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Abstract There are significant discrepancies between the experimental results and numerical analysis outcomes for steel-reinforced concrete-filled steel tubular (SRCFST) columns. This is primarily due to the lack of understanding of the confinement mechanisms of SRCFST and the corresponding models for confined concrete. Therefore, based on the confinement mechanisms of square steel tubes and steel reinforcements on concrete, this paper calculates the effective lateral confining stress to determine the strength enhancement factors for concrete in various confined regions. Drawing from the classical Mander model, the key parameters are modified to establish stress–strain models for concrete in different confined regions. By comparing and analyzing axial compression test data for steel tube-reinforced concrete short columns with different parameters, the study identifies the most suitable axial compression bearing capacity calculation formula for these columns. Additionally, the introduction of stress–strain models into finite element analysis, compared with experimental results, demonstrates that the proposed confinement mechanism and the established stress–strain model for steel-reinforced concrete are reasonable and effective. The theoretical calculation results for the ultimate bearing capacity based on this are well aligned with the simulation and experimental values.

Abstract The Homo sapiens Chromosomal Location Ontology (HSCLO) is designed to facilitate the integration of human genomic features into biomedical knowledge graphs from releases GRCh37 and GRCh38 at multiple resolutions. HSCLO comprises two distinct versions, HSCLO37 and HSCLO38, each tailored to its respective human genome release. This ontology supports the efficient integration and analysis of human genomic data across scales ranging from entire chromosomes to individual base pairs, thereby enhancing data retrieval and interoperability within large-scale biomedical datasets. Unlike existing ontologies that primarily focus on genomic feature identification or annotation, HSCLO is specifically engineered to optimize the interoperability and scalability of genomic data within biomedical knowledge graphs. The utility and performance of HSCLO are demonstrated through a case study involving the integration of high-resolution chromatin interaction data, which reveals significant improvements in query efficiency and data linkage. HSCLO represents a valuable resource for advancing research in disease genetics, personalized medicine, and other domains that require complex genomic data integration.

Abstract Over the past decade, there has been substantial growth in both the quantity and complexity of available biomedical data. In order to more efficiently harness this extensive data and alleviate challenges associated with integration of multi-omics data, we developed Petagraph, a biomedical knowledge graph that encompasses over 32 million nodes and 118 million relationships. Petagraph leverages more than 180 ontologies and standards in the Unified Biomedical Knowledge Graph (UBKG) to embed millions of quantitative genomics data points. Petagraph provides a cohesive data environment that enables users to efficiently analyze, annotate, and discern relationships within and across complex multi-omics datasets supported by UBKG’s annotation scaffold. We demonstrate how queries on Petagraph can generate meaningful results across various research contexts and use cases.

The study aimed to estimate the proportions of lactoferrin and IgG immunoglobulins, and to separate lactoferrin from buffalo colostrum. Buffalo colostrum samples were collected from the first hour to the five days after birth. Then, the percentages of lactoferrin were estimated using HPLC technology. The percentage of IgG using an ELISA device in colostrum, after that the lactoferrin protein was separated from the colostrum by the sodium dodecyl sulfate-polyacrylamide Gel electrophoresis (SDS-PAGE) method, and the protein was extracted from the Gel (SDS-PAGE). The results showed that the lactoferrin level was higher on the first day, after and decrease within days of milk production. The IgG level was higher in the first hour; afterward it decreased and then increased on the fourth day, reaching 30.46 mg/ml. Lactoferrin was separated by electrophoresis based on the molecular weight of the standard lactoferrin sample. Clear lactoferrin separation areas appeared on the acrylamide Gel. Lactoferrin was then extracted by SDS-PAGE and eluted from the Gel.

In generative syntax, two major types of proposals – syntax-oriented and semantics-oriented proposals – have been used to examine adverbs and adverbials. Despite these proposals explaining the remarkable properties of adverb positioning, this class of words is heterogeneous and problematic in terms of their displacement. This study adopts scopal theories and proposes a partial semantic analysis using phases to describe adverbial positioning in Modern Standard Arabic. We argue that the semantic scope and the modification domain are the main determinants of adverbial position, which can best be analysed in terms of phases. In this regard, adverbials are classified into lower and higher adverbials. Lower adverbials have a narrow semantic scope and modification domain. They include subject-oriented and verb-oriented modifiers and freely adjoin the vP layer. Higher adverbials have a wider scope and modification domain. They include discourse-oriented modifiers and tend to attach to the Complementiser Phrase layer. In terms of their hierarchical order, discourse-oriented adverbials are higher than subject-oriented and verb-oriented modifiers in the articulated clause structure. This conclusion suggests that scopal theories along with language-specific rules may provide a unified generalization and straightforward account of the cross-linguistic distribution of adverbs and adverbials.

Ganoderma lucidum has had great importance in healthcare in the Chinese for many decades. Polysaccharides and triterpenoids are one of the most important components of G. lucidum. Biological evidence indicates that this mushroom can be a promising treatment in many cancer cases and reduce the toxic effect of chemotherapy and radiotherapy if taken synchronously. This study highlights preparing an extract with therapeutic effects capable of removing free radicals and protecting cell membranes from hyperoxidation effects. The antitumor effect was evaluated on two types of cancer cell lines in vitro, Human Oral Squamous Cell Carcinoma (HOSCC) and Human Skin Squamous Cell Carcinoma (HSSCC), at different concentrations 0.0-1600 µg/mL. Antioxidant by DPPH assay was assessed at concentrations from 0.0-500 µg/mL, in addition to their effects on cytogenetic indicators such as mitotic index (MI), blastogenic index (BI) and total chromosomal aberration (TCAs) for three types of extracts (ethanol extract, water extract and acidified water extract). The results recorded an increase in the antioxidant activity of the three extracts, and that the acidified water extract had the highest effect, reaching a killing rate of 78.53% for the acidified water extract on the HOSCC cell line. Chromosomal stability indicates that the three extracts enhanced the cytogenetics parameters and supported chromosomal stability by increasing both mitotic index (MI) and blastogenic index (BI), while reducing chromosomal aberrations.

Research has identified certain bio-based products, such as probiotics, as alternatives to antibiotics for use in animal feed. They are capable of controlling, preventing or minimizing the colonization of the gastrointestinal tract by pathogenic bacteria. To isolate Pediococcus spp. and assess its technological properties for possible probiotic development, maize and pearl millet were used. The cereals were steeped and wet milled after 48 h of fermentation. The milled cereals were kneaded into dough for 24 h, after which a 10% slurry was prepared for tenfold serial dilution to enumerate the LAB by employing pour plate techniques using MRS Agar. Based on the cell morphology of the isolated bacteria, eight isolates (four from maize and four from millet) that were selected for identification using MALDI-TOF MS showed that five were Pediococcus pentosaceus (P. pentosaceus), one was Pediococcus acidilactici, and two did not match any organism. Subsequently, the six isolates were labeled as MZ1, MZ2, MZ3, MZ4 for the maize isolate and MLT5 and MLT7 for the millet isolate. The six Pediococcus spp. were assessed in vitro for acid and bile salt tolerance, gastric juice and intestinal fluid tolerance and antibiotic resistance and antimicrobial susceptibility tests were performed, and the survivability rate of the strains was calculated. With regard to the mean count, there was a reduction in log10 CFU/mL under the lower pH conditions and their duration of exposure with regard to time. Among the isolates, no differences were noted at the various periods of exposure (0 h, 1 h, 2 h and 3 h) at pH 4 (p > 0.05). However, significant differences were noted at pH 3, 2 and 1 among the isolates (p < 0.05). The percentage survival of MZ4 and MLT7 at pH 1 was higher compared to the other isolates at 0 h. Significant differences were observed among the isolated at pH 2, 3 and 4 across the various periods. The mean count of the isolates in gastric juice was similar at 0 and 1 h, but significant differences were noted at 2 and 3 h, where MLT7 was highest (p < 0.05). A similar trend was observed for percentage survival. The mean count and the percentage survival of isolates under different concentrations of bile salt were similar. Significant differences were noted among isolates in both mean count and percentage survival when exposed to intestinal fluid (p < 0.05). All of the isolates were highly tolerant to the antibiotics tested and possessed antibacterial properties against the selected pathogens. The LABs proved to be good probiotic materials, according to the results obtained. However, the Pediococcus strain MLT7 proved to be the LAB of choice; therefore, its molecular identity was verified using the 16S rRNA sequence and was labeled as Pediococcus pentosaceus GT001 after it was discovered to have 100% similarity with some strains of Pediococcus pentosaceus.

Objective(s): In Iran, half of all deaths and 79% of deaths from non-communicable diseases are attributed to cardiovascular diseases. On the other hand, more than 76% of the total burden of diseases and the first cause of catastrophic health expenses in Iran are related to these diseases. This study was conducted with the aim of determining the status and trend of providing cardiovascular disease risk assessment services by gender, in order to carry out the necessary interventions in the comprehensive health service centers of Ardabil province, Iran. Methods: The present descriptive study was conducted in Ardabil University of Medical Sciences. It used the data available in the registration system of the Health Network. The research population consisted of all men and women aged between 40 and 80 who visited the comprehensive health service centers to perform risk assessment of cardiovascular strokes in the province from 2018 to the end of 2022. The data were entered into Excel software. FORCAST function was used to predict the future through a linear regression analysis. To compare the final results, which is actually a reduction in mortality due to cardiovascular diseases, the difference test of two mortality rates due to cardiovascular diseases was used in 2018 and march 2023. Results: The results showed a relatively high prevalence of some risk factors for cardiovascular diseases including history of hypertension, diabetes, abdominal obesity, suspected diabetes, lipid disorder, body mass index of 30 and above in women. Also, the results of the study showed that 38.3% of men and 61.72% of women were at the risk level of 10-20%, 34.8% of men and 65.2% of women were at the risk level of 20-30%, and 28.9% of men and 71.1% of women were at the risk level above 30%. conclusion: Women were more at risk of cardiovascular diseases and complications than men. Knowing the common risk factors in the region helps to focus interventions on effective prevention and treatment measures and to adopt evidence-informed policies in order to reduce these risk factors.

Abstract Background The claim that septoplasty in children should not be done was raised in the early last century. Pediatric septoplasty is highly controversial. Some surgeons are concerned that early surgical intervention before age 17 can adversely affect the normal growth of the nose and face. On the contrary, there is evidence of significant dental, palatal, and facial abnormalities following traumatic damage to the septal cartilage. Therefore, surgical correction of the deviated nasal septum may be performed regardless of the patient’s age. The recommendation of early surgery is based on the explanation that the earlier the correction of septal deviation, the better the outcome of developing normal breath and acceptable facial growth. This study evaluates the nasal and facial bony growth after endoscopic septoplasty for patients below the age of 17 years. Methods This retrospective study reviewed 39 patients who underwent endoscopic septoplasty. The involved patients’ age at surgery was below 17 years old. Postoperative evaluation was done for all patients subjectively using the visual analog scale (VAS) and objectively by endoscopic nose examination. The nasal and facial bony growth were evaluated using lateral cephalometry, which was carried out for each patient when they reached the age of 17. Results Thirty-nine patients underwent endoscopic septoplasty. The median visual analog scale for nose block and headache significantly declined after the procedure significant differences were observed between patients and controls regarding the following parameters: palatal length, anterior skull base, mid-face protrusion, and mid-face length. Conclusion Early endoscopic septoplasty below the age of 17 is a safe procedure and does not compromise the nasal or facial growth when indicated for patients with severe persistent nose block and poor quality of life.

Introduction Despite the high level of patient satisfaction with functional endoscopic sinus surgery (FESS) and the clinical improvement, polyp recurrence is observed in 23% to 87% of patients and requires reoperation.

Abstract Background Birth defects are functional and structural abnormalities that impact about 1 in 33 births in the United States. They have been attributed to genetic and other factors such as drugs, cosmetics, food, and environmental pollutants during pregnancy, but for most birth defects there are no known causes. Methods To further characterize associations between small molecule compounds and their potential to induce specific birth abnormalities, we gathered knowledge from multiple sources to construct a reproductive toxicity Knowledge Graph (ReproTox-KG) with a focus on associations between birth defects, drugs, and genes. Specifically, we gathered data from drug/birth-defect associations from co-mentions in published abstracts, gene/birth-defect associations from genetic studies, drug- and preclinical-compound-induced gene expression changes in cell lines, known drug targets, genetic burden scores for human genes, and placental crossing scores for small molecules. Results Using ReproTox-KG and semi-supervised learning (SSL), we scored >30,000 preclinical small molecules for their potential to cross the placenta and induce birth defects, and identified >500 birth-defect/gene/drug cliques that can be used to explain molecular mechanisms for drug-induced birth defects. The ReproTox-KG can be accessed via a web-based user interface available at https://maayanlab.cloud/reprotox-kg . This site enables users to explore the associations between birth defects, approved and preclinical drugs, and all human genes. Conclusions ReproTox-KG provides a resource for exploring knowledge about the molecular mechanisms of birth defects with the potential of predicting the likelihood of genes and preclinical small molecules to induce birth defects.

The novel coronavirus outbreak reached pandemic status in March-2020. Since then, many countries have collaborated in the fight against COVID-19. The main objective of these governments is the rapid and effective identification of COVID-19-positive patients. While many molecular tests currently exist, not all hospitals have immediate access to these. However, X-rays, which are easily accessible in the majority of hospitals, provide different ways to detect COVID-19. This article discusses the use of neural networks for the classification of radiographic images of patients with pneumonia and COVID-19. Precision, Recall, and F1-score were used to select the best resizing parameters and adaptive equalization of the brightness histogram of images, as well as the optimal architecture of the neural network and its hyperparameters. The high values of these classification quality metrics obtained accuracy (97%) for patients with COVID-19, and accuracy (99%) for patients with pneumonia. These results strongly indicate a reliable differentiation of radiographic images. This opens up the possibility of creating a model with good predictive ability without involving ready-made complex models and preliminary training on third-party data.

The interest of researchers in the subject of biometrics has increased, which has opened new horizons in people identification systems, and one of these measurements is the contactless palm print. Identification of people through a contactless palm print is very important in the process of identifying terrorists and criminals whose faces are often covered. Therefore, a contactless palm print recognition system has been proposed through two pre-processing methods using a neural network. A Contrast Limited Adaptive Histogram Equalization (CLAHE) filter was used in the first processing of the data stage as well as the normalization method. The system was applied to several databases, including the standard Indian Institute of Technology Delhi (IITD) ones, and those collected from the Computer Department, College of Science, University of Diyala, After the process of data division, training and testing, the proposed system reached satisfactory results compared to previous work, and the accuracy was 99.95.

Cancer treatment has become one of the biggest challenges in the world today. Different treatments are used against cancer; drug-based treatments have shown better results. On the other hand, designing new drugs for cancer is costly and time-consuming. Some computational methods, such as machine learning and deep learning, have been suggested to solve these challenges using drug repurposing. Despite the promise of classical machine-learning methods in repurposing cancer drugs and predicting responses, deep-learning methods performed better. This study aims to develop a deep-learning model that predicts cancer drug response based on multi-omics data, drug descriptors, and drug fingerprints and facilitates the repurposing of drugs based on those responses. To reduce multi-omics data's dimensionality, we use autoencoders. As a multi-task learning model, autoencoders are connected to MLPs. We extensively tested our model using three primary datasets: GDSC, CTRP, and CCLE to determine its efficacy. In multiple experiments, our model consistently outperforms existing state-of-the-art methods. Compared to state-of-the-art models, our model achieves an impressive AUPRC of 0.99. Furthermore, in a cross-dataset evaluation, where the model is trained on GDSC and tested on CCLE, it surpasses the performance of three previous works, achieving an AUPRC of 0.72. In conclusion, we presented a deep learning model that outperforms the current state-of-the-art regarding generalization. Using this model, we could assess drug responses and explore drug repurposing, leading to the discovery of novel cancer drugs. Our study highlights the potential for advanced deep learning to advance cancer therapeutic precision.

Background and Objective: Considering the significant number of injured people in spas, the main goal of this research is to provide a model for measuring and managing risk in spas. Materials and Methods: To prepare the conceptual model of risk, four steps were taken, which include determining the general outline of the model, identifying the parameters, evaluating and scoring the parameters based on the questionnaire, using the hierarchical analysis method, and evaluating and determining the final risk of the pools. According to the allowed standard range of each parameter, five ranges for each parameter were obtained based on the obtained weights, health, safety and environmental risk classes. Finally, by summing up these parameters, the final score of the risk of using each pool is obtained. In order to evaluate the presented model, the risk value of hot mineral water pools in Ardabil province was obtained with the innovative method of this research. Results: According to the results, according to the risk score, Gutursoi and Gamish-Goli spas have an unacceptable risk level, while Qainarjeh, Shabil, Barjelo and Sablan spas are at a high-risk level. Conclusion: The presented model was validated with the evidence of forensic events. According to the results of the conceptual model of risk and the score obtained for each component and sub-components, appropriate solutions were presented, including the need to modify the current standards in each spa.

Electromagnetic interference (EMI) remains a critical roadblock to fully benefitting from the various advantages provided by wide-bandgap devices. Of particular concern is the common-mode (CM) emissions generated during the device operation. This work aims to inform EMI mitigation strategies that can be implemented at the power module design stage and that can result in modules with lower noise emissions in the conducted EMI frequency range. Four 1.2 kV SiC MOSFET power modules are fabricated with different architectures found from literature to better understand their impact on EMI mitigation and to identify trade-offs. Module architectures with integrated CM screens connected to two different DC nodes are experimentally tested and an in-depth analysis on the EMI results is presented. Experimental results show that using a CM screen connected to the DC–link midpoint allows for up to 26 dB of CM current reduction at the baseplate of the module and the input of the converter. Furthermore, this integrated CM screen configuration enables a 0.5% increase in efficiency.

Facial rejuvenation and augmentation with autologous fat injection are common and effective techniques worldwide. This procedure has few complications and is usually used for soft-tissue augmentation. Although this procedure is considered safe, many patients have experienced different complications such as visual loss, stroke, or skin necrosis after these procedures. Herein, a case of embolic stroke along with blindness and facial necrosis due to facial filler injection is described. In this case, a patient developed decreased level of consciousness, left hemiparesis, and blindness that was finally diagnosed based on imaging as embolic stroke following facial autologous fat injection. The symptoms improved partially and gradually by conservative treatment and the patient was discharged with some sequels.

Cost estimation in the early stages of construction projects is one of the crucial problems of project sustainability because costs are an integral component of any construction project contract; the completion of a project can be affected by the accuracy with which construction costs dose projected. Various machine learning algorithms were employed for estimate purposes, but neither of the techniques can be considered the best for all circumstances. This research used actual project data for rural roads in Iraq to predict the target variable actual construction cost of road structures based on machine learning techniques. For more accurate cost value two algorithms were compared: the linear support vector regression (SVR) model and Multilayer Perceptron Neural Network (MLP). The highest accuracy has been obtained with linear SVR model. The result R2=0.999 about (100 %), and MAPE=0.00001 shows excellent predictive capabilities of the SVR, regarding that these results are for real problems from the practice. When the outcomes of the models were compared, it was discovered that forecasting with SVR was much more accurate.

Summary: Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection. It remains unclear how MIS-C phenotypes vary across SARS-CoV-2 variants. We aimed to investigate clinical characteristics and outcomes of MIS-C across SARS-CoV-2 eras. Methods: We performed a multicentre observational retrospective study including seven paediatric hospitals in four countries (France, Spain, U.K., and U.S.). All consecutive confirmed patients with MIS-C hospitalised between February 1st, 2020, and May 31st, 2022, were included. Electronic Health Records (EHR) data were used to calculate pooled risk differences (RD) and effect sizes (ES) at site level, using Alpha as reference. Meta-analysis was used to pool data across sites. Findings: Of 598 patients with MIS-C (61% male, 39% female; mean age 9.7 years [SD 4.5]), 383 (64%) were admitted in the Alpha era, 111 (19%) in the Delta era, and 104 (17%) in the Omicron era. Compared with patients admitted in the Alpha era, those admitted in the Delta era were younger (ES −1.18 years [95% CI −2.05, −0.32]), had fewer respiratory symptoms (RD −0.15 [95% CI −0.33, −0.04]), less frequent non-cardiogenic shock or systemic inflammatory response syndrome (SIRS) (RD −0.35 [95% CI −0.64, −0.07]), lower lymphocyte count (ES −0.16 × 109/uL [95% CI −0.30, −0.01]), lower C-reactive protein (ES −28.5 mg/L [95% CI −46.3, −10.7]), and lower troponin (ES −0.14 ng/mL [95% CI −0.26, −0.03]). Patients admitted in the Omicron versus Alpha eras were younger (ES −1.6 years [95% CI −2.5, −0.8]), had less frequent SIRS (RD −0.18 [95% CI −0.30, −0.05]), lower lymphocyte count (ES −0.39 × 109/uL [95% CI −0.52, −0.25]), lower troponin (ES −0.16 ng/mL [95% CI −0.30, −0.01]) and less frequently received anticoagulation therapy (RD −0.19 [95% CI −0.37, −0.04]). Length of hospitalization was shorter in the Delta versus Alpha eras (−1.3 days [95% CI −2.3, −0.4]). Interpretation: Our study suggested that MIS-C clinical phenotypes varied across SARS-CoV-2 eras, with patients in Delta and Omicron eras being younger and less sick. EHR data can be effectively leveraged to identify rare complications of pandemic diseases and their variation over time. Funding: None.

Summary: Background: Characterizing Post-Acute Sequelae of COVID (SARS-CoV-2 Infection), or PASC has been challenging due to the multitude of sub-phenotypes, temporal attributes, and definitions. Scalable characterization of PASC sub-phenotypes can enhance screening capacities, disease management, and treatment planning. Methods: We conducted a retrospective multi-centre observational cohort study, leveraging longitudinal electronic health record (EHR) data of 30,422 patients from three healthcare systems in the Consortium for the Clinical Characterization of COVID-19 by EHR (4CE). From the total cohort, we applied a deductive approach on 12,424 individuals with follow-up data and developed a distributed representation learning process for providing augmented definitions for PASC sub-phenotypes. Findings: Our framework characterized seven PASC sub-phenotypes. We estimated that on average 15.7% of the hospitalized COVID-19 patients were likely to suffer from at least one PASC symptom and almost 5.98%, on average, had multiple symptoms. Joint pain and dyspnea had the highest prevalence, with an average prevalence of 5.45% and 4.53%, respectively. Interpretation: We provided a scalable framework to every participating healthcare system for estimating PASC sub-phenotypes prevalence and temporal attributes, thus developing a unified model that characterizes augmented sub-phenotypes across the different systems. Funding: Authors are supported by National Institute of Allergy and Infectious Diseases, National Institute on Aging, National Center for Advancing Translational Sciences, National Medical Research Council, National Institute of Neurological Disorders and Stroke, European Union, National Institutes of Health, National Center for Advancing Translational Sciences.

This study evaluated the effects of Pediococcus pentosaceus GT001 on Salmonella typhimurium (S. typhimurium)-challenged broiler chickens. Two hundred Ross 708 broiler day-old chicks with comparable weight were distributed at random into four treatments with five replicates and ten chicks per replicate. The following were the treatment groups: (B) basal diet (control); (B + S) basal diet and birds were challenged with S. typhimurium at 1.0 × 107 cfu/g; (B + P) basal diet + Pediococcus pentosaceus GT001 at 4.0 × 108 cfu/g; (B + P + S) basal diet + P. pentosaceus GT001 at 4.0 × 108 cfu/g and birds were challenged with S. typhimurium at 1.0 × 107 cfu/g. There was a significant reduction (p < 0.05) in the body weight of the Salmonella-infected birds compared to the other treatment groups. However, the FCRs of the broilers were comparable among the different treatment groups (p > 0.05). The lipid profile and liver function indices measured were significantly enhanced in the P. pentosaceus GT001-supplemented groups (B + P and B + P + S) compared to the group that was Salmonella-challenged (p < 0.05) but were similar to those in the control group. The serum antioxidant activities, such as the T-AOC, SOD, CAT, GHS-Px and MDA, were significantly improved in the P. pentosaceus GT001-supplemented groups (B + P and B + P + S) (p < 0.05). The MDA was similar in the B + P and B + P + S groups, but both were significantly lower than the control and the Salmonella groups. The administration of P. pentosaceus GT001 enhanced the lipase and amylase levels in both the serum and intestine of the broilers (p < 0.05). The immunoglobin (IgA, IgG, IgM) and cytokine (IL-10 and IL-6) levels in the serum were significantly higher in the B, B + P and B + P + S treatment groups (p < 0.05). The immune-related organs (bursa and spleen) were significantly influenced in the birds fed with P. pentosaceus GT001. No significant variation was noted among all the dietary treatments in terms of the measured meat quality indices. The small intestinal digesta content of the Salmonella load was below a detectable range after 14 days of infection (p < 0.05). No significant differences were observed among the different treatment groups in terms of the breast pH, drip loss and meat color (p > 0.05). The inclusion of P. pentosaceus GT001 also modified the community structure in the cecum. This indicates that it has health benefits and could be incorporated in the broiler diet.

Helicobacter pylori is a microaerophile Gram-negative bacillus, resistant to the activity of gastric juice. The bacteria may take the vegetative form (spiral shape) or sporulation form .Liver cirrhosis and H.Pylori infection are two common diseases in our population and reducing the incidence of complications in cirrhotic subjects is an important step in current gastroenterology practice. The aim of the present study is to determine incidence of H. Pylori infection among patients with liver cirrhosis secondary to HCV infection and study the correlation between esophageal varices degree and H. Pylori infection. This study involved 50 patients with liver cirrhosis secondary to Hepatitis C Virus infection were selected from gastroenterology and internal medicine clinics at Beni-Suef general hospital and Beni-Suef university hospital. Our results illustrate that the percent of H. pylori infection among studied patients was 68%, our results illustrate that there is statistically significant association between the grade of varices and the detection of H. pylori; p value is less than 0.001.

Cloud computing is a model that enables users to store their data remotely and enjoy the applications and services provided by this model on demand through a common set of configurable computing resources, without the burden of local data storage as well as maintenance. However, users no longer have physical possession of external data, and this makes the task of protecting data integrity in cloud computing extremely important so that users can use the cloud storage as if it were local, without worrying about the need to verify its integrity. Hence, public cloud storage auditing is critical, so users can use a Third-party auditor (TPA) to verify data integrity. In order to provide effective TPA security, the audit should not achieves any security vulnerabilities to the privacy of user data and does not provide any additional online burden to the user. In this paper, we propose an effective public auditing system for cloud data based on the signature of Boneh-Lynn-Shacham (BLS), in order to ensure public auditing and maintain data privacy. The proposed system also realizes batch auditing and data dynamic process. In addition, the proposed system enhances the level of security authentication through an Automatic Blocker Protocol (ABP) to protect the system from unauthorized TPA. An extensive security and performance analysis shows that the proposed system is very secure and effective

Background and aims: Lichen planus (LP) and discoid lupus erythematosus (DLE) are two relatively common mucocutaneous lesions whose clinical and histopathological features overlap in some cases. The present study aimed to distinguish between these two lesions histopathologically in order to treat them more accurately. Methods: In a cross-sectional descriptive-analytical study, 29 and 48 microscopic slides of skin samples of DLE and LP, respectively, were examined in the pathology archive of Al-Zahra hospital of Isfahan from 2008 to 2018. The slides prepared by hematoxylin-eosin staining were examined simultaneously and blindly by three pathologists with a light microscope and compared according to certain histopathological criteria. Then obtained data were analyzed by SPSS version 24 using chi-square, Fisher’s exact, Mann-Whitney, and t tests (P

The present work successfully incorporated the composite surface matrices of tantalum carbide (TaC) and niobium carbide (NbC) hybrids and mono-nanoparticles into wrought AA2024 using friction stir processing (FSP). The mechanical, electrical, and microstructural properties were analyzed and evaluated. The microstructure of the refined grains created during the FSP process was observed using polarized optical microscopy. Elongated grains were refined and equiaxed 33 times. Scanning electron microscopy and energy-dispersive X-ray spectroscopy analyses showed good dispersion of the reinforcement nanoparticles in the base matrix. The mechanical properties of the hybrid AA2024/TaC_NbC nanocomposites, thus, the ultimate compressive stress showed an improvement of about 15.2, 16.7, and 20.6%, respectively, compared to the base alloy. Aging time significantly affected the hardness behavior of the hybrid nanocomposites; hence, a maximum value of 73% was reached compared to the base alloy. At the same time, the thermal expansion coefficient and electrical conductivity were reduced by 38.5 and 19.5%, respectively.

Abstract Background Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that typically affects multiple organs and can lead to potentially fatal complications. Central nervous system (CNS) involvement in SLE is common, especially in children, and can present nonspecifically with various neuropsychiatric manifestations, described as neuropsychiatric SLE (NPSLE). Chronic headache is a common feature of NPSLE, secondary to increased intracranial pressure (also called pseudotumor cerebri (PTC)) due to inflammation or medication. Here, we highlight the importance of evaluating refractory headache (HA) in SLE patients to rule out PTC as a cause of severe morbidity. Methods Single tertiary care pediatric center case series of 8 children who developed NPSLE in the form of intracranial hypertension at or after SLE diagnosis. Conclusion Neurologic and ophthalmologic evaluation of refractory HA in patients with SLE, especially children, is warranted to decrease the burden of the disease and rule out treatable causes like PTC.

Abstract Background Most of the surgeons tend to avoid exposing and identification the external branch of the superior laryngeal nerve (EBSLN) during thyroidectomy. In this study, our aim is to assess sequential steps to ligate superior thyroid vessels safely away from the External branch of superior laryngeal nerve (EBSLN). Methods This prospective case series study was conducted on 60 patients going for either total or hemi thyroidectomy in a tertiary teaching hospital between January 2016 and June 2019. During thyroidectomy, firstly we skeletonized the upper pole of the thyroid gland by its capsular dissection followed by anterolateral down retraction of the superior pole. Then, entry and opening of the cricothyroid space and lastly clamping and ligating superior thyroid pedicle close to the upper pole away from EBSLN. Results This study included 60 cases; 19 total thyroidectomy and 41 hemi thyroidectomy with 79 superior thyroid vessels ligation and EBSLN at risk. In all patients, no evidence of superior laryngeal nerve (SLN) palsy or bleeding was detected. Postoperative video laryngoendoscopy showed apparently normal mobility, length, level, and position of the vocal folds with symmetry of the larynx. The patients’ voice showed no changes from preoperative evaluation in all studied patients at 3 months postoperative evaluation. No patients complained of any changes in their voice or voice activities. Conclusion The described stepwise approach for preservation of the EBSLN serves to completely remove the superior pole of the thyroid gland and ligate superior thyroid vascular pedicle without risk of SLN injury.

Summary: Background: While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking. Methods: A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1–365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021. Findings: Advanced age (HR 2.77, 95%CI 2.53–3.04, p

Exploring alternatives to antibiotics is imperative in reducing antibiotic resistance and antibiotic residues in poultry products. The beneficial effects of antibiotic products derived from natural sources in comparison with the synthetic ones has been reported. Pediococcus pentosaceus has been applied as an animal growth bio-promoter and probiotic. To elucidate the protective mechanisms of P. pentosaceus, this study investigated the effects of different doses of P. pentosaceus supplementation on broiler growth performance, immune function, intestinal development and histomorphology. Five hundred (500) one-day-old Ross 708 broiler chicks were randomly enrolled into five experimental groups with 20 chicks per replicate. The treatments were imposed as follows: (T1) basal diet (control); (T2) basal diet with 1 g/kg antibact 3X; (T3) basal diet with P. pentosaceus GT001 at 4.0 × 108 cfu/g; (T4) basal diet with P. pentosaceus GT001 at 8.0 × 108 cfu/g; and (T5) basal diet with P. pentosaceus GT001 at 1.2 × 109 cfu/g. Dietary inclusion of P. pentosaceus GT001 at 4.0 × 108 cfu/g significantly improved body weight gain, feed intake and lipid profile of the broilers compared to the control group (p < 0.05). The addition of P. pentosaceus GT001 significantly improved the intestinal pH of the broilers. The digestive enzymes of the broilers were impacted with the supplementation of P. pentosaceus GT001 at 4.0 × 108 cfu/g. The highest serum antioxidant production was observed in the P. pentosaceus-treated group compared to the control. P. pentosaceus GT001 at 4.0 × 108 cfu/g increased the levels of serum cytokines and immunoglobin and improved the small intestinal morphology of the broilers in comparison with the control. The load of Pedococcus spp was similar among T3, T4 and T5 but significantly higher than that of the control (T1) and the antibiotics (T2)-fed birds. The load of E. coli in the gut was significantly reduced in T3, T4 and T5 compared to T1 and T2. There was no Salmonella growth among the treatments. This study highlights the importance of probiotics in broiler diets and suggests that Pediococcus pentosaceus GT001 could be used as a feasible substitute to antimicrobials in broiler production.

It was assumed that dietary inclusion of Lactobacillus reuteri SL001 isolated from the gastric contents of rabbits could act as an alternative to feed antibiotics to improve the growth performance of broiler chickens. We randomly assigned 360 one-day-old AA white-feathered chicks in three treatments: basal diet (control), basal diet plus zinc bacitracin (antibiotic), and basal diet plus L. reuteri SL001 (SL001) treatment. The results showed the total BW gain and average daily gain (ADG) of broilers in SL001 treatment increased significantly (p < 0.05, respectively) compared with the control group from day 0 to 42. Moreover, we observed higher levels of immune globulins in both the SL001 group and the antibiotic group. Total antioxidant capacity and levels of antioxidant factors were also significantly increased (p ≤ 0.05, respectively) in the SL001 treatment group, while the interleukin 6, interleukin 4, creatinine, uric acid, total cholesterol, triglyceride, VLDL, LDL and malondialdehyde were remarkably decreased (p < 0.05, respectively). In the ileum of SL001 treatment broilers, the height of villi and the ratio of villi height to crypt depth were significantly increased (p < 0.05). Meanwhile, the crypt depth reduced (p < 0.01) and the ratio of villi height to crypt depth increased (p < 0.05) in the jejunum compared to the control. The abundance of microbiota increased in the gut of broilers supplemented with SL001. Dietary SL001 significantly increased the relative abundance of Actinobacteria in the cecal contents of broilers (p < 0.01) at the phylum level. In conclusion, L. reuteri SL001 supplementation promotes the growth performance of broiler chickens and exhibits the potential application value in the industry of broiler feeding.

Regarding significant number of the people affecting by factors, such as gas poisoning, microbial, and heat exhaustion in mineral hot spas, the present study was conducted aimed at providing a model for measuring and managing the risk of using hot mineral spas. In this research, a conceptual model of risk was prepared in four stages. Firstly, 16 qualitative parameters were extracted, their effect weight of which was obtained based on the amount of risk for users was determined by fuzzy analysis method. According to the amount and standard range allowed for each parameter, quantitative and qualitative risk categories were obtained in five ranges for each parameter based on the obtained weights and opinions of the health experts. Then, the final result regarding risk of using each spa was obtained by combining these parameters. For assessing risk of using hot mineral spas in Ardabil province by the method invented in this research, at first, water samples were collected from six spas in different parts of Ardabil province. Then, risk management of six spas was evaluated. According to the results, the Qotursuyi spa had a high level of risk, the spas of Shabil, Gavmishgoli, and Qinarjeh had a moderate level of risk. Under responsible risk management, natural hot springs present a renewable resource for sustainable tourism development on a long-term basis.

The human epidermal growth factor receptor 2 (HER2) is a critical oncogene implicated in the development of various aggressive cancers, particularly breast cancer. Discovering novel HER2 inhibitors is crucial for expanding therapeutic options for HER2-related malignancies. In this study, we present a computational workflow that focuses on generating pharmacophores derived from docked poses of a selected list of 15 diverse, potent HER2 inhibitors, utilizing flexible docking. The resulting pharmacophores, along with other physicochemical molecular descriptors, were then evaluated in a machine learning-quantitative structure-activity relationship (ML-QSAR) analysis against 1,272 HER2 inhibitors. Several machine learning methods were assessed, and a genetic function algorithm (GFA) was employed for feature selection. Ultimately, GFA combined with Bagging and J48Graft classifiers produced the best self-consistent and predictive models. These models highlighted the significance of two pharmacophores, Hypo&#95;1 and Hypo&#95;2, in distinguishing potent from less active inhibitors. The successful ML-QSAR models and their associated pharmacophores were used to screen the National Cancer Institute (NCI) database for novel HER2 inhibitors. Three promising anti-HER2 leads were identified, with the top-performing lead demonstrating an experimental anti-HER2 IC 50 value of 3.85 μM. Notably, the three inhibitors exhibited distinct chemical scaffolds compared to existing HER2 inhibitors, as indicated by principal component analysis., (© 2025 Wiley-VCH GmbH.)

Aurora-A (AURKA) is serine/threonine protein kinase involved in the regulation of numerous processes of cell division. Numerous studies have demonstrated strong association between AURKA and cancer. AURKA is overexpressed in many cancers, such as colon, breast and prostate cancers. Consequently, AURKA has emerged as promising target for therapeutic intervention in cancer management. Herein, we describe a computational workflow for the discovery of novel anti-AURKA inhibitory leads starting with ligand-based assessment of the pharmacophoric space of six diverse sets of inhibitors. Subsequently, machine learning/QSAR modeling was coupled with genetic function algorithm to search for the best possible combination of machine learner, ligand-based pharmacophore(s) and molecular descriptors capable of explaining variation in anti-AURKA bioactivities within a collected list of inhibitors. Two learners succeeded in achieving acceptable structure/activity correlations, namely, random forests and extreme gradient boosting (XGBoost). Three pharmacophores emerged in the successful ML models. These were then used as 3D search queries to mine the National Cancer Institute database for novel anti-AURKA leads. Top-ranking 38 hits were assessed in vitro for their anti-AURKA bioactivities. Among them, three compounds exhibited promising dose-response curves, demonstrating experimental IC 50 values ranging from sub-micromolar to low micromolar values. Remarkably, two of these compounds are of novel chemotypes., Competing Interests: Declarations. Conflict of interest: The authors declare that there are no financial or non-financial interests that are directly or indirectly related to the current research., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Myeloproliferative neoplasms (MPNs) are rare hematopoietic disorders driven by mutations in the JAK-STAT signaling pathway genes. While JAK2 inhibitors have transformed MPN treatment, they do not eliminate the malignant clone or prevent disease progression in most patients. This limitation underscores the need for more effective therapies., Area Covered: This review examines the evolution of JAK2 inhibitors for treating MPNs. Current JAK2 inhibitors primarily function as type I inhibitors, targeting the active kinase conformation, but their effectiveness is limited by ongoing JAK-STAT signaling. To overcome these limitations, next-generation therapies, such as type II JAK2 inhibitors and pseudokinase domain inhibitors, are being developed to target inactive kinase conformations and alternative signaling pathways. Furthermore, combination therapies with PI3K, mTOR, CDK4/6 inhibitors, and epigenetic modulators are being investigated for their potential synergistic effects, aiming for deeper and more durable responses in MPN patients., Expert Opinion: Next-generation JAK2 inhibitors are needed to enhance current MPNs treatments by overcoming resistance, improving selectivity, targeting specific patient groups, and exploring combination therapies. Addressing challenges in drug design, preclinical testing, and clinical trials is crucial. Developing dual or multiple inhibitors targeting JAK2 and other MPN-related pathways is urgent to address complex signaling networks and improve efficacy.

Background/Objectives: Treatment of patients with myocardial ischemic diseases crucially involves cardiac reperfusion (CR). However, oxidative stress and tissue lesions caused by CR may also lead to lethal complications, such as arrythmias and vasoplegic syndrome (VS). Although methylene blue (MB) has long been used to treat VS due to cardiac ischemia and reperfusion (CIR) and/or surgery because of its vascular effects, MB's effects on the heart are unclear. Therefore, we investigated the potential cardioprotective or arrhythmogenic effects of MB in an animal model of CIR. To this end, 12-16-week-old male Wistar rats were divided into four experimental groups: (a) rats subjected to SHAM surgery with no ischemia; (b) rats subjected to CIR and treated with a vehicle (SS + CIR); and (c) rats subjected to CIR and treated with 2 mg/kg i.v. MB before ischemia (MB + ISQ) or (d) after ischemia but before reperfusion (ISQ + MB). An ECG analysis was used to evaluate the incidence of ventricular arrhythmias (VAs), atrioventricular blocks (AVBs), and lethality (LET) resulting from CIR. After CIR, rat hearts were removed for histopathological analysis and lipid hydroperoxide (LH) measurements. Results: The incidence of VA, AVB, and LET was significantly increased in the MB + ISQ group (VA = 100%; AVB = 100%; LET = 100%) but significantly reduced in the ISQ + MB group (VA = 42.8%; AVB = 28.5%; LET = 21.4%) compared with the SS + CIR group (VA = 85.7%; AVB = 71.4%; LET = 64.2%). LH concentration was significantly reduced in both MB-treated groups, but myocardial injuries were increased only in the MB + ISQ group when compared with the SS + CIR group. Conclusions: These results indicate that MB produces a biphasic effect on CIR, with cardiotoxic effects when administered before cardiac ischemia and cardioprotective effects when administered after ischemia but before cardiac reperfusion.

Purpose: Shock, cardiovascular problems, and respiratory failure constitute the main causes of death in patients cared in medical emergency rooms. Patients commonly require orotracheal intubation (OTI), a fact that has been intensified by diseases that generate important and fatal hemodynamic and respiratory problems in the affected patient., Methods: Although etomidate (ETO) is a highly used anesthetic for OTI, its use remains controversial in several scenarios. Some studies refer to an increase in mortality with its use in critically patients, while others do not refer to a difference. Therefore, we evaluated the mortality of patients submitted to OTI in the public hospital of a public federal university, with the use of ETO and other sedative-hypnotic drugs used in the induction of the performance of OTI, with the in-hospital mortality of patients cared in hospital., Results: The results demonstrate that the use of ETO as a hypnotic for OTI in the emergency room is not associated with a significant difference in morbidity or early mortality, within 30 days of hospitalization, compared with other hypnotics., Conclusions: There was no difference in mortality between patients intubated in the emergency department who used ETO and those who used non-ETO hypnotic within 72 hours and 30 days.

Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase within the insulin receptor superfamily. Alterations in ALK, such as rearrangements, mutations, or amplifications, have been detected in various tumours, including lymphoma, neuroblastoma, and non-small cell lung cancer. In this study, we outline a computational workflow designed to uncover new inhibitors of ALK. This process starts with a ligand-based exploration of the pharmacophoric space using 13 diverse sets of ALK inhibitors. Subsequently, quantitative structure-activity relationship (QSAR) modelling is employed in combination with a genetic function algorithm to identify the optimal combination of pharmacophores and molecular descriptors capable of elucidating variations in anti-ALK bioactivities within a compiled list of inhibitors. The successful QSAR model revealed three pharmacophores, two of which share three similar features, prompting their merger into a single pharmacophore model. The merged pharmacophore was used as a 3D search query to mine the National Cancer Institute (NCI) database for novel anti-ALK leads. Subsequent in vitro bioassay of the top 40 hits identified two compounds with low micromolar IC 50 values. Remarkably, one of the identified leads possesses a novel chemotype compared to known ALK inhibitors.

Aims: Micellar systems have the advantage of being easily prepared, cheap, and readily loadable with bioactive molecular cargo. However, their fundamental pitfall is poor stability, particularly under dilution conditions. We propose to use simple quaternary ammonium surfactants, namely, hexadecylamine (HDA) and hexadecylpyridinium (HDAP), together with tripolyphosphate (TPP) anion, to generate ionotropically stabilized micelles capable of drug delivery into cancer cells., Methods: optimized mixed HDA/HDAP micelles were prepared and stabilized with TPP. Curcumin was used as a loaded model drug. The prepared nanoparticles were characterized by dynamic light scattering, infrared spectroscopy, transmission electron microscopy, and differential scanning calorimetry. Moreover, their cellular uptake was assessed using flow cytometry and confocal fluorescence microscopy., Results: The prepared nanoparticles were found to be stable under dilution and at high temperatures and to have a size range from 139 nm to 580 nm, depending on pH (4.6-7.4), dilution (up to 100 times), and temperature (25 - 80 °C). They were effective at delivering their load into cancer cells. Additionally, flow cytometry indicated the resulting stabilized micellar nanoparticles to be non-cytotoxic., Conclusions: The described novel stabilized micelles are simple to prepare and viable for cancer delivery.

Defined as systemic hypotension caused by intense vasodilation due to the loss of systemic vascular resistance, vasoplegic syndrome (VS) is associated with elevated morbidity and mortality in humans. Although vasopressors such as norepinephrine and vasopressin are the first-choice drugs for VS treatment, several other drugs such as methylene blue (MB) can be used as adjuvant therapy including rescue therapy. To develop new pharmacological strategies to reduce the risk of VS, we investigated the effects of treatments with MB (2 mg/kg/IV), omeprazole (OME, 10 mg/kg/IV), and their combination in an animal model of cardiac ischemia-reperfusion (CIR). The ventricular arrhythmia (VA), atrioventricular block (AVB), and lethality (LET) incidence rates caused by CIR (evaluated via ECG) and serum levels of the cardiac lesion biomarkers creatine kinase-MB (CK-MB) and troponin I (TnI) in adult rats pretreated with saline solution 0.9% and submitted to CIR (SS + CIR group) were compared to those pretreated with MB (MB + CIR group), OME (OME + CIR group), or the MB + OME combination (MB + OME + CIR group). The AVB and LET incidence rates in the MB + CIR (100%), OME + CIR (100%), and MB + OME + CIR (100%) groups were significantly higher compared to the SS + CIR group (60%). The serum level of CK-MB in these groups were also significantly higher compared to the SS + CIR group, demonstrating that the treatments before CIR with MB, OME, and MB + OME produced similar effects in relation to cardiac function and the occurrence of lesions. These results demonstrate that the treatment of animals subjected to the CIR protocol with OME produced the same effects promoted by the treatment with MB, which may suggest the possibility of using OME alone or in combination with MB in medical clinics in treatment of VS.

A set of cyclopenten-[ g ]annelated isoindigos ( 5a-g ) has been prepared and tested for their in vitro antiproliferative activities against MCF-7 and HL60 cells. Among, the N -1-methyl-5'-nitro derivative ( 5g ) displayed the highest activity against HL60 cells (IC 50  = 67 nM) and acted as the most potent Flt3 inhibitor. Compounds 5d-g exhibited moderate activity against MCF-7 (IC 50  = 50-80 μM)., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

STAT3 belongs to a family of seven transcription factors. It plays an important role in activating the transcription of various genes involved in a variety of cellular processes. High levels of STAT3 are detected in several types of cancer. Hence, STAT3 inhibition is considered a promising therapeutic anti-cancer strategy. However, since STAT3 inhibitors bind to the shallow SH2 domain of the protein, it is expected that hydration water molecules play significant role in ligand-binding complicating the discovery of potent binders. To remedy this issue, we herein propose to extract pharmacophores from molecular dynamics (MD) frames of a potent co-crystallized ligand complexed within STAT3 SH2 domain. Subsequently, we employ genetic function algorithm coupled with machine learning (GFA-ML) to explore the optimal combination of MD-derived pharmacophores that can account for the variations in bioactivity among a list of inhibitors. To enhance the dataset, the training and testing lists were augmented nearly a 100-fold by considering multiple conformers of the ligands. A single significant pharmacophore emerged after 188 ns of MD simulation to represent STAT3-ligand binding. Screening the National Cancer Institute (NCI) database with this model identified one low micromolar inhibitor most likely binds to the SH2 domain of STAT3 and inhibits this pathway., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Acute myocardial infarction (AMI) is the main cause of morbidity and mortality worldwide and is characterized by severe and fatal arrhythmias induced by cardiac ischemia/reperfusion (CIR). However, the molecular mechanisms involved in these arrhythmias are still little understood. To investigate the cardioprotective role of the cardiac Ca 2+ /cAMP/adenosine signaling pathway in AMI, L-type Ca 2+ channels (LTCC) were blocked with either nifedipine (NIF) or verapamil (VER), with or without A 1 -adenosine (ADO), receptors (A 1 R), antagonist (DPCPX), or cAMP efflux blocker probenecid (PROB), and the incidence of ventricular arrhythmias (VA), atrioventricular block (AVB), and lethality (LET) induced by CIR in rats was evaluated. VA, AVB and LET incidences were evaluated by ECG analysis and compared between control (CIR group) and intravenously treated 5 min before CIR with NIF 1, 10, and 30 mg/kg and VER 1 mg/kg in the presence or absence of PROB 100 mg/kg or DPCPX 100 µg/kg. The serum levels of cardiac injury biomarkers total creatine kinase (CK) and CK-MB were quantified. Both NIF and VER treatment were able to attenuate cardiac arrhythmias caused by CIR; however, these antiarrhythmic effects were abolished by pretreatment with PROB and DPCPX. The total serum CK and CK-MB were similar in all groups. These results indicate that the pharmacological modulation of Ca 2+ /cAMP/ADO in cardiac cells by means of attenuation of Ca 2+ influx via LTCC and the activation of A 1 R by endogenous ADO could be a promising therapeutic strategy to reduce the incidence of severe and fatal arrhythmias caused by AMI in humans.

Purpose: To evaluate the modulatory properties of Calendula officinalis L. (Asteraceae) (C. officinalis) extract on cafeteria diet-fed rats., Methods: A cafeteria diet was administered ad libitum for 45 days to induce dyslipidemia. Then, the rats were treated with the formulations containing C. officinalis in the doses of 50, 100, and 150 mg/kg or only with the vehicle formulation; the control group received a commercial ration., Results: The cafeteria diet decreased glutathione S-transferase activity and high-density lipoprotein plasmatic levels and damaged the hepatic architecture. The C. officinalis extract was able to reduce lipid infiltration in liver tissue and to modulate oxidative stress and lipid profile markers., Conclusions: The correlations between the variables suggest a pathological connection between oxidative stress markers and serum lipid profile.

Aims: Although reduced life expectancy in Parkinson's Disease (PD) patients has been related to severe cardiac arrhythmias due to autonomic dysfunctions, its molecular mechanisms remain unclear. To investigate the role of cardiac β 1 -Adrenergic (β 1 AR) and A 1 -Adenosine (A 1 R) receptors in these dysfunctions, the pharmacological effects of stimulation of cardiac β 1 AR (isoproterenol, ISO), in the absence and presence of cardiac β 1 AR (atenolol, AT) or A 1 R (1,3-dipropyl-8-cyclopentyl xanthine, DPCPX) blockade, on the arrhythmias induced by Ischemia/Reperfusion (CIR) in an animal PD model were studied., Methods: PD was produced by dopaminergic lesions (confirmed by immunohistochemistry analysis) caused by the injection of 6-hydroxydopamine (6-OHDA, 6 μg) in rat striatum. CIR was produced by a surgical interruption for 10 min followed by reestablishment of blood circulation in the descendent left coronary artery. On the incidence of CIR-Induced Ventricular Arrhythmias (VA), Atrioventricular Block (AVB), and Lethality (LET), evaluated by Electrocardiogram (ECG) analysis, the effects of intravenous treatment with ISO, AT and DPCPX (before CIR) were studied., Results: VA, AVB and LET incidences were significantly higher in 6-OHDA (83%, 92%, 100%, respectively) than in control rats (58%, 67% and 67%, respectively). ISO treatment significantly reduced these incidences in 6-OHDA (33%, 33% and 42%, respectively) and control rats (25%, 25%, 33%, respectively), indicating that stimulation of cardiac β 1 AR induced cardioprotection. This response was prevented by pretreatment with AT and DPCPX, confirming the involvement of cardiac β 1 AR and A 1 R., Conclusion: Pharmacological modulation of cardiac β 1 AR and A 1 R could be a potential therapeutic strategy to reduce severe arrhythmias and increase life expectancy in PD patients., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Anti-tachycardia pacing therapy (ATP) has shown comparable efficacy to shock therapy in ventricular tachycardia (VT) termination with better quality of life. However, some ATPs may lead to VT acceleration or degeneration to ventricular fibrillation (VF), which will result in more ICD shocks. The aim of this study was to investigate the predictors of VT acceleration by ATP therapy in a real-life patient cohort., Results: We retrospectively reviewed 448 monomorphic VT episodes that required ATP therapy in 60 patients with structural heart diseases implanted with ICD or CRTD. The clinical data of the patients and the episodes' details were evaluated. We found that patients with a higher ejection fraction (EF) were more likely to be cardioverted by ATP therapy (P: 0.024). VT acceleration was more frequent in patients with lower EF (mean 31.24 ± 4.08) compared with the non-accelerated patients with higher EF (mean 37.00 ± 9.4, P: 0.016). The percentage of accelerated episodes was 8.5%. VT episodes with a mean cycle length (CL) < 310 ms are more likely to accelerate (sensitivity 76.3%, specificity 67.7%, PPV value 45%, NPV 86%, and AUC 0.790). There was a statistically significant difference in the accelerated VT episodes as compared to non-accelerated episodes regarding the number of ATP bursts (mean 3.66 ± 2.22 vs. 1.76 ± 1.35, P: < 0.001), ramp (23.7% vs. 4.2%, P: < 0.001), scanning (55.3% vs. 31.3%, P: 0.003) and burst adaptive cycle length (mean 83.55 ± 2.92 vs. 84.64 ± 2.61, P: 0.016). In a multivariate analysis, the VT CL, number of ATP bursts and ramp pacing predicted VT acceleration by ATP therapy., Conclusions: Ventricular tachycardia in patients with low LV EF and fast VTs with a CL less than 310 ms were more likely to accelerate with ATP therapy. The number of ATP bursts and the use of ramp had a significant effect on VT acceleration. To avoid VT acceleration by ATP therapy, ramp pacing better be avoided, especially in fast VTs, and lesser number of bursts should be delivered., (© 2023. The Author(s).)

Dual specificity protein kinase threonine/Tyrosine kinase (TTK) is one of the mitotic kinases. High levels of TTK are detected in several types of cancer. Hence, TTK inhibition is considered a promising therapeutic anti-cancer strategy. In this work, we used multiple docked poses of TTK inhibitors to augment training data for machine learning QSAR modeling. Ligand-Receptor Contacts Fingerprints and docking scoring values were used as descriptor variables. Escalating docking-scoring consensus levels were scanned against orthogonal machine learners, and the best learners (Random Forests and XGBoost) were coupled with genetic algorithm and Shapley additive explanations (SHAP) to determine critical descriptors for predicting anti-TTK bioactivity and for pharmacophore generation. Three successful pharmacophores were deduced and subsequently used for in silico screening against the NCI database. A total of 14 hits were evaluated in vitro for their anti-TTK bioactivities. One hit of novel chemotype showed reasonable dose-response curve with experimental IC 50 of 1.0 μM. The presented work indicates the validity of data augmentation using multiple docked poses for building successful machine learning models and pharmacophore hypotheses., (© 2023 Wiley-VCH GmbH.)

STAT3 belongs to a family of seven vital transcription factors. High levels of STAT3 are detected in several types of cancer. Hence, STAT3 inhibition is considered a promising therapeutic anti-cancer strategy. In this work, we used multiple docked poses of STAT3 inhibitors to augment training data for machine learning QSAR modeling. Ligand-Receptor Contact Fingerprints and scoring values were implemented as descriptor variables. Escalating docking-scoring consensus levels were scanned against orthogonal machine learners, and the best learners (Random Forests and XGBoost) were coupled with genetic algorithm and Shapley additive explanations (SHAP) to identify critical descriptors that determine anti-STAT3 bioactivity to be translated into pharmacophore model(s). Two successful pharmacophores were deduced and subsequently used for in silico screening against the National Cancer Institute (NCI) database. A total of 26 hits were evaluated in vitro for their anti-STAT3 bioactivities. Out of which, three hits of novel chemotypes, showed cytotoxic IC 50 values in the nanomolar range (35 nM to 6.7 μM). However, two are potent dihydrofolate reductase (DHFR) inhibitors and therefore should have significant indirect STAT3 inhibitory effects. The third hit (cytotoxic IC 50 = 0.44 μM) is purely direct STAT3 inhibitor (devoid of DHFR activity) and caused, at its cytotoxic IC 50 , more than two-fold reduction in the expression of STAT3 downstream genes (c-Myc and Bcl-xL). The presented work indicates that the concept of data augmentation using multiple docked poses is a promising strategy for generating valid machine learning models capable of discriminating active from inactive compounds., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)