditis from septic colitis. One case required lower leg amputation due to the wound recurrence, and one case achieved wound reduction and wound healing in approximately 9 months. Conclusion: Biotube obtained via iBTA promoted wound healing and were extremely useful for intractable diabetic foot ulcers involving heel area.

In order to study the effects of irradiation on the physicochemical properties and digestion behavior of chickpea protein, chickpea protein concentrate (CPC) was treated with electron beam irradiation (EBI) at doses of 5, 10, 15 and 20 kGy, respectively. After irradiation, protein solubility first increased at 10 kGy and 15 kGy, and then decreased at higher dose of 20 kGy. This was supported by SDS-PAGE where the intensity of major protein bands first increased and then decreased. Increased does of EBI generally led to greater oxidative modification of proteins in CPC, indicated by reduced sulfhydryls and increased carbonyls. In addition, protein structure was modified by EBI shown by Fourier transform infrared spectroscopy analysis where α-helix generally decreased and β-sheet increased. Although the protein digestibility was not significantly affected by EBI, the peptidomic analysis of the digests revealed significant difference among CPC irradiated with varying doses. A total of 337 peptides were identified from CPC irradiated with 0 kGy, 10 kGy and 20 kGy, respectively, with 18 overlapping peptides and 60, 29 and 40 peptides specific to the groups of 0, 10 and 20 kGy respectively. Theoretical calculation showed that the distribution of peptide length, hydrophobicity, net charge, and C-terminal residues were affected by irradiation. The 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity showed a marginal decrease with increasing dose of irradiation. In conclusion, EBI led to oxidative modification and structural changes of the chickpea protein, which subsequently affected the physicochemical properties of peptides obtained from in-vitro digestion of CPC despite of similar digestibility.

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.

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.

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.

This study focuses on enhancing controllable fibrin-based hydrogels for tissue engineering, addressing existing weaknesses. By integrating a novel copolymer, we improve the foundation for cell-based angiogenesis with adaptable structural features. Tissue engineering often faces challenges like waste disposal and nutrient supply beyond the 200 µm diffusion limit. Angiogenesis breaks through this limitation, allowing the construction of larger constructs. Our innovative scaffold combination significantly boosts angiogenesis, resulting in longer branches and more capillary network junctions. The copolymer attached to fibrin fibers enables precise adjustment of hydrogel mechanical-dynamic properties for specific applications. Our material proves effective for angiogenesis, even under suppression factors like suramin. In our study, we prepared fibrin-based hydrogels with and without the copolymer PVP12400-co-GMA10mol%. Using a co-culture system of human umbilical vein endothelial cells (HUVEC) and mesenchymal stem cells (MSC), we analyzed angiogenetic behavior on and within the modified hydrogels. Capillary-like structures were reproducibly formed on different surfaces, demonstrating the general feasibility of three-dimensional endothelial cell networks in fibrin-based hydrogels. This highlights the biomaterial's suitability for in vitro pre-vascularization of biohybrid implants.

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.

Agricultural activities are the second largest source of greenhouse gas emissions, and carbon emissions from agricultural land use (CEALU) have become a hot issue across the world. However, few scholars explored the impact of agricultural land policies on carbon emissions, such as the High-standard farmland construction(HSFC) in China.Thus，by relying on provincial panel data for China for the period 2005-2017, the effect of the high-standard basic farmland construction policy on carbon emissions from agricultural land use per unit area and its regional differences were quantitatively analyzed using the difference-in-difference (DID) model. The results showed that: 1) China's CEALU per unit area presented a fluctuating upward trend during the period 2005-2017, from 392.58 kg/ha to 457.72 kg/ha, with an average annual growth rate of 1.31%. 2) The high-standard farmland construction(HSFC) policy produced a significant carbon emission reduction effect in agricultural land use, and reduced the CEALU per unit area by 10.80% on average. With the promotion of this policy, its carbon emission reduction effect in agricultural land use presented an overall increasing trend. 3) The carbon emission reduction effect of the high-standard farmland construction policy in agricultural land use was significant in central China, but non-significant in eastern China and western China.

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

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

The 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.

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.

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.

Introduction: The combination of Virtual Screening (VS) techniques with in vivo screening in the zebrafish model is currently being used in tandem for drug development in a faster and more efficient way. Areas covered: We review the different virtual screening techniques, the use of zebrafish as a vertebrate model for drug discovery and the synergy that exists between them. Expert opinion: We highlight the advantages of combining virtual and zebrafish larvae screening for drug discovery. On the one hand, VS is a faster and cheaper tool for searching active compounds and possible candidates for therapy than in vivo screening when processing large compound libraries. On the other hand, zebrafish larvae form a vertebrate model which allows in vivo screening of large amounts of the compounds. Importantly physiology and chemical response are mostly conserved between zebrafish and mammals. The availability of the transgenic and mutant zebrafish lines allows an analysis of a specific phenotype upon treatment along with toxicity, off-target effect, side effects, and dosage. Advantages of VS, in vivo whole animal approach screening, and the screening combinations are also reviewed.

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 food system, the most important driver of planetary transformation, is in a deep crisis. Therefore, seeking a sustainable and socially-fair transition pathway becomes an issue of utmost priority for our own survival. The consideration of food as a commodity, a social construct that played a central role in driving this crisis, remains the uncontested narrative to lead the different transition pathways what seems rather contradictory. By exploring the normative values in the transition landscape, this paper seeks to understand how relevant is the hegemonic narrative of “food as commodity” and its alternative of “food as commons” to determine transition trajectories and food policy beliefs. Applying the Multi-level Perspective framework and developing the ill-studied “agency in transition”, this research enquired food-related professionals that belong to an online community of practice (N=95) on valuation of food dimensions and agency in food transitions to check whether the valuation of food is relevant to explain personal stances in transition. Results suggest the socially-constructed view of food as commodity is positively correlated to the gradual reforming attitude, whereas food as commons is positively correlated to the counter-hegemonic transformers regardless the self-defined position in the transition landscape (regime or niches). At personal level, there are multiple loci of resistance with counter-hegemonic attitudes in varied institutions of the regime and the innovative niches, many of them holding this discourse of food as commons. Conversely, alter-hegemonic attitudes are not positively correlated to this alternative discourse and they may inadvertently or purportedly reinforce the ‘‘neoliberal narrative’’. Food as commons, a different narrative whose rationale is explained in the paper, seems to be a relevant framework that could enrich the multiple transformative constituencies that challenge the industrial food system and therefore facilitate the convergence of movements that reject the commodification of food.

Knowledge about ecological conditions and processes in centers of endemism (CoEs) is still limited with respect to various systematic groups of organisms, ecosystem types, ecological conditions and ecosystem functions. Endemics and CoEs play a prominent role in nature conservation monitoring and management, and in the organization of zoos, aquaria and botanical gardens. We review the meaning of different groups of organisms and indicators for the characterization of endemic-rich regions, the importance of heterogeneity in space, continuity in time, isolation and ex-situ management for the survival of endemic and threatened species. Currently, conversion of land cover and land use change are the most important causes of biodiversity decline and extinction risk of endemic and endangered species concentrated in CoEs. These are followed by climate change, including severe weather, and then natural processes such as volcanism, landslides or tsunamis. For conservation purposes the management of zoos, aquaria, botanical gardens, of regional land use, and social aspects of the diversity of endemics and CoEs have to be taken into account as well. We need better answers to questions about the relationship between ecoregions, CoEs and regional awareness of biodiversity, which is linked with human culture including the management of zoos, aquaria and botanical gardens, aesthetics, wellbeing, health and trade.

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.

Abstract Octreotide is the first synthetic peptide hormone, consisted of eight amino acids, that mimics the activity of somatostatin, a natural hormone in the body. During the past decades, advanced instrumentation and crystallographic software established X-ray Powder Diffraction (XRPD) as a valuable tool for extracting structural information of biological macromolecules. The latter was demonstrated by the successful structural determination of octreotide at a remarkably high d-spacing resolution (1.87 Å) (PDB code: 6vc1). This study focuses on the response of octreotide to different humidity levels and temperatures, with a particular focus on the stability of the polycrystalline sample. XRPD measurements were accomplished employing an Anton Paar MHC-trans humidity-temperature chamber installed within a laboratory X’Pert Pro diffractometer (Malvern Panalytical). The chamber is employed to control and maintain precise humidity and temperature levels of samples during XRPD data collection. Pawley analysis of the collected data sets revealed that the octreotide polycrystalline sample is remarkably stable and no structural transitions were observed. The compound retains its orthorhombic symmetry (space group: P212121, a = 18.57744(4) Å, b = 30.17338(6) Å, c = 39.70590(9) Å, d~ 2.35 Å). However, a characteristic structural evolution in terms of lattice parameters and volume of the unit-cell is reported mainly upon controlled relative humidity variation. In addition, an improvement of signal-to-noise ratio in the XRPD data under a cycle of dehydration/rehydration is reported. These results underline the importance of considering the impact of environmental factors, as humidity and temperature, in the context of structure-based drug design, thereby contributing to the development of more effective and stable pharmaceutical products.

Nowadays, unmanned vehicles are widely used in various fields. However, the safety of unmanned vehicles is directly determined by the autopilot systems, and sensor faults are a very critical factor that affects the normal operation of the autopilot systems. To efficiently and comprehensively test unmanned systems for sensor faults, this paper proposes a chip-level testing platform for unmanned vehicle autopilot systems based on FPGA hardware-in-the-loop simulation. Unlike existing testing platforms, the introduction of FPGA technology allows us to achieve nanosecond real-time simulation frequency, thus realizing chip-level simulation of sensors and black-box automated testing. Firstly, we propose a set of general platform and modeling methods, and the paper presents a detailed application of the four most common necessary sensors in autopilot systems as examples. Secondly, we propose for the first time a chip-level fault testing method for unmanned systems, and build a test platform with a quadrotor vehicle, the PX4 software platform, and the Pixhawk4 hardware platform as examples. Finally, the experimental results verify that the testing platform proposed in this paper can adapt to various autopilot systems and has high simulation test reliability.

This study was to designed to develop sorafenib-loaded polymeric nanoparticles, surface-modified with pluronic F-127 for the effective treatment of hepatocellular (HCC) and renal cell carcinomas (RCC). Poly lactic coglycolic acid (PLGA) was used to encapsulate different concentrations of sorafenib by a simple modified solvent evaporation method applying pluronic F-127 as a surfactant and coating agent. The preformulation and characterization studies were conducted to evaluate the incompatibilities among sorafenib, PLGA and pluronic F-127, and physicochemical properties of the formulations, respectively. The sizes of the coated and plain PLGA nanoparticles were ~140 ± 14.7 nm and ~ 120 ± 10.1 nm, respectively. It has been confirmed from the in vitro release studies that PLGA sustained the release of sorafenib, avoiding the initial burst release, while the in vivo studies demonstared that surface-modified nanoparticles have greater affinity in the target aorgans than plain PLGA nanoparticles and free drug keeping the dose constant (20 mg/kg body weight). The delivery of sorafenib-loaded polymeric PLGA nanoparticles into the target tissues and their pharmacokinetic parameters have been improved significantly compared to the reported formulations.

Academic entrepreneurship focuses on commercialization of research. Even though it is practiced worldwide for decades, Bangladesh is a newcomer in this segment. In Bangladesh only 2 Universities have Technology Transfer Offices or TTOs which are established with the sole focus of commercialization of researches of the students and the faculty members of the Universities. This article focuses on worldwide practices of technology transfer and academic entrepreneurial activities and also explores the opportunities and challenges of such entrepreneurs through detail investigation of the existing body of knowledge. Apart from exploring the problems and prospect of academic entrepreneurship in Bangladesh, this article also introduces the concept of Full-Service Knowledge Transfer Office (KTO), which existing literatures do not offer. The authors believe that by establishing such KTOs as a self-sustaining body, it is possible for an academic entrepreneur to stimulate, support and sustain their activities in Bangladesh. The concept of full service KTOs can also become models for other nations, specially the developing ones, to establish and nurture a culture of academic entrepreneurship.

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.

Purpose: When it comes to improving citizen service delivery standard and processes, or broadly, management in government (MIG), many reform programs and improvement efforts are ongoing across different ministries, departments, and agencies. This paper is part of a larger empirical research where we are interested to know what those programs and projects are, and how they are doing, and what the gaps are. Design/methodology/approach: Analyzing the publicly available data on the government portal and donors’ website, this article provides an overall idea of current reforms in various places of government. In parallel, field research was conducted through visiting agency offices, observing office environment and mechanisms, and interviewing public managers who are working at district and sub-district level offices of directorates or agencies.Findings: As a trend, state-led development process and the traditional mode of administration have moved to New Public Management based quality and performance approach. All donors have their own strategy framework document like ‘Country Assistance strategy’, ‘Country Operations and Business Plan’, Logical Framework Document, Focus or Priority Streams, etc. Many of the projects are sectoral and agency or ministry specific and have an inherent limitations, due to ‘cadre’ based organizational structural arrangement. So, it is common ‘not to own the projects’, rather ‘using the fund as much as possible anyway within the given project duration’. When the fund ends, implementing units, either government or NGOs, abandon the projects. That is why many projects are actually half done without significant and sustained direction.Originality/value: We can conclude that the typical ‘top-down’ or ‘trickle down’ conception is still dominant in design and implementation of reforms programs and service quality efforts. So, how to reach systemically at the bottom where public managers provide services to citizens, needs even more deliberation.

The static formation temperature (SFT) is required to determine the thermophysical properties and production parameters in geothermal and oil reservoirs. However, the SFT is not easy to be obtained by both experimental and physical methods. In this paper, a mathematical approach to predicting SFT based on a new model describing the relationship between bottom hole temperature (BHT) and shut-in time was proposed. The unknown coefficients of the model were derived from least squares fit by Particle Swarm Optimization (PSO) algorithm. Besides, the ability to predict SFT based on a few BHT data (such as first 3, 4, or 5 ones of a data set) was evaluated. The accuracy of the proposed method to predict SFT was testified with a deviation percentage less than ±4% and high values of regression coefficient R² (>0.98). The proposed method could be used as a practical tool to predict SFT in both geothermal and oil wells.

In the context of improving aircraft safety, this study focuses on the development and evaluation of a graphene-based ice detection system using an environmental chamber. The research is driven by the need for more accurate and efficient ice detection methods, crucial in mitigating in-flight icing hazards. The methodology employed involves testing flat graphene-based sensors in a controlled environment, simulating a variety of climatic conditions that could be experienced in an aircraft during its entire flight. The environmental chamber enabled precise manipulation of temperature and humidity levels, thereby providing a realistic and comprehensive test bed for sensor performance evaluation. The results were significant, revealing the graphene sensors’ heightened sensitivity and rapid response to the subtle changes in environmental conditions, especially the critical phase transition from water to ice. This sensitivity is the key to detecting ice formation at its onset, a critical requirement for aviation safety. The study concludes that graphene-based sensors, tested under varied and controlled atmospheric conditions, exhibit a remarkable potential in enhancing ice detection systems for aircraft. Their lightweight, efficient and highly responsive nature makes them a superior alternative to traditional ice detection technologies, paving the way for more advanced and reliable aircraft safety solutions.

The Environmental interactions contributed to the processes of settlement and development of the first settlers at southern Peru 15,000 BC. The determination of this process is based on paleoclimatic studies at southern Peru and ethnoarchaeological evidence. The determination of this process is based on paleoclimatic studies of southern Peru and ethnoarchaeological evidence; establishing as a result of this analysis the hypothesis of environmental interaction and territorial occupation of the first hunter-gatherer populations until their consolidation, dominating the geographical space from Tacna. The Disruptive disaster events and their effects on climate during the Peruvian Paleolithic resulted in the origin of local societies that shaped the Tiawanaku societies of the early horizon at Southern Peru and Northern Chile.

Human eye is a specialized organ with complex anatomy and physiology, because it is characterized by different cell types with specific physiological functions. Given the complexity of the eye, ocular tissues are finely organized and orchestrated. In the last few years many in vitro models have been developed, in order to meet the 3Rs principle (Replacement, Reduction and Refinement) for eye toxicity testing. This procedure is highly necessary to ensure that the risks associated with ophthalmic products meet appropriate safety criteria. In vitro preclinical testing is now a well-established practice of significant importance for evaluating the efficacy and safety of cosmetic, pharmaceutical, and nutraceutical products. Along with in vitro testing, also computational procedures, herein described, for evaluating the pharmacological profile of potential ocular drug candidates including their toxicity, are in rapid expansion. In this review the ocular cell types and functionality are described providing an overview about the scientific challenge for the development of three-dimensional in vitro models.

The aim of this study is to solve the problems of complicated pretreatment and high analytical cost in the detection technology of trace drug toxicants in municipal wastewater. A high-performance magnetic sorbent was synthesized for enrichment of trace drug substances in wastewater to develop magnetic solid-phase extraction pretreatment combined with the acoustic ejection mass spectrometry (AEMS) analytical methods for the molecules in wastewater drug toxicants. The magnetic nanospheres was successfully prepared by magnetic nanoparticles modified with divinylbenzene and vinyl pyrrolidone.The results showed that the linear dynamic range of 17 drugs was 1-500 ng/L, the recovery was 43%-105%, the matrix effect was more than 67%, the limit of quantitative detection was 1-2 ng/L, and the detection time of each sample was 2.98s. It can be seen that the developed magnetic solid-phase extraction (MSPE) method is a good solution to the problem of complicated pre-treatment and analytical cost in the detection of drugs in wastewater. The developed magnetic material and acoustic excitation coupled mass spectrometry analysis method can realize the low-cost, efficient enrichment and fast analysis of different kinds of drug molecules in urban sewage.