To examine the effect of synchronous dance movements on social bonding and perceived closeness between generations, 168 young (20-45 years) and older (65-90 years) participants were randomly assigned to six dyad conditions. These included dancing synchronously or asynchronously with an in-age-group or an out-age-group unfamiliar partner for 11 minutes. Participants completed social bonding and groups’ closeness questionnaires. To assess variation across individuals’ and dyads’ measurements, a generalized estimating equations modeling analysis was conducted. In line with the first two hypotheses, synchronized dance increased social bonding, and young adults showed enhanced perception of closeness between generations. Hypothesis 3 that synchronous dance with out-age-group members would foster greater perceived closeness compared to in-age-group members was not confirmed. Surprisingly, results indicated that asynchronous movements with the in-age-group led to a higher degree of closeness between generations than asynchronous movements with the out-age-group. The study offers new directions for practitioners in welfare, nursing, and therapy fields, particularly for engaging young adults in intergenerational dance interventions.

Background/Purpose: Multimorbidity of malaria, anaemia, and malnutrition (MAMM) is a condition in which an individual cohabits with two or more of these health outcomes and is becoming an emergent public health concern in sub-Saharan African countries. The independent associations of a child’s demographic variables and socioeconomic disparities with a child’s health outcomes have been established in literature. However, the effects of the intersection of these factors on MAMM, while accounting for other covariates have not been studied. Therefore, this study aimed to determine how children’s sex, age and socioeconomic status interact to explain the variations in MAMM among children aged 6-59 months in Nigeria. Methods: Data from the 2018 Nigeria Demographic and Health Survey and the 2018 National Human Development Report (NHDR) were used. The study includes weighted samples of 10,184 children aged 6-59 months in Nigeria. A three-level multilevel mixed effect ordinal logistic regression model such that individual characteristics at level 1 are nested in communities at level 2 and nested in states at level 3 was used. Subsequently, predictive probability charts and average adjusted probability tables were used to interpret the intersectional effects. Five models were created in this scenario. Model 1 is the interaction between the child's sex and wealth status; model 2, child's sex and age; model 3 is between child's age and wealth status; model 4 has the three 2-way interactions of child's sex, age, and household wealth status, and model 5 includes model 4 and the 3-way interactions between a child's sex, age, and wealth quintiles. Results: The prevalence of children with ‘none of the three diseases’ outcomes was 17.3% (1767/10,184), while, 34.4% (3499/10,184) had ‘only one of the diseases’, and 48.3% (4,918/10,184) cohabit with ‘two or more’ of MAMM. However, in the multivariate analyses, model 3 was the best fit compared with other models, so, that the two-way interaction effects of a child's age and wealth status are significant predictors in the model. Children aged 36-47 months living in the poorest households have the probability of 0.11, 0.18, and 0.32 of contracting MAMM above the probability of children of the same age and live in the middle, more prosperous and richest households, respectively, while all other covariates are held constant. Thus, the variation in MAMM over a child's age differs depending on the household wealth quintile. In other words, as the children grow older, variations in MAMM become more evident between the rich and the poor household. Conclusion: Therefore, it is recommended that policies that are geared toward economic redistribution will help bridged the disparities observed in multiple diseases among children aged 6-59 months in Nigeria

Recent experiments devoted to characterizing the behavior of sessile ferroelectric liquid droplets on ferroelectric solid substrates, showed the existence of a droplet electromechanical Rayleigh-like instability. The instability is induced by the bulk polarization of the ferroelectric fluid which couples to the polarization of the underlying substrate through its fringing field and solid-fluid interface coupling. With the aim of characterizing this phenomenon, namely the coupling between the polarizations of a fluid and a solid material, we studied the behavior of ferroelectric liquid droplets confined between two solid substrates, arranged in different configurations realized so to generate fringing fields with different profiles. Results show that the features of the droplets instability are indeed affected by the specific fringing field shape in a way dominated by the minimization of the electrostatic energy associated to the bulk polarization of the ferroelectric fluid.

In this work, a novel approach is presented for the multivariate prediction of hydrological variables, employing a specialized type of recurrent neural network (RNN) known as the long-term memory network (LSTM).The central objective is to develop a flood prediction model using data collected from two hydrological stations situated along the Atrato River in the Choc´o Department, Colombia. The interconnected variables of water level, water flow, and water precipitation are analyzed in this model to enhance flood prediction accuracy. The LSTM model, integrated into an RNN structure, is designed to capture the complex dynamics and cross-correlations inherent in these hydrological variables. Validation involves a comparison with linear and nonlinear Nonlinear AutoRegressive with eXogenous input (NARX) models, considering factors such as estimation error and computational time. Additionally, the study conducts further analysis for water level prediction under two scenarios: utilizing only outflow and inflow measurements or predicting outflow alongside measuring inflow, with the objective of utilizing the proposed approach as a flood early warning system. † This article is a revised and expanded version of a paper entitled Multivariable NARX based Neural Networks Models for Short-term Water Level Forecasting, which was presented at International Conference on Time Series and Forecasting (ITISE-2023), Gran Canaria, Spain, 12th-14th July, 2023.

The most frequent cause of cardiac failure globally is ischemic heart disease, with chemothera-py-related cardiovascular side effects emerging as the second most frequent cause. Cancer therapy can result in acute cardiac events, such as coronary artery spasm, acute myocardial infarction, thromboembolism, myocarditis, bradycardia, tachyarrhythmias, atrio-ventricular blocks, QT pro-longation, torsades de pointes, pericardial effusion and hypotension, as well as chronic conditions, such as hypertension, systolic and diastolic left ventricular dysfunction presenting clinically as heart failure or cardiomyopathy. In cardio-oncology, when referring to cardiac toxicity and cardiovas-cular hypersensitivity, there is a great deal of misunderstanding. When a dose-related cardiovas-cular side effect continues even after the causative medication is stopped, it is referred to as cardi-otoxicity. A fibrotic response is the ultimate outcome of cardiac toxicity, which is defined as a dose-related cardiovascular adverse impact that lasts even after the causative treatment is stopped. Cardiotoxicity can occur after a single or brief exposure. On the other hand, the term cardiac or cardiovascular hypersensitivity describes an inflammatory reaction that is not dose-dependent, can occur at any point during therapy, even with very low medication dosages, and can show up as Kounis syndrome. It may also be accompanied by anti-drug antibodies and tryptase levels. In this comprehensive review, we present the current views on cardiac toxicity and cardiovascular hypersensitivity, together with the reviewed cardiac literature on the chemotherapeutic agents inducing hypersensitivity reactions. Cardiac hypersensitivity seems to be the pathophysiologic basis of coronary artery spasm, acute coronary syndromes such as Kounis syndrome and myocardi-tis caused by cancer therapy.

Abstract—Hydraulic switching actuators are high efficiency, fast response, and low cost solutions for hydraulic control systems. One of the challenging problems is throttling losses during valve transitions. Previously the authors proposed a zero-flowrate switching method to reduce throttling energy loss of the switching valve, where a hydraulic resonator is applied to make the flowrates through the lines approaching zero before the valves are switched off. The major challenge of this approach is fast switching valves whose transition times are less than 2 ms. In this paper, an improved zero-flowrate switching method is presented. It utilizes the capacity with independent inlet/outlet ports to regulate flowrates through the lines. Models of capacity applied in a simple line with different pressure signals are developed to explore characteristics of the capacity, based on which a complete actuation system is developed. In the complete model, resistance and inductance are optimized to achieve desired flowrate response. The improved zero-flowrate switching method reduces throttling energy losses by 99.945% compared to a hard switching system. The simulation results demonstrated that the improved zero-flowrate switching method performs as expected in the design condition. A capacity with proper volume is able to regulate flowrates through all the lines to zero, with the help of appropriate resistance and inductance. Compared to previous zero-flowrate switching method, the novel strategy allows slower switching valves applied in hydraulic actuation systems and achieves better efficiency performance. This research paves a new avenue for reducing throttling energy losses and improves system efficiency in hydraulic switching actuators, as well as most of the hydraulic switch-mode circuits.

Currently, in some domestic and foreign mines, the backfill drilling pipeline experience a rupture phenomenon even when the wear degree is low. This results in a delay in production due to the filling becoming 'sick'. This paper presents, for the first time, the damage mechanism from a mechanical perspective and re-derives the anti-extrusion strength model of the backfill drilling pipeline. We investigate the influence of law on the anti-extrusion strength of pipelines from the perspective of stratum and cement ring. We then verify the theoretical and simulation results through engineering examples. The results demonstrate that the Mises stress criterion is a suitable modification principle for the anti-extrusion strength model of the backfill drilling pipeline. The anti-extrusion strength of the pipeline is related to the elastic modulus and Poisson's ratio of the stratum, and the thickness of the cement ring. It is negatively affected by the depth of the stratum. For hard strata, a cement ring with a smaller elastic modulus is suitable, while for soft stratum, a cement ring with a larger elastic modulus is recommended. When the missing angle of the cement ring is less than 60°, the stress concentration factor increases up to 2.2. The stress unloading capacity of the cement ring ranges from 32.7% to 37.8%, and optimal performance of the cement ring is achieved when it has high strength and low rigidity. The backfill filling pipeline of a copper mine abroad was destroyed due to external extrusion force exceeding its anti-extrusion strength value. The modified pipeline anti-extrusion strength model is 18.2% higher than the casing API strength value. This finding can inform the design of the backfill filling pipeline for China's kilometer-deep wells in the future.

The escalating demand for multifunctional and advanced materials for growing industries has turned scientific exploration to graphene-based hybrid filler polymer composites. The introduction of graphene with other fillers into polymer matrices results in astonishing properties and thus has gained significant attention in recent years. This study addresses the significance of graphene-based hybrid filler polymer composites in progressive materials science and engineering. The paper encloses some traditional and current preparation techniques employed in the fabrication of composites and a comprehensive review of successfully prepared graphene hybrid polymer composites with enhanced mechanical, thermal, and electrical properties reported in published research. The role of different factors, e.g., filler type, aspect ratios, filler-matrix compatibility, dispersion effects, homogeneity, filler orientation through polymer matrices, and curing conditions, are summarized. Finally, the applications in heavy industries, e.g., aerospace, electronics, energy storage, and automotive sectors were also analyzed. We hope this study will serve as a practical resource for new researchers and practitioners to understand and harness the full potential of these composites in various scientific and industrial fields.

This paper provides the first-time ever analytic modelling for Pointwise Stationary Fluid Flow Approximation(PSFFA) model of the non-stationary

Epidemiological and clinical evidence have extensively documented the role of obesity in the develop-ment of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer, and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effec-tively reversed the effects of palmitic acid on cell proliferation, apoptosis and invasive capacity in the endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation, inva-sion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer

The article discusses how tourism policy has changed since World War II, highlighting how the everchanging political and economic climate has shaped policies that were formerly centered on promoting inbound travel and tourist growth to becoming more inclusive and sustainable. Within that framework, the paper systematically examines the development of Indian tourism policy and thoroughly explores the implications of its most recent version. It concludes that modern tourism policies have evolved into comprehensive frameworks that structure the growth of the industry and make it more inclusive and sustainable. Nations such as India are well-suited to meet the demands of modern tourism and offer appropriate frameworks for sustainable and resilient tourist growth.

The electronic nose (e-nose) is an innovative device that mimics the human olfactory system, allowing for the detection and identification of numerous scents. This abstract gives an in-depth examination of the current status of electronic nose technologies, with an emphasis on sensing mechanisms, applications, and recent breakthroughs. The research delves into the many uses of e-nose, such as food quality control, environmental monitoring, medical diagnostics, and industrial operations. It also covers the problems and potential future applications of electronic nose technology. The literature review highlights the importance of this technology in improving our capacity to evaluate complex scents in several domains.

Human sepsis is one of the leading cause of death worldwide and is known to be a harmful damaging host inflammatory condition, primarily caused by endotoxin released by gram-negative bacteria. Despite antibiotics administration being widely used to treat disease, effective targeted therapeutic strategies for the sepsis are still lacking. Here, we demonstrate that CM1, a derivative of natural polyphenol chrysin, exerts anti-inflammatory activity by inducing the ubiquitin-editing protein TNFAIP3 and NAD-dependent deacetylase sirtuin 1 (SIRT1). We found that CM1 attenuated Toll-like receptor 4 (TLR4)-induced the generation of inflammatory cytokines by inhibiting the extracellular-signal-regulated kinase (ERK)/MAPK and nuclear factor kappa B (NF-κB) signaling pathway. In addition, the treatment of macrophages with CM1 induced the expression of TNFAIP3 and SIRT1 in TLR4-stimulated primary macrophages, however the anti-inflammatory properties of CM1 was disappeared by siRNA silencing of TNFAPI3 or by the genetic and pharmacologic inhibition of SIRT1. Importantly, intravenously administration of CM1 resulted in the decreased susceptibility to endotoxin-induced sepsis, leading to inhibition of the generation of proinflammatory cytokines and neutrophils infiltration into lung than control mice. Collectively, these findings suggest that CM1 has the potential to be a treatment candidate for diverse inflammatory diseases including sepsis.

Subacute sclerosing panencephalitis (SSPE) is a progressive neurological complication that affects the central nervous system. It occurs as a late complication of the measles infection the young children and adolescents who are commonly affected present with personality changes and neurological deficits. The diagnosis can be done via clinical features, electroencephalography, and cerebrospinal fluid analysis. At present, there is no cure for SSPE. The immunisation against measles is the main strategy in preventing this condition. Here, we present a case of a 22-year-old Indian male diagnosed with Subacute sclerosing panencephalitis.

Urinary tract infections (UTIs) are among the most common bacterial infections in community and hospital settings. Infections of the urinary system can range from pyelonephritis to urethritis. Acute renal infections encompass entities such as acute pyelonephritis, acute focal bacterial nephritis, renal and perinephric abscesses, emphysematous pyelonephritis, and pyonephrosis,while xanthogranulomatous pyelonephritis is a chronic granulomatous inflammatory condition that affects the kidneys. The diagnosis of UTIs predominantly relies on clinical assessment and confirmation through abnormal laboratory results. Therefore, routine medical imaging is typically reserved for complicated cases, aiming to identify contributing factors such as renal calculi, determine the type of infection, and evaluate the extent of the infection and its associated complications. Furthermore, imaging has become crucial for radiologists during interventional procedures in the treatment of pyonephrosis and renal abscesses. Traditional imaging tools, like abdominal X-rays, are vital for identifying renal calculi and gas shadows in emphysematous pyelonephritis, while ultrasonography emerges as an excellent modality for assessing urinary infections in emergency scenarios, pregnancy, and paediatric cases. Contrast-enhanced computed tomography (CECT) or non-contrast computed tomography (NCCT) is the imaging method of choice in the most complex situations, allowing for precise assessment of the disease burden. Current MRI sequences yield promising results in specific scenarios, such as pregnancy and paediatric subjects, where minimising radiation exposure is a concern. This article focuses on elucidating the essential radiological modalities and their distinctive features in the context of renal infections, offering valuable guidance to microbiologists and physicians.

The classification and summarization of online reviews using machine learning and deep learningbased approaches are the subject of this systematic literature review. Consumers, companies, and researchers can now find vital information from online reviews. Automatically categorizing and summarizing these reviews can offer useful information and facilitate decision-making. The purpose of this study is to offer a thorough overview of the current methodology, approaches, and developments in this area. The review concentrates on machine learning-based methods for categorization and summarizing tasks, highlighting their advantages, drawbacks, and new developments. This systematic review provides insights into the most recent methodologies and indicates prospective directions for further investigation by synthesizing the data from a wide range of pertinent research publications

Abstract: The septum pellucidum is a thin, translucent double-membrane structure located between the anterior horns of the lateral ventricles. This mini-review explores the gross and radiological anatomy, variations, and clinical significance of the septum pellucidum. The article elaborates on the different types of variations, including cavum septum pellucidum (CSP), cavum vergae (CV), and cavum veli interpositi (CVI). The CSP is a fluid-filled pocket located within the two leaflets of the SP. It forms during fetal development and gradually obliterates before birth. However, the fusion may be prolonged or persist into adulthood in some individuals. The CV is formed when the two commissural plates fail to fuse completely during foetal development. When associated with CSP, the CV is collectively known as the cavum septum pellucidum et vergae (CSPV). However, the isolated CV is rare. The CVI is a CSF-filled space between two tela choroidea layers and communicates with the quadrigeminal cistern, superior to the pineal gland. This article discusses the radiological features of these variations using imaging techniques such as ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT). Ultrasonography is particularly useful for evaluating the SP in fetuses and infants, while MRI and CT scans provide detailed visualisation of the SP and its variations. The SP has the potential to be associated with cerebral anomalies, hydrocephalus, mental disorders, and neurological symptoms. Knowing the related anatomy and detecting variations using imaging modalities are crucial for accurately diagnosing and managing these conditions.

Gene therapy is becoming increasingly prevalent, with new gene therapy medicinal products (GTMPs) being approved for use every year. Hospital pharmacists are expected to prepare and dispense these products, but there is substantial heterogeneity in the availability of up-to-date, practical guidance at a national level in Europe. Many institutions have no or very limited experience in handling GTMPs. As such, there is a need for updated, practical guidance to aid hospital pharmacy teams in developing institutional standard operating procedures (SOPs) for the safe handling of GTMPs across the entire workflow. Here, we present the European Association of Hospital Pharmacists’ updated guidance on the handling of GTMPs, developed by a team of recognised experts from around Europe. Each aspect of the GTMP handling process is addressed, including receipt and storage, dispensing and reconstitution, transportation, administration, waste disposal, decontamination of spills and accidental exposure. A series of charts are provided to aid the development of practical workflows. This guidance document is intended as a framework to help develop institutional SOPs and should always be used in conjunction with local regulations.

The material undergoes high temperature and high strain rate deformation process during cutting process, may induce the dynamic recrystallization behavior and result the evolution of dynamic mechanical properties of the material to be machined. In this paper, the modified Johnson-Cook(J-C) model for Nickel based powder metallurgy superalloy considering dynamic recrystallization behavior in high strain rate and temperature is proposed. The dynamic mechanical properties of the material under different strain rates and temperature conditions are obtained by quasi-static compression test and split Hopkinson pressure bar (SHPB) test. The coefficients of the modified J-C model are obtained by linear regression method. The modified model is verified by comparison with experimental and model prediction results. The results show that the modified J-C model proposed in this paper can accurately describe the mechanical properties of nickel-based powder metallurgy superalloys at high temperature and high strain rate. Which provides help for studying the cutting mechanism and finite element simulation of nickel-based powder metallurgy superalloy.

Antibiotic Resistance (ABR) is increasing the mortality and morbidity associated with infectious diseases, besides increasing the cost of healthcare, saturating health-system capacity, and adversely affecting food security. Framing an appropriate narrative and engaging local communities through ‘One Health’ approach is essential to complement the top down measures. However, the absence of objective criteria to measure the performance of ABR interventions at community settings make it difficult to mobilize interest and investment for such interventions. An exercise was therefore done to develop an indicator framework for this purpose. An exhaustive list of indicators was developed from experiences gathered through community engagement work in a local panchayat (small administrative area) in Kerala, India, and a consultative process with health, veterinary, environment, and development experts. A prioritization exercise was done, looking at appropriateness, feasibility and validity, by global experts on ABR. A 15-point indicator framework was designed based on the prioritization process. The final set of indicators covers human health, animal health, environment management and Water Sanitation and hygiene (WASH) domains. The indicator framework was piloted in the panchayat(located in Kerala), which attained a score of 34 (maximum 45). The score increased when interventions were implemented to mitigate the ABR drives, indicating the framework is sensitive to change. Simultaneously, the indicator framework was tested in four sites from three other Indian states with different socioeconomic and health profiles, yielding different scores. Those collecting the field data were able to use it with minimal training. To conclude, this indicator framework can help policymakers broadly understand the factors contributing to ABR and measure the performance of interventions they choose to implement in the community

Physical activity is especially important of children's everyday life with chronic disease. The aim of the study was to show whether asthma is a barrier to physical activity in our society. The correlation between the severity of the disease, body mass index, and physical activity were analyzed, and, parents' opinion whether children should participate in active sports was assessed. Physical activity of children with asthma was analyzed by questionnaires and activity-measuring armbands. 93 parents and their children were involved in the survey, while 20 children were wearing the armband. The age of children was 12.6±3.5 years (mean±SD), 69.9% were boys, 30.1% were girls. 93.4% of the respondents participated in physical education program and 56.5% also attended sporting activities on a regular basis. 61.2% of the children had mild, 37.6% moderate, and 1.2% severe asthma. 6.5% of the respondents stated that their illness had been consistently or frequently limiting the performance concerning their school or home duties over the past 4 weeks. Twelve percent of parents felt that physical activity was not appropriate in the context of this disease. We conclude, that fear of the consequences of physical activity depends largely on education which should involve their parents, teachers and coaches.

In the realm of molecular science, intricate relationships between molecular structures and their biomedical and pharmacological characteristics have been revealed through empirical experiments. This exploration hinges on the application of numerical descriptors, known as Topological Indices, which illuminate the inherent properties of diverse molecular structures. With particular significance in the medical and pharmaceutical domains, these indices facilitate the prediction of biological features for new chemical compounds and drugs by quantifying weighted entropies. In the context of this paper, we delve into the concept of graph entropy, weaving it intricately with the topological properties of the crystalline framework of the copper oxide molecule, denoted as Cu\textsubscript{2}O$[i,j,t]$. Our primary objective is to unravel the mathematical symphony underlying the structural intricacies of Cu\textsubscript{2}O$[i,j,t]$ and to imbue it with the conceptual essence of entropy. We accomplish this through the computation of entropy, leveraging various topological indices, including weight. In addition to our analytical journey, we present a graphical comparison that juxtaposes the computed indices and entropies, shedding light on the interplay between mathematical analysis and the structural elegance of Cu\textsubscript{2}O$[i,j,t]$. This endeavor contributes to a deeper understanding of the material's multifaceted applications, spanning domains from chemical sensors to solar cells, photocatalysis, and batteries, where Cu\textsubscript{2}O's crystallographic structure plays a pivotal role.

Natural Gas (NG) processing is a prominent industrial separation process. Among the available techniques, the innovative membrane process shows potential for efficient removal of impurities, including carbon dioxide (CO₂). This study focuses on utilizing breakthroughs in membrane separation to drive sustainable CO₂ extraction from natural gas. Through comprehensive research and analysis, we explore the effectiveness and feasibility of membrane-based systems in removing CO₂ impurities from NG, thus promoting greener and more sustainable industrial practices. Our findings underscore the transformative nature of membrane separation technology, presenting new possibilities for a more environmentally-friendly and sustainable approach to CO₂ extraction from natural gas.Natural Gas (NG) processing utilizes various techniques for impurity removal, with the membrane process emerging as a promising option for efficient carbon dioxide (CO₂) extraction. This research proposes the integration of a simple mathematical model into ASPEN HYSYS to design a membrane system for CO₂/CH₄ separation. The study also investigates parameter sensitivities by altering operating conditions, such as feed composition and pressure, as well as membrane properties, including selectivity. By analyzing these variables, we aim to optimize the performance and efficiency of the membrane system, facilitating the sustainable extraction of CO₂ from NG. The findings contribute to advancing the design and operation of membrane-based processes for CO₂ separation, paving the way for greener and more sustainable industrial practices. In addition, this study explores various configurations for optimizing the design of the membrane system, including single-stage with and without recycling as well as double-stage configurations. The investigation demonstrates that methane recovery can be enhanced through the recycling of the permeate stream and by implementing a double stage membrane system. These findings highlight the potential for improving the efficiency and performance of the membrane system, enabling higher methane recovery rates. By considering different configurations, this research contributes to the development of more effective and sustainable CO₂ extraction processes from natural gas.

This mini-review explores the comparative efficacy, safety, and clinical outcomes of high-dose proton pump inhibitor (PPI) intravenous infusion versus oral acid pump inhibitor therapy following endoscopic treatment for bleeding peptic ulcers. Recent evidence suggests that intravenous PPIs can significantly reduce the rebleeding rates within the critical first 72 hours post-intervention, with a noted rebleeding rate of 6% compared to 14% in patients receiving oral Vonoprazan (VPZ) therapy. Additionally, the rapid onset of action associated with intravenous administration leads to faster stabilization of vital signs and a reduced need for subsequent blood transfusions. Safety profiles for both intravenous and oral VPZ were favourable, with minimal adverse effects, the most common being transient headaches.However, the findings from our single-centre study with a moderate sample size prompt consideration of more extensive, multicentre trials to enhance the generalizability of the results. Current limitations include potential biases, short-term focus, missing data issues, and a need for long-term outcome data, necessitating further research. Future studies should also explore the cost-effectiveness of intravenous versus oral VPZ and the impact on patient quality of life and long-term mortality rates.This review underscores the importance of tailored PPI therapy in managing bleeding peptic ulcers post-endoscopy. It suggests a potentially pivotal role for intravenous PPIs in high-risk patient groups, advocating for a shift towards more aggressive and immediate care protocols in specific clinical settings.

Worldwide, the COVID-19 pandemic, which was brought on by the brand-new coronavirus SARS-CoV-2, has claimed a sizable number of lives. Despite the urgency, COVID-19 does not have any particular antiviral treatments at this time. As a result, scientists are concentrating on repurposing already existing antiviral medications or creating brand-new ones. The SARS-CoV-2 main protease, which is necessary for viral replication, has been identified as a possible target for a family of medicines called main protease inhibitors (MPIs). Studies of the major proteases from SARS-CoV and MERS-CoV, which have remarkably similar structures and functions to SARS-CoV-2, have provided insight for the creation of MPIs. By analyzing the MPI trials for SARS-CoV and MERS-CoV, this review sheds light on the possible therapeutic uses of MPIs for COVID-19. The review talks about how MPIs work, how effective they are against SARS-CoV and MERS-CoV, and how safe they are. The paper also emphasizes current developments in the creation of MPIs for SARS-CoV-2, including as computational studies, in vitro and in vivo research, and clinical trials. According to the review, there is a lot of hope for MPIs in the treatment of COVID-19, and numerous medications are in the works. Although more research is needed to assess their safety and effectiveness in clinical settings, these medications may offer patients with COVID-19 a much-needed therapeutic option. The review also emphasizes the importance of ongoing research into the structure and function of the SARS-CoV-2 main protease, as this information will be critical for the development of effective MPIs and other antiviral drugs in the future.

Background: Atherosclerotic plaque (AP) vulnerability can be assessed by coronary artery imaging techniques. Modern lipid-lowering therapy (LLT) has a stabilizing effect on the AP and reduces the likelihood of progression of vascular remodeling. Methods: Databases searched comprised PubMed, and the Web of Science up to April 2023. In total, 8 relevant articles were selected, and all of them are original clinical studies. Results Based on the results of ODISSEY-J-IVUS, there was a decrease in the percentage change in the normalized total volume of AP by 3.1% in the monotherapy group and by 4.8% in the combined LLT group (p = 0.23). According to GLACOV study normalized total atheroma volume decreased by 0.9 mm3 in the placebo group and by 5.8 mm3 in the evolocumab group (95% CI -7.3 -2.5; p<0.001). Plaque regression was observed in 64.3% of patients receiving evolocumab versus 47.3% of those on placebo. The dynamics of the minimum thickness of the fibrous cap varied within 18.0-62.67 microns while on combined LLT and 13.2-33.19 microns on monotherapy (PACMAN-AMI, Gao F). In the HUYGENS study, a lipid arc regression of 57.5° was obtained on combined LLT and by 31.4° with the statin alone. Conclusion: significant progress in the development of cardiovascular imaging has made it possible to expand our understanding of the morphology of AP, the features of coronary vessel remodeling, and the development of acute cardiovascular complications.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide. Accumulating clinical and experimental evidence suggests the role of cyclo-oxygenase (COX) enzymes in the pathogenesis of cancers including HCC. Deuterium-enriched water (DEW) and deuterium-depleted water (DDW) play a role both in the treatment and prevention of cancers. Combination therapy using COX-inhibitors and DDW/DEW could be a rational strategy to enhance the cytotoxicity of either agent in HCC. The cytotoxicity of celecoxib or indomethacin, alone and in combination with DDW or DEW was determined in the Hep-G2 HCC cell line by MTT assay. The COX-2, MAPK pathway proteins, the anti-apoptotic Bcl2 and pro-apoptotic Bax proteins, and caspase-3 activity were determined by SDS-PAGE and western blot. Co-treatment of selective and non-selective COX-2 inhibitors with DEW led to a remarkable increase in cytotoxicity and apoptosis of Hep-G2 cells. These events were associated with the activation of p38 and JNK MAPKs and a decrease in pro-survival proteins Bcl-2, COX-2, and ERK1/2. Furthermore, the combination therapy activated caspase-3, and the apoptosis mediator, and disabled poly ADP-ribose polymerase (PARP), the key DNA repair enzyme, by cleaving it. The combination of DEW with NSAIDs might be effective against HCC cells by influencing principal cell signaling pathways, and this has a potential to become a candidate for chemotherapy.

Immune checkpoint blockade (ICB) has revolutionized the prognosis of several advanced-stage solid tumors. However, its success has been far more limited in hematological malignancies and is mostly restricted to classical Hodgkin lymphoma (cHL) and primary mediastinal B cell lymphoma (PMBCL). In patients with non-Hodgkin lymphoma (NHL), response to PD-1/PD-L1 ICB monotherapy has been relatively limited, although some subtypes are more sensitive than others. Numerous predictive biomarkers have been investigated in solid malignancies, such as PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability (MSI), among others. This case-illustrated review aims to appraise the current knowledge on PD-1/PD-L1 ICB efficacy in lymphoid malignancies, when used either as monotherapy or combined with other agents, and describes potential biomarkers of response in this specific setting.

Metallo-β-lactamases (MBLs) are a group of Zn(II)-dependent enzymes that pose a major threat to global health. They are linked to an increasing number of multi-drug resistant bacterial pathogens, but no clinically useful inhibitor is yet available. Since β-lactam antibiotics, which are inactivated by MBLs, constitute ~65% of all antibiotics used to treat infections, the search for clinically relevant MBL inhibitors is urgent. Here, derivatives of a 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (1a) were synthesised and their inhibitory effects assessed against representatives of each of the three subgroups of MBLs (B1, B2, B3). Several compounds are potent inhibitors of each MBL tested, making them excellent candidates for the development of broad-spectrum drug leads. In particular, compound 5f is highly potent across the MBL subfamilies, with Ki values in the low µM range. Furthermore, this compound also dis-plays synergy in combination with antibiotics such as penicillin G, cefuroxime or meropenem. This molecule thus represents one of the most promising compounds developed yet to combat MBLs.

In a wide range of lymphoid neoplasms, the process of malignant transformation is associated to somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in non-Hodgkin B-cell lymphoma. Furthermore, we aim to present in close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have greatest potential to improve the prognosis of lymphoma patients.

The acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are only a way to control HIV infection but not to cure AIDS. As such, effective treatment must be developed to control AIDS. Developing a drug is not an easy task, and there is an enormous amount of work and economic resources invested. For this reason, it is highly convenient to employ computer-aided drug design methods, which can help generate and identify novel molecules. Using the de novo design, new novel molecules can be developed using fragments as building blocks. In this work, we develop a virtual-focused compound library of HIV-1 viral protease inhibitors from natural product fragments. Natural products are characterized by a large diversity of functional groups, many sp3 atoms, and chiral centers. Pseudo-natural products are a combination of natural products fragments that keep the desired structural characteristics from different natural products. An interactive version of chemical space visualization of virtual compounds focused on HIV-1 viral protease inhibitors from natural product fragments is freely available at https://figshare.com/s/ceb58d58e8f5585ce67e.

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites (e.g., exosites, ectosites) through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches such as proteomics and N-terminomics to identify new MMP substrates and achieve a better understanding of the roles of these proteases in diseases.

Nanoprecipitation by liquid anti-solvent precipitation is one of the most versatile methods to produce pure drug nanoparticles (PDNPs) owing to the ability to optimize the properties of the product. Nevertheless, nanoprecipitation shows broad particle size distribution and low physical stability, leading to high batch-to-batch variability and challenging the bench-to-bedside translation. Microfluidics has emerged as a powerful tool to produce PDNPs in a simple, reproducible, and cost-effective manner with excellent control over NP size. In this work, we designed and fabricated T- and Y-shaped Si-made microfluidics device and used it to produce pure NPs of three kinase inhibitors of different lipophilicity and water-solubility, namely imatinib, dasatinib and tofacitinib, without the use of colloidal stabilizers. PDNPs display sizes in the 90-350 nm range (dynamic light scattering) and a rounded shape (high-resolution scanning electron microscopy). Analysis by X-rays diffraction and differential scanning calorimetry confirmed that this method results in highly amorphous NPs. In addition, we show that the flow rate of solvent, the anti-solvent, and the channel geometry of the device play a key role in the size of the generated NPs.

With the inclusion of snakebite envenoming on the World Health Organisation’s list of Neglected Tropical Diseases, an incentive has been established to promote research and development effort in novel snakebite antivenom therapies. Different technological approaches are being pursued by different research groups, including the use of small molecule inhibitors against enzymatic toxins, as well as peptide and oligonucleotide-based aptamers and antibody-based biotherapeutics against both enzymatic and non-enzymatic toxins. In this article, the most recent advances in these fields are presented, and the advantages, disadvantages, and feasibility of using different toxin-neutralizing molecules are reviewed. Particular focus within small molecules is directed towards the inhibitors, varespladib, batimastat, and marimastat, while in the field of antibody-based therapies, novel recombinant polyclonal plantivenom technology is discussed.

In this paper, we investigate the proftability of investing in movies for retail investors, focusing on the return on investment (ROI) metric, which is calculated as revenue divided by budget. Our analysis encompasses 5000 movies from the movie database TMDB, examining factors such as production scale, genres, key actors, directors, and more. Additionally, we employ textual analysis techniques like Latent Semantic Analysis (LSA) on movie overviews and tags to incorporate movie themes. We then evaluate various supervised classifcation models including Logistic Regression, Random Forest, and Light Gradient Boosting (LightGBM), comparing their performance. Our fndings highlight the signifcance of production scale, team structure, and movie themes in identifying potential high-return opportunities for investors.

Commercial production of Choromytilus meridionalis (black mussel) and Mytilus galloprovincialis (Mediterranean mussel) contributes to half of the South African marine aquaculture production per year. However, limited ready-to-eat black mussel products are available. The aim of this preliminary study was to investigate the effects of storage (15 days at room temperature) on the total viable counts (TVC), coliforms, proximate composition, and fat oxidation (TBARS) of a small-scale kitchen-based ready-to-eat hot smoked black mussel product preserved with vegetable oil. Three batches of black mussel meat were smoked at 80ºC for 15 minutes. Half of each batch were packaged in sterile glass jars with heated (50ºC) vegetable oil and half without oil. Microbiological analyses were done at days 1, 3, 9 and 15. Proximate composition was determined at day 1 and TBARS at days 1 and 15. Coliforms for all samples throughout the storage period were undetected. TVC plates for mussels stored without oil had no growth at days 1 to 5, however, reached TVC > 5 log10.g-1 at day 15. TVC for mussels with oil increased from 0 at day 1 to > 5 log10.g-1 at day 3 and remained at counts > 5 log10.g-1. There was no significant difference (P > 0.05) in moisture, protein, and ash for mussels stored with oil and those without oil, while significant differences (P < 0.001) in total fat and carbohydrates (10.27 ± 2.10% and 6.80 ± 2.22% with oil, and 5.05 ± 1.49% and 10.59 ± 3.00% without oil) were detected. These differences were due to the presence of additional fats from the vegetable oil. TBARS at day 15 showed no significant difference (P > 0.05) between mussels stored with oil and those without oil. There were no significant differences in TBARS from day 1 to 15 for both oil and without oil. Small-scale kitchen-based smoked black mussels preserved without vegetable oil could be stored for up to 9 days at room temperature.

Due to its potential harm to space payload, microwave corona breakdown of microstrip circuits has attracted much attention. This work describes an efficient way to suppress corona breakdown. Since corona breakdown threshold is determined by the highest electric field intensity at the surface of microstrip circuits, lacquer coating with thickness of tens of microns is sprayed on the top of microstrip circuits. The applied dielectric coating is used to move the discharge location away from circuit’s surface which is equivalent to reduce the highest electric field intensity on the in-terface of solid/air of the circuit and thus results into higher breakdown threshold. Two designs of classic coupled-line band-pass filter were used for verification. Corona experimental results at 2.5 GHz show that, in the interested low pressure range (100 to 4500 Pa), 5.3 dB improvement of mi-crowave corona breakdown threshold can be achieved for a filter with narrowest gap of 0.2 mm while its electrical performances like insertion loss, Q-factor are still acceptable. A threshold improvement prediction method is also presented and validated.

To meet the dual-carbon objective, China's economy needs to move from a carbon-intensive to a green economy. Green technology innovation and renewable energy development are key to promoting green economic growth. The study uses 2010–2022 provincial panel data from 30 Chinese provinces. The super-efficient SBM model measures the province's green economic growth index. A panel fixed-effects model is used to experimentally evaluate how green technology innovation and renewable energy development affect green economic growth. Green financing moderates and a panel threshold model tests the threshold effect of renewable energy development on green economic growth. The results demonstrate that (1) China's green economic growth is rising and has a "U" shape. (2) all selected variables significantly impact green economic growth. However, population density, government intervention, and industrial structure are inversely associated with GEG. Green economic growth is significantly boosted by the moderate role of green finance in the development of renewable energy and green technological innovation. (3) Renewable energy development has a single threshold non-linear effect on green economic growth, depending on its development level and green technological innovation. Considering China's current condition and research findings, this study examines the green energy transition to promote green economic growth and high-quality economic development. Meanwhile, puts forward some important policy recommendations.

Background: GaitSmart (GS) is a sensor-based digital medical device that can be used with the integrated app vGym to provide a personalised rehabilitation programme for older people undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA). This study aimed to determine whether the GS intervention used in the rehabilitation of older people undergoing THA or TKA is potentially cost-effective compared to the current standard of care (SoC). Methods: Decision-analytic modelling was conducted to estimate cost-effectiveness over a seventeen- week time horizon, from an NHS perspective. UK clinical and cost data from the GaitSmart randomised clinical trial was used to obtain input parameters, and sensitivity analysis was performed to address uncertainty. Results: Over a seventeen-week time horizon, GS incurred cost savings of £450.56 and a 0.02 gain in quality-adjusted life years (QALYs) compared to the SoC. These results indicate that GS is the dominant intervention because the device demonstrated greater effectiveness and lower costs. Probabilistic sensitivity analyses confirm the robustness of our results. Conclusion: GS appears to offer short-term efficiency benefits and demonstrates cost-effectiveness for the improvement of gait in people undergoing THA or TKA, compared to the SoC. These findings provided new evidence to inform policymakers.

We humans are natural-born engineers. As such, we model after machines not only isolated, naturally occurring systems, but also the basic laws of physics, sharing with machines a local-evolution-of-state `grammar'. However, previous work by the author casts doubt upon this mechanistic paradigm, suggesting that it is to blame for the stubbornness of many open problems in physics. Simple experiments are therefore proposed to identify `non-machines'. In one experiment, `non mechanistic correlations' in the spirit of Bell are sought in a pair of separated but previously coupled (macroscopic) chaotic systems. In another it is tested whether chaotic systems could fuzzily `remember their future' in the sense that a future binary perturbation applied to them could be inferred from their present behavior with probability>1/2. Chaotic systems are chosen as candidates because the long-time application of their (deterministic) mechanistic description is conceptually groundless: All scales are significant and mutually coupled in that regime, down to scales governed by QM, yet the quantum-classical transition remains inexplicable---if only due to the measurement problem. Similarly for non-deterministic chaotic systems, modeled as such purely for defying a short-time deterministic mechanistic description. Should a non mechanistic signature be found in such simple systems, the implications for science as a whole and life sciences in particular cannot be overstated.

The paper suggests that the physical priciple of special relativity's space-time transformation effect is wrong, Uniform linear motion without acceleration does not exist objectively, nor does its same reference frames. Therefore, it is inferred that the space-time transformation effect of special relativity is caused by the acceleration of moving objects, special relativity is only a part of general relativity, not a theoretical system that exists independently from general relativity. The corresponding mathematical demonstration and calculation verification are carried out, and the result proves that the inference of the paper is correct. At the same time, it further explains that the concept of absolute airspace is correct. Special relativity has serious errors in the concept of space, the principle of relativity and the physical principle of space-time transformation effect. Therefore, it is necessary to make a series of revisions to the theory of relativity and to reinterpret some related physical problems.

Throughout the Covid19 period, families were forced to stay indoors, adapting to online school-ing, remote work, and virtual social engagements, inevitably altering the dynamics within households. There is a notable increase in mental health challenges in terms of anxiety and de-pression in children and adolescents. This study intends to explore the psychosocial effects of the Covid-19 pandemic in Italian families adopting self- and proxy-report questionnaires on anxiety, anger, and health-related quality of life. The results showed that approximately 20% obtained a clinical anxiety score and only 10% obtained a clinical anger score. There was found a difference in the perception of the quality of life reported by the child and that perceived by the parent. The stepwise regression model showed that total anxiety scores were predicted by sex, quality of life scores from the parents' self-report version and total anger score. Another stepwise regression model identified physiological and social anxiety as the best predictors that impact the quality of life. Parental well-being actively influences the well-being of children, so it is fundamental to implement preventive programmes and promote child well-being providing parents the most adequate support possible.

Financial fraud poses a severe threat to the integrity of corporate financial statements and market efficiency. While auditors play a crucial role in detecting and preventing such fraud, the unique characteristics of this domain, including class imbalance, high misclassification costs, and am-biguous attributes, pose significant challenges. Traditional classification algorithms may not be optimally suited for this task. This paper proposes a novel stacking ensemble learning approach to enhanced detecting of Financial Statement Scam. By combining the strengths of multiple base learners, including Random Forest, XGBoost, and Gradient Boosting Decision Trees, our model leverages their diverse predictions to improve overall performance. A Logistic Regression me-ta-learner is employed to integrate the outputs of the base learners, capturing their collective wisdom while mitigating individual weaknesses. Extensive experimentation using a real-world dataset shown the superiority of our approach, achieving remarkable recall, precision, accuracy, and area under the curve metrics. The proposed model outperforms individual base learners, under-scoring the efficacy of ensemble learning in tackling the intricate problem of financial fraud detection. This research contributes to the creation of substantial and robust fraud detection systems, fostering trust and transparency in financial markets.

Though nowadays germanium do not reach the range of popularity than other metals, i.e. rare earth elements, its utility in target industries makes of it also a strategic metal. Though germanium can be find in a series of raw materials, the principal source for its recovery is from secondary wastes of the zinc industry, and also, the recycle of germanium-bearing waste materials is becoming of interest. In this recovery, Hydrometallurgy is performing a key role to the successful achievement of this goal. The present work reviews the most recent applications (2023 and 2024 years) of hydrometallurgical operations on the recovery of germanium from different solid and liquid sources.

Paratuberculosis, or Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic granulomatous enteritis affecting both domestic and wild ruminants. The agent was also found in wild mammals such as wild boar (Sus scrofa), however, the role of wild mammals in the epidemiology of MAP is unclear. During the research period, 941 free-ranging wild boar (S. scrofa) legally hunted in two locations in the Centre-eastern region of Portugal were examined. Ninety-seven wild boar exhibited one or more gross lesions and were tested for the presence of Mycobacterium avium subsp. paratuberculosis using acid-fast staining, mycobacterial culture, poly-merase chain reaction (PCR), and histopathological examination. Forty-five animals (46.4%, 95% CI: 36.5-56.3%) were identified as infected, as indicated by positive results in culture and/or PCR. The findings revealed that the most significant risk factor was being a juvenile compared to year-lings and adults (OR = 10.2, 95% CI: 2.2-48.0). Based on our results, 37.9% (n = 11) of the infected animals were considered suitable for human consumption. Our findings offer novel insights into mycobacterial infections in wild boar populations in Portugal and suggest that wild boar could be a source of human infection if zoonotic potential is considered.

Objective. To evaluate serum neuronal and inflammatory biomarkers in asphyctic newborns treated with hypothermia alone or hypothermia plus melatonin, and whether biomarkers correlate with neurodevelopmental outcomes. Design. This is a pilot multicentre, randomised, controlled, double blind clinical trial. Neuronal glial fibrillary acidic protein (GFAP), granulocyte-macrophage colony-stimulating factor (GM-CSF), and inflammatory cytokines (interleukin (IL)-1, IL-2, IL-7 and IL-13) were measured in serum samples at hospital admission (T0), 24 hours (T1), 72 hours (T2) and 7-10 days of age (T3). Neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-III scales, Gross Motor Function Classification System (GMFCS) and the Tardieu scale) were performed at 6 and 18 months. Setting: Level 3 neonatal intensive care unit. Patients and interventions: 25 newborns were recruited. The treated patients received a daily dose of intravenous melatonin, 5 mg per kg body weight, for 3 days. Results. After adjusting the data for severity, in the group treated with melatonin, there is a decrease in plasma levels of GM-CSF, IL-2 and IL-13 at T1 compared to placebo, as well as, at T2, in GM-CSF concentrations, as well as IL-7 and IL-13 at T3. Evolutionarily, we found a significant decrease in GM-CSF concentrations in the treatment group compared to placebo, with no differences for the rest of the biomarkers. It is noteworthy that the sustained decrease in GM-CSF and inflammatory cytokines IL-2, IL-7 and IL-13 correlated with better neurodevelopmental outcomes at 6 and 18 months. Conclusions. In neonates with hypoxic-ischemic encephalopathy, the addition of iv melatonin to hypothermia therapy affects the plasma concentration of biomarkers in the first week of life, with a high correlation with long-term neurological prognosis.

Hazelnut, pistachio and cashew are tree nuts with health benefits but also with allergenic properties being prevalent food allergens in Europe. The allergic characteristics of these tree nuts after processing combining heat, pressure and enzymatic digestion were analyzed through in vitro (Western blot and ELISA) and in vivo test (Prick-Prick). In the analyzed population, the patients sensitized to Cor a 8 (nsLTP) were predominant over those sensitized against hazelnut seed storage proteins (Sprot, Cor a 9 and 14), which displayed higher IgE reactivity. The protease E5 effectively hydrolyzed proteins from hazelnut and pistachio, while E7 was efficient for cashew protein hydrolysis. When combined with pressured heating (autoclave and Controlled Instantaneous Depressurization (DIC)), these proteases notably reduced the allergenic reactivity. The combination of DIC treatment before enzymatic digestion resulted in the most effective methodology to drastically reduce or indeed eliminate the allergenic capacity of tree nuts.

The therapeutic, attenuative, and morphological effects of proprietary neural stem cell-derived extracellular vesicles (NSC EVs, AB126) produced by Aruna Bio, Inc. were assessed in a range of in vitro and in vivo models of stroke. We emphasize that modulation of neuroinflammation is a key target and suggest further studies to advance our understanding of the mechanisms of action and ultimately how best to dose and monitor the benefits of AB126 in stroke patients.

Permafrost covers about 23% ~ 25% of the land in the northern hemisphere, mainly in Russia, Canada, Alaska, Northeast and Qinghai Tibet Plateau (QTP) in China. Many engineering especially the transportation has been in the permafrost regions above. Under the action of highways construction and global warming, permafrost under infrastructures is degraded and causes serious damage. Two phases closed thermosyphon (TPCT) is a widely accepted green countermeasure against the problem in permafrost regions. Although it has been applied to prevent permafrost degradation, their application presents significant challenges on account of the stronger endothermic action of asphalt pavement. This paper focused on the thermosyphon technology and application in the permafrost. Moreover, the article highlighted the excellent working performance of the TPCT that improving the stability of the infrastructures and prevent it degrading due its excellent efficiency of heat transfer. The industrial applications of the TPCT were also summarized, along with their limitations. Finally, the results reported in this paper can provide a valuable guidance for the design of the TPCT and construction of the permafrost regions in the future.

In "genome editing," a type of genetic engineering, DNA is added, taken away, or changed in an organism's genome. Biomedicine, biotechnology, and synthetic biology, just to name a few, have all gained a lot from how often this method is used. Before the editing process can start, a Double-Strand Breaks (DSB) must be made in the DNA at a specific gene. Researchers have made nucleases, which are sometimes called "molecular scissors," to fix this DSB. Transcription activator-like effector nucleases (TALENs), Zinc-finger nucleases (ZFNs), and homing endonucleases are all examples of protein targets that have been studied and changed. The last part gave an overview of these study projects and explained how to make Cas12a for specific uses. The applications of Cas12a have been extensively studied in recent years, but the protein still holds a lot of promise as a treatment and screening tool. In order to give a quick review of CRISPR-Cas12a and its uses, we will briefly talk about the structure and function of the different parts of the reaction pathway that lead up to the catalysis of the target DNA. Cas12a uses a multistep process to make sure that it is selecting the right DNA. This is a good trait for a device that changes the DNA because it makes it less likely that something bad will happen. Even though data shows that a new CRISPR RNAs (crRNA) molecule can stop Cas12a from randomly destroying ssDNA, it may still hurt the host cell while trying to change the genome. The action of Cas12a catalysis, which is a powerful tool for changing the genome, needs to be changed so that it can be more easily controlled and managed. Using what we know about how Cas12a works, we have made mutants that are less active on ssDNA and more active on dsDNA. So far, only Cas9 and Cas12a, which are both part of the CRISPR family, have been used to change the genome. Because of how similar and different these two endonucleases are, CRISPR can now be used for multiple scientific purposes. Cas12a is better than Cas9 because it makes double-strand breaks (DSBs) that favor Homology-Directed Repair (HDR) over Non-homologous end joining (NHEJ) and can change more than one copy of the genome at the same time. Both Cas9 and Cas12a are being changed to make them better at detecting Protospacer Adjacent Motif (PAM) than they are in their natural state. This will make it possible to start focusing on more genes.

This article describes a novel topical composition constituted by gamma-amino butyric acid (GABA) and microbial chondroitin sulfate. This composition exhibits potential for non-invasive intervention in anxiety management, sleep quality enhancement, and promotion of brain-related functions like meditation and nonlocal consciousness. The core component comprises GABA, a key inhibitory neurotransmitter within the central nervous system, complexed with a suitable carrier molecule, microbial chondroitin sulfate. This complexation aims to enhance transdermal absorption and optimize delivery of GABA to target tissues. The proposed mechanism of action involves modulation of GABAergic signal transduction pathways. Application of the topical composition allows GABA penetration into the skin and potentially deeper tissues, where it interacts with GABA receptors. This interaction leads to mental calmness and relaxation as assessed by electroencephalography. The influence of GABAergic signaling on brain circuits demonstrated in this article, when associated with meditation and nonlocal consciousness, suggests potential for the composition to support these practices. The advantage of such an approach consists in avoiding the potential systemic side effects associated with oral or injectable administration of GABA, anxiolytics or hypnotics. Furthermore, the combination of GABA and microbial chondroitin sulfate may offer synergistic benefits, potentially enhancing the overall biological effects. In conclusion, this article presents a novel topical approach for managing anxiety, enhancing sleep quality, and potentially facilitating meditation and nonlocal consciousness through modulation of GABAergic signaling pathways. While further research is necessary, the potential for a non-invasive and potentially side-effect-free intervention in these areas is promising.

Nanoindentation load-depth (P-h) plots is the basis for determination of mechanical properties of the samples and is especially vital for thin coatings deposited on substrates of various mechanical makeup from amorphous-brittle (borosilicate glass) to Silicon (having different crystallographic texture) to ductile substrates like stainless steel as well other aspects like indenter tip shape. The elastic-plastic response by simulated P-h plots as per modified empirical relations have been presented. The outcomes of this computational studies enlighten the database on the P-h plots for various coating/substrate systems and shall aid in the analysis of experimental P-h plots obtained,

Among other fossil fuels, natural gas is a major energy source. It is generally created saturated with water vapor. Dehydration of natural gas is vital in the gas business to remove water vapor from the gas supply, which may cause hydrate development in pipes. Gas dehydration employs Tri ethylene glycol (TEG) to remove water vapor from natural gas flow. The wet gas is dehydrated with lean glycol in an absorber, and the rich glycol is recovered and reused. This work investigates the use of dry natural gas instead of nitrogen in the glycol dehydration re-generator, and compares the results using HYSYS modeling and simulation. The two techniques were compared for capital and utility expenses, while maintaining the identical glycol purity criteria. The wet gas from the stripping mechanisms may also be utilized to run steam pumps and compressors or recycled. The model is based on the real mechanism flow diagram. Finally, the findings of this model might be used to design a new heat and material balance for the plant.

Solid-state transformer (SST) is a promising technology for smart grids due to its flexible power control (better reliability) and high efficacy (by decreasing losses) compared with traditional transformers. The SST is designed in tandem with three stages, i.e., the input, isolation, and output stages. As three converter stages are used to design the SST to make a more reliable device in practice, it is highly prone to instabilities. Moreover, the key objective of SST design is to implement a modern power distribution system to make it more intelligent and reliable. The stability issue can be even more complicated by the presence of distributed energy resources in the distribution system. Thus, the stability of SST must be measured prior to /during the design, and to determine, a state-space model is used, which is developed in this paper. Each stage of SST is modeled with its controller, and the system's stability is measured through the controllability and observability test. Further, the conversion from state-space to transfer function model is done, and the stability of SST is shown using frequency and time-domain diagrams. With these, the different plots, namely, the Bode plot, Nyquist plot, Nichols chart, Root locus, pole-zero plot, and Eigen plot, are used to ascertain the relative and absolute stability. Finally, the SST Simulink model is tested and validated through hardwate-in-the-loop simulation, i.e., OPALRT, to show its effectiveness and applicability.

Traditional methods of non-metallic materials joining for industrial uses are limited to lasers, or induction or conduction heating. The precision and efficiency for large-scale applications are difficult to be achieved at the same time. Here in this paper, we report a precise microwave welding method induced by localized surface plasmon of metallic macro-gaps under microwave excitation. The proposed method utilizes energy from well-developed commercial microwaver, and benefits from the precision of localized surface plasmon, an oscillating electron cloud excited by electromagnetic waves, which is currently under hot investigation only at micro- or nano-scales. The method is applied to the welding of polymers to solve the problems of complex processing equipment and high processing energy consumption in the traditional welding process, so as to cope with the growing energy and environmental crisis. Finite element numerical simulations are used to study the distribution characteristics of electric fields and temperature fields. The results show that the process is a high quality, efficient, low consumption and environmentally friendly green process compared to traditional polymer welding methods.

The cycling of soil phosphorus (P) is inherently linked with soil organic carbon-iron (C-Fe) cycling, yet empirical integration of these processes within paddy soils remains scarce. In this study, we conducted a microcosm experiment using paddy soils subjected to six distinct fertilization regimes involving varying P inputs for five years. In addition to evaluating P activation under reflooding conditions, we assessed the Fe reduction process and characterized the properties of dissolved organic matter (DOM) at the molecular level using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS), alongside profiling the composition of soil microbial communities with high-throughput sequencing. Our findings revealed that after 25 days of reflooding, soil Olsen-P content increased by an average of 73% compared to its initial state, showing a strong correlation with the Fe reduction process. Specifically, treatments involving pig manure application exhibited higher Fe reduction rates and enhanced P activation, highlighting the role of organic matter in facilitating Fe reduction. Investigations on the relative abundance of typical iron-reducing microbes further supported their importance in P activation, but the rate of iron reduction is limited by soil organic matter content. Delving deeper into DOM properties, soil DOM composition profiling and network analysis suggested that high-molecular-weight DOM, particularly lignins, served as the primary resources driving Fe reduction by iron-reducing microbes, consequently promoting Fe reduction and P release. Taken together, our study assembled the C-Fe-P cycling dynamics in paddy soils, emphasizing the pivotal role of microbial-driven Fe reduction facilitated by soil DOM in P availability and subsequently sustainable agricultural practices.

This study investigated how broader parental factors including parental happiness, parental play engagement, and parenting stress are related to Korean children’s happiness and weight status across three years via indirect pathways through the children’s energy-related behaviors of healthy and unhealthy food intake, physical activity, and screen time. Data from 1551 Korean parent pairs and 7-yaer-old children in the Panel Study on Korean Children were analyzed. Path analysis and gender-based structural equation modeling were conducted. Maternal happiness was negatively related to child screen time. Maternal play engagement showed positive concurrent associations with child healthy food intake and physical activity and negative associations with screen time. Maternal parenting stress was negatively related to child healthy eating. There was one significant finding related to fathers’ role on children’s energy-related behaviors, happiness, and weight status: the positive association between parental happiness and boys’ unhealthy food intake. Child screen time was positively related to child weight status and negatively to child happiness at each age. Broader maternal parenting factors can serve as a protective factor for childhood happiness and weight status in 7-to 9-year-olds through being associated with a reduction in child screen time.

The decade of research concentrating on the area of Easter Slavonia revealed abundance of large on complex late Neolithic sites. It changed profoundly how we perceive late Neolithic settlement and space size and organization. As s first step in particular site detection we mostly conducted aerial reconnaissance and satellite image analysis but also data from the field such as excavation. On detected potential sites we conducted intensive field surveys and confirmed the attribution to the late Neolithic by surface finds. On those confirmed sites in the vicinity of Đakovo, Croatia, magnetic survey was conducted on 5 sites so far and the results confirmed presence of large scale late Neolithic settlements with complex spatial organization and enclosure(s). Most complex remains so far is site Gorjani Kremenjača and Topole which we present in this paper where a remains of one or two settlements covers the area of 70 hectares and is currently in the process of formal protection as a cultural landscape by the Ministry of Culture and Media of the Republic of Croatia. Special focus of the paper is the application of remote sensing in detection, archaeological confirmation and protection of the position Gorjani Topole.

Background: Poisoning is a growing public problem that has shown increased prevalence in many countries worldwide, contributing to increased costs and mortalities. A lack of or insufficient information regarding the circumstances, chemicals, drugs and people at risk due to imperfect reporting system is regarded as a barrier to successful poisoning prevention and intervention efforts. In Saudi Arabia, poisoning cases are monitored at the central level in the Ministry of Health, with meticulous follow-up of cases across country areas through public health departments. The current study's objective was to describe the poisoning notification and reporting system in Makkah.Subjects and methods: All reports of chemical and drug overdose poisoning delivered to the environmental health and occupational safety department in Makkah Almukarramah over two years (2018-2019) were reviewed, together with verification of all systems, rules and guidelines organizing the performance of the department.Results: The total number of cases reported in 2018 was 209 cases, while it reached 42 cases in 2019. The overwhelming majority of the cases were Saudi (91.6%), with a slight predominance of males (57.4%) over females (42.6%). Generally, almost two-thirds of the cases occurred in children below 13 years (61.4%), most of the poisoning cases resulted from drug overdose (63.3%), while 34.7% were chemical poisoning. The most common drug poisoning was attributed to analgesics followed by antiepileptics, antihypertensive drugs, antipsychotics and antimicrobials, while cleaning and detergent agents were the most commonly poisoned chemicals. The majority of these agents were taken by the oral route. Children's chemical poisoning was significantly higher than that in older age groups (p<0.05). All intentional poisoning occurred in adults; the great majority of them (88.9%) used drug overdosing rather than chemical substances.Conclusion and recommendations: The current study results are consistent with most of the previous studies carried out in different regions in Saudi Arabia. Reviewing the performance and adherence of the “Environmental Health and Occupational Safety Department” to the guidelines and instruction regulating monitoring, notification and reporting of poison cases are satisfactory and the poisoning surveillance system is effective. Further in-depth studies are needed to elaborate other socioeconomic and demographic factors associated with chemical and drug overdose poisoning. Public health plans, policies and legislations should be implemented to reduce these factors, including prohibition over-the-counter pharmaceutical sales, selling the possibly harmful substances in kid-proof bottles and additional stringent rules governing chemical sale and storage. Intensive supervision of children is needed. Suicidal poisoning patients should seek psychiatric help to limit the possibility of attempting suicide again in the future. Furthermore, efforts are needed to plan and implement health education programs and campaigns about the factors proven in the current study to be significantly related to chemical and drug overdose poisoning to raise public knowledge about exposure to chemicals and its consequences. Popular communication media, commercial malls, road ads, learning institutions and workplaces can be used to deliver health education campaigns and programs. Advice on how to store chemicals safely and how to keep kids safe should be focused on during such programs.

The different systems in the nuclear power plants (NPP) are critical and complex which requires a continuous rigorous monitoring for both normal and abnormal conditions. However, due to the nonlinearity of the dynamic behavior of these systems, implementation of artificial intelligence within the NPP components is crucial to enhance the monitoring and the predictability of the key operating parameters trend. On the other hand, lessons learned from large nuclear accident proves that a remote real-time coordination between the different stakeholders involved in the safety of the nuclear reactor is needed. This remote feature can be implemented in the existing power plants by embedding a mobile computing networks within the plant components. This network will send early warning and transmit the NPP data on real-time to different authorities such as the regulatory authority and the decision-making committees, to enhance the interpretability of the nuclear event and deliver a collaborative decision which in return mitigate the risk associated with these events and increase the overall safety of the plant. The integration of AI and mobile computing in NPP would be most of interest in countries where nuclear reactors data are challenged to reach during an accident. For instance, during the meltdown of Chernobyl, the Soviet government covered the accident from the news in an attempt to contain the consequences but there was a spread of radioactive contamination to some other Europe countries. Therefore, in the case of such scenario the implementation of mobile computing and AI would result in different outcomes as the European countries would be notified through the mobile networking and the spread of contamination would be forecasted by the AI algorithms. In this paper, we examine the different modern AI and mobile computing technologies, the different potential application, the associated features and challenges, and future work direction.

Reducing fertilizer-N rate, applying nitrification inhibitor (NI), and incorporating straw are widely recommended to improve N use efficiency of crops and decrease N losses. However, how these practices affect crop N uptake by regulating the fertilizer-N fate during the growing season is not well understood. We conducted a field 15N tracer study to explore the effectiveness of reduced N application, NI, and straw incorporation on fertilizer-N fates for maize cultivation in Northeast China. The following six treatments were used: 1) no N fertilization (control); 2) 200 kg urea-N ha−1 (100%N); 3) 200 kg urea-N ha−1 and 2400 kg dry-straw ha−1 (100%N+S); 4) 160 kg urea-N ha−1 (80%N, i.e., 20% reduction of N fertilization); 5) 160 kg urea-N ha−1 and nitrification inhibitor (Nitrapyrin) (80%N+NI); 6) 160 kg urea-N ha−1, nitrification inhibitor and 2400 kg dry-straw ha−1 (80%N+NI+S). Our results showed that the five N fertilization treatments yielded 16%–25% more grain and 39%–60% more crop N uptake than the control receiving no N fertilizer, but the differences among the five treatments were not statistically significant. In contrast to plant growth, changes in fertilizer-N fates in soil and plant pools were more pronounced. Compared with the 100%N treatment, 20% fertilizer-N reduction (80%N) decreased 15N concentration in topsoil and plant pools but increased the proportion of plant 15N recovery at harvesting (N use efficiency, NUE15N, 60% vs. 50%) (P &lt; 0.05). Nitrapyrin co-application (80%N+NI) delayed soil nitrification and increased soil 15N retention at harvesting (52% vs. 36%), thereby decreasing NUE15N significantly (P &lt; 0.05). Straw incorporation (100%N+S) decreased fertilizer-N retention compared with NI co-application because it promoted NUE15N significantly (P &lt; 0.05). The combined application of NI and straw (80%N+NI+S) was more conducive to fertilizer-N retention in soil. Our findings demonstrate that NI and straw additions are efficient strategies for stabilizing fertilizer-N in soils and potentially minimizing N loss; however, their effects on NUE15N vary and the related mechanism must be further clarified in long-term trials.

Background: Tumor mutational burden (TMB) is increasingly recognized as a vital biomarker for predicting the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment. Despite its growing importance, the effectiveness of TMB as a predictive marker are well established in lung cancer and melanoma but remain ambiguous for breast and prostate cancers. Objective: This study aims to evaluate the role of TMB in predicting response to ICIs across four major cancer types—lung, melanoma, breast, and prostate—and to address the variability in TMB's predictive value in different cancers. Methods: A comprehensive review of the current literature was performed, analysing studies that investigated TMB and its association with ICI therapy outcomes in the specified cancer types. Results: The analysis reveals a strong consensus on the predictive value of TMB in lung cancer and melanoma, where high TMB levels are associated with improved clinical outcomes and better responses to ICIs. In contrast, the evidence for breast and prostate cancers is less conclusive, with variability in results highlighting the need for further research. Specifically, high TMB in these cancers does not consistently predict better responses to ICIs, suggesting that additional biomarkers or refined criteria might be necessary. Conclusion: TMB is a promising biomarker for predicting responses to ICI therapy, particularly in lung cancer and melanoma. However, its predictive value in breast and prostate cancers remains uncertain, underscoring the need for more extensive studies. Future research should focus on standardizing TMB evaluation methods and exploring additional biomarkers to improve treatment personalization and outcomes in these cancer types.

BReast CAncer gene 1 (BRCA1) and BReast CAncer gene 2 (BRCA2) encode for tumor suppressor proteins which are critical regulators of the homologous recombination (HR) pathway, the most precise and important DNA damage response mechanism. Dysfunctional HR proteins cannot repair double-stranded DNA breaks in mammalian cells, a situation called HR deficiency. Since their identification, pathogenic variants and other alterations of BRCA1 and BRCA2 genes have been associated with an increased risk of developing mainly breast and ovarian cancer. Interestingly, HR deficiency is also detected in tumors not carrying BRCA1/2 mutations, a condition termed “BRCAness”. One of the main mechanisms causing the BRCAness phenotype is the methylation of the BRCA1/2 promoters and this epigenetic modification is associated with carcinogenesis and poor prognosis mainly among patients with breast and ovarian cancer. BRCA1 promoter methylation has been suggested as an emerging biomarker of great predictive significance, especially concerning Poly (ADP-ribose) Polymerase inhibitors (PARP inhibitor-PARPi) responsiveness, along with or beyond BRCA1/2 mutations. However, as its clinical exploitation is still insufficient, the impact of BRCA1/2 promoter methylation status needs to be further evaluated. The current review aims to gather the latest findings about the mechanisms that underline BRCA1/2 function as well as the molecular characteristics of tumors associated with BRCA1/2 defects, by focusing on DNA methylation. Furthermore, we critically analyze their translational meaning and the validity of BRCA methylation biomarkers in predicting treatment response and we suggest a diagnostic pipeline that could be implemented in liquid biopsy to aid precision pharmacotherapy in BRCA-associated tumors.

The advent of immunotherapy has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), improving the prognosis of this disease and becoming a key part of the treatment, especially in the population without an oncogenic driver mutation. Two different groups of immune checkpoint inhibitors (ICIs) are used in lung cancer: Anti- Cytotoxic T-lymphocyte antigen-4 (Anti-CTLA 4) and Anti- T-cell receptor programmed cell death-1 or its ligand (Anti-PD-1 and Anti PD-L1). Here in, we review an uptodate on the use of immunotherapy for advanced NSCLC.

Similarly to our healthy organs, tumor tissue also generates an ecosystem. This implies that stromal cells acquire an altered phenotype in tandem with tumor cells, thereby promoting tumor survival. Cancer cells are fueled by abnormal blood vessels, allowing them to develop and proliferate. Tumor-associated fibroblasts adapt their cytokine and chemokine production to the needs of tumor cells, alter the peritumoral stroma by generating more collagen, thereby stiffening the matrix, all promoting the epithelial-mesenchymal transition and tumor cell invasion. Chronic inflammation and the mobilization of pro-tumorigenic inflammatory cells further facilitate tumor expansion. All of these events can impede the effective administration of tumor treatment, so the successful inhibition of tumorous matrix remodeling could further enhance the success of tumor treatment. Numerous publications describe efforts to inhibit tumor matrix components, but the true breakthrough has yet to be achieved. If, on the other hand, we assume that tumorous blood vessels and inflammatory cells are residents of the tumorous stroma, then two steps forward have occurred.

Modern oncological therapy utilizes various types of immunotherapy. Immune checkpoint inhib-itors (ICIs), chimeric antigen receptor T cells (CAR-T) therapy, cancer vaccines and bispecific an-tibodies are improving patients’ outcomes. However, stimulation of the immune system, benefi-cial in terms of fighting against cancer, generates the risk of harm to other cells in a patient's body. Kidney damage belongs to the relatively rare adverse events (AEs). Best described, but still, su-perficially, are renal AEs in patients treated with ICIs. International guidelines issued by Euro-pean Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) cover the management of immune-related adverse events (irAEs) during ICI therapy. There are scarce data concerning renal adverse drug reactions of other immunotherapeutic methods. This implicates the need for the collection of safety data during ongoing clinical trials and in the re-al-life world to characterize the hazard related to the use of new immunotherapies and manage-ment of irAEs.

Given that the outcome of hepatic arterial infusion chemotherapy (HAIC) with cisplatin for intrahepatic advanced hepatocellular carcinoma (HCC) is unclear, we aimed to compare prognostic factors for overall survival (OS) following HAIC with cisplatin versus sorafenib for intrahepatic advanced HCC using propensity score-matched analysis. We enrolled 348 patients with intrahepatic advanced HCC who received HAIC with cisplatin (n = 97) or sorafenib (n = 251) between June 2006 and March 2020. No significant difference was observed in OS between HAIC with cisplatin and sorafenib cohorts (median survival time [MST]: 13.9 vs. 12.7 months; p = 0.0989). To reduce confounding effects, 176 patients were selected using propensity score-matched analysis (n = 88 for each treatment). HAIC with cisplatin significantly prolonged OS compared with sorafenib (MST: 16.2 vs. 12.2 months; p = 0.0060). Following stratification according to the Child–Pugh classification, for both patients with class A (MST: 24.0 vs. 15.6 months; p = 0.0097) and class B (MST: 8.5 vs. 6.9 months; p = 0.0391), HAIC with cisplatin rather than sorafenib significantly prolonged OS. Our findings suggest that HAIC with cisplatin demonstrates longer prognostic effects than sorafenib in intrahepatic advanced HCC, regardless of the hepatic reserve.

Immune checkpoint inhibitors (ICIs) – anti-programmed death-1 (PD-1) and their ligands (PD-L1 and PD-L2) have become widely used in the treatment of several malignancies. Many immune-related adverse events have been linked to these agents. However, tuberculosis (TB) reactivation during their use is increasingly reported. Herein, we present a 58-year-old lady with advanced non-small cell lung cancer (NSCLC) ALK-negative, EGFR wild, and PD-L1 Immune histochemistry (IHC) strongly positive in 95% of tumor cells. The patient presented with high-grade fever and a history of productive cough for a 1-week duration. A few days later, she was diagnosed with pulmonary tuberculosis following the 6th cycle of Pembrolizumab, an anti-PD-1 monoclonal antibody. AFB smear and TB PCR from BAL were positive (rifampin resistance not detected), and she was accordingly started on Anti-TB medications. Immunotherapy was held. Of note, the patient had a history of sick contact with a patient with active TB infection ten years ago, but there was no documentation of latent TB or previous TB infection. Her HIV status is negative. Her sputum AFB smear continued to be positive after four weeks of anti-TB medications. Later, the patient was discharged after her sputum was cleared from AFB (negative x 2 sets). We assumed that our patient developed reactivation of pulmonary tuberculosis secondary to an immune checkpoint inhibitor (Pembrolizumab). She was not re-challenged with Pembrolizumab following TB diagnosis. To our knowledge, this is the first reported case from the Arab and the Middle East; it reinforces the previous observations of the association between ICIs administration and the development of MTB. Nevertheless, further studies in the clinical setting are necessary to establish the exact mechanism involved in this association. Oncologists' awareness & prompt recognition of this potential hazardous consequence are essential. Since there is no clear evidence whether LTBT prior PD-1/PD targeted immunotherapy is required, targeted LTBT before starting ICIs immunotherapy with TB chemoprophylaxis; yet to be explored, particularly in the regions where the MTB prevalence is high.

In the last two decades, the discovery of various pathways involved in renal cell carcinoma (RCC) have led to the development of biologically-driven targeted therapies. Hypoxia inducible factors (HIFs), angiogenic growth factors, von Hippel-Lindau (VHL) gene mutations and oncogenic miRNAs play essential roles in the pathogenesis and drug resistance of clear cell renal cell carcinoma. These insights have led to the development of VEGF inhibitors, mTOR inhibitors and immunotherapeutic agents which have significantly improved outcomes of patients with advanced RCC. HIF inhibitors will be a valuable asset in the growing therapeutic armamentarium of RCC. Various histone deacetylase (HDAC)inhibitors, including selenium and agents such as PT2385 and PT2977, are being explored in various clinical trials as potential HIF inhibitors to ameliorate the outcomes of RCC patients. In this article, we will review the current treatment options and highlight the potential role of selenium in the modulation of drug resistance biomarkers expressed in ccRCC tumors.

Chronological age represents the greatest risk factor for many life-threatening diseases including neurodegeneration, cancer and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current therapies that effectively tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR is a regulatory nexus heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

a Special Issue of Microorganisms devoted to ‘Microbial Biocatalysis and Biodegradation’ would be incomplete without some form of acknowledgement of the many important roles that dioxygen-dependent enzymes (principally mono- and dioxygenases) play in relevant aspects of biooxygenation. This is reflected by the multiple strategic roles that dioxygen -dependent microbial enzymes play both in generating valuable synthons for chemoenzymatic synthesis, and in facilitating key reactions that drive the global geochemical Carbon Cycle. A useful insight into this relationship can be gained by reviewing the evolution of the current status of 2,5-diketocamphane 1,2-monooxygenase (EC 1.14.14.108) from camphor-grown Pseudomonas putida ATCC 17453. Over the last sixty years, the perceived nature of this monooxygenase has transmogrified significantly. Commencing in the 1960s, extensive initial studies consistently reported that the enzyme was a monomeric true flavoprotein dependent on both FMNH₂ and nonheme iron as bound cofactors. However, over the last decade all those criteria have changed absolutely, and the enzyme is currently acknowledged to be a metal ion-independent homodimeric flavin-dependent two-component monooxygenase deploying FMNH₂ as a cosubstrate. That transition is a paradigm of the ever evolving nature of scientific knowledge.

This study examines the aggregate consumption function of Saudi Arabia from 2000 to 2022, focusing on identifying key determinants of household consumption and evaluating the impacts of disposable income, household wealth, government expenditure, interest rates, and oil revenues. The research uses advanced econometric methods, including the Autoregressive Distributed Lag (ARDL) model and Johansen cointegration test, to analyze the relationships among these variables. The findings reveal that disposable income, household wealth, and government expenditure significantly and positively influence consumption, whereas interest rates show a negative correlation. Oil revenues also play a critical role, reflecting the country's economic reliance on oil. The study highlights the necessity for economic diversification to reduce the impact of oil price volatility on household income and consumption stability. The results offer crucial insights for policymakers, emphasizing the need for strategies that enhance household income and wealth, maintain robust public sector spending, and effectively manage interest rates. These findings also support the importance of consistent and predictable income sources for sustaining consumption. Additionally, this study suggests directions for future research, including developing sophisticated forecasting models to predict consumption trends and exploring other influencing factors such as demographic shifts and technological progress.

The distribution of zakat, which is still carried out directly through mosques or zakat amil bodies, can hinder the payment process due to inaccurate calculations and difficulties in finding zakat amil institutions. In the digital era, information technology is very important in the management of zakat, alms, and infaq. Therefore, a zakat information management system was created. The e-Zakat program, developed using the waterfall method, plays an important role in five main aspects of zakat management: muzaki and mustahiq data collection, zakat collection, zakat distribution, mustahiq development, and reporting. The use of information technology in this program is expected to increase efficiency, accountability, transparency, as well as the reach of zakat and muzaki involvement.

The normative and safeguarding role of ethics and law in the development of biomedical science and technology, as well as their importance in promoting the progress of the industry, analyzed the key role of ethics and law in the field of biomedical science and technology, by restricting scientific research behavior, protecting the rights and safety of subjects, providing a solid guarantee for scientific research activities, and promoting the healthy development of biomedical science and technology. At the same time, the positive role of ethics and law in promoting international cooperation and exchange of biomedical science and technology is also discussed, which will inject strong impetus into the global development of biomedical science and technology. In addition, through case analysis, the paper demonstrates the key role of ethical review in the field of biomedical science and technology, as well as the importance of law in maintaining market order, protecting subjects' rights and interests, and fairness and justice. The successful practice of ethics and law in the development of biomedical science and technology is emphasized, which proves that following ethical principles and legal framework is the key factor to promote the progress of biomedical science and technology. This paper explores the important role of ethics and law in the development of biomedical science and technology, and provides valuable reference and guidance for practitioners in the industry. By following ethical principles and legal norms, we will jointly promote the prosperity and development of biomedical science and technology, and contribute to the common progress of human health.

This bibliometric study explores the cryptocurrency accounting (CA) literature and the connections between authors, institutions, and countries where cryptocurrency activity involves transactions that must be legally recognized in accounting, assure accuracy and reliability for auditing, and adhere to tax compliance. The design involves data selection from Web of Science Core Collection (WoS) and Scopus, published between 2007 - 2023. The technique helps identify influential publications, collaboration networks, thematic clusters, and trends in research on CA using tools VOSviewer, Biblioshiny, and MS Excel. The originality of the study lies in its dual role as a support for accounting professionals and academics to develop innovative solutions for the challenges posed by crypto technology across core accounting areas: financial and managerial accounting, taxation, and auditing. The findings offer insights into the themes mentioned, and even if the collaboration between the authors is not very developed, the innovation and public recognition of the subject could raise researchers' interest. The limitation of the dataset is that it does not cover all relevant publications in a different period from the one in which the data was retrieved, 9-11 May 2024. This review might need periodic updates because the CA landscape is constantly changing.

Evidence is emerging on the role of maternal diet, gut microbiota, and other lifestyle factors in establishing lifelong health and disease, which are determined by trans-generationally inherited epigenetic modifications. Understanding epigenetic mechanisms may help identify novel biomarkers for pregnancy-related exposure, burden, or disease risk. Such biomarkers are essential for developing tools for the early detection of risk factors and exposure levels. It is necessary to establish the exposure threshold to the fetus due to nutrient deficiencies or other environmental factors that can lead to clinically relevant epigenetic changes that modulate disease risks. This narrative review summarizes the latest updates on the roles of maternal nutrients (n-3 fatty acids, polyphenols, vitamins) and gut microbiota on the placental epigenome and its impacts on fetal brain development.

The dynamic landscape of AI adoption and its impact on employment in Malaysia demands a multifaceted approach to navigate the challenges and harness the opportunities presented. While the government's commitment to fostering AI adoption through initiatives like the National AI Framework and the Malaysia Digital Economy Blueprint is commendable, it is imperative to address concerns regarding job displacement and ensure inclusive growth. This study identifies the pressing research problem of workforce readiness for the AI-driven future, emphasizing the need to explore strategies for reskilling and upskilling affected workers. By employing critical lenses such as Marxist, feminist, and postcolonial perspectives, scholars highlight the power dynamics and societal implications inherent in AI deployment, guiding the development of policies and interventions that prioritize workers' interests and address social inequalities. Moving forward, a comprehensive approach combining policy interventions, educational reforms, and inclusive strategies is essential to maximize the benefits of AI adoption while mitigating its potential risks. Longitudinal studies, interdisciplinary research, and comparative analyses will further advance our understanding and inform evidence-based policymaking in this evolving field. Ultimately, by prioritizing workforce preparedness, social equity, and sustainable development, Malaysia can position itself as a leader in the AI-driven global economy, fostering a resilient, inclusive, and prosperous society for all.

Individuals with BPD grapple with unstable relationships, marked by extreme emotional swings and interpersonal conflicts. Emotional instability, a distorted self-image, and impulsivity further complicate matters, often leading to self-harm and suicide attempts as desperate coping mechanisms. Genetics and adverse childhood experiences contribute to BPD's development, shaping brain function and emotional regulation. Diagnosis involves meticulous assessments, paving the way for personalized treatments like dialectical behavior therapy and, in severe cases, hospitalization. Early intervention, professional support, and societal understanding are pivotal for positive outcomes, and challenging mental health stigma.

We show that one of the two important uncertainty principles derived by Maccone and Pati \textit{[Phys. Rev. Lett., 2014]} can be derived for arbitrary maps defined on subsets of $\mathcal{L}^p$ spaces for $1< p<\infty$. Our main tool is the Clarkson inequalities. We also derive a nonlinear uncertainty principle for weak parallelogram spaces and Type-p Banach spaces.

Keywords: Innovation ecosystems, Economic sustainability, Hydrocarbon-based economies, Economic diversification, Qualitative approach

Machine learning is a fundamental aspect of artificial intelligence that involves the development of algorithms and models that allow computers to learn and make predictions or decisions without explicit programming. With the development of neural networks, back-propagation algorithms and deep learning, machine learning has made breakthroughs in the fields of image recognition, natural language processing and handwriting recognition using machine learning techniques. The advent of deep learning has revolutionized the field of handwriting recognition, using convolutional neural networks, recurrent neural networks, and sequence-to-sequence models to provide solutions that go beyond machine learning methods and significantly improve the accuracy and robustness of handwriting recognition systems. But challenges remain, including the need for large labelled datasets, computational resources and addressing potential biases. As research in deep learning techniques continues to drive handwriting recognition closer towards realisability, machine learning approaches remain at the forefront.

Regular weight measurement is important in fattening geese to assess their health status. Failure to gain weight may indicate a potential illness. Standard weight gain analysis involves direct contact with the animal, which can cause stress to the animal, resulting in overall negative impacts on animal welfare. The focus of this study was to design a smart solution for monitoring weight changes in the breeding of farm animals. The proposed IoT system with a weighing device equipped with RFID technology for animal registration aimed to minimise the negative aspects associated with measuring in contact with humans. The designed system aims to incorporate modern approaches in animal husbandry and utilise the acquired data for the potential development of breeding approaches for various animal breeds. The system consisted of three main components: a data acquisition system, a weighing system with RFID, and an environmental monitoring system. In this study, the RFID system accuracy for detecting geese in the weighing system environment was assessed. The entire system evaluation yielded a sensitivity of 93.87%, specificity of 99.94%, accuracy of 99.85%, and precision of 95.09%. Regression analysis revealed a good correlation between observed feeding and RFID registrations with a determination coefficient of R2 = 0.9813.

Albert Einstein, shortly after publishing his General Relativity Theory (GRT) applied it to the entire universe in a paper of 1917. Einstein assumed that such a universe was static in time and possessed a uniform distribution of matter on the largest scales, obtaining a static and finite universe of spherical spatial curvature of radius R. Although this model was refuted by Edwin Hubble's discovery of the expansion of the universe, it is still often studied as a theoretical framework for some problems, such as the twin paradox. This paper will show that Einstein's static universe model leads to a privileged frame of reference, so that any observer moving at the speed v will be able to measure speeds of light other than c depending on the direction of beam transmission. The above will refute the validity of the application to this closed and static universe of the Special Relativity Theory (SRT) proposed by Einstein in 1905 in his article . In addition, a new synchronization convention and new coordinate transformations will be deduced, the "generic" transformations, which will replace those of Lorentz. Finally, the twin paradox in this universe will be solved by making use of them.

The assessment of Histone deacetylases in conjunction with Curcumin, conducted through the Mcule Database employing the Autodock Vina algorithm, involves an examination of molecular interactions. This analysis includes the calculation of binding energies, revealing the strength and stability of the interactions between Curcumin and various Histone deacetylase targets. The comparison encompasses diverse aspects such as binding energies, specific binding sites, interactions across different targets, structural details, and potential implications for biological activity. The results imply that Curcumin shows heightened affinity for Histone deacetylase 4 in comparison to other investigated histone deacetylases.

Background: Hepatic erythrophagocytosis is augmented in NASH and amplifies inflammation and fibrosis. Although various pro-phagocytic signals have been identified on erythrocytes of NASH patients, the role of bound thrombospondin-1 (TSP-1), which acts as an “eat-me” signal, arginase-1, which regulates the levels of nitric oxide in erythrocytes, and phosphatidylethano-lamine (PE) which can amplify erythrophagocytosis and hepatic inflammation have not been explored. Hence, we sought to investigate the levels of arginase-1 and TSP-1 in erythrocyte lysate and PE in erythrocyte membranes of NASH patients. Methods: Twenty-four patients and 14 healthy controls participated in our study. The levels of TSP-1 and arginase were quantified by ELISA in erythrocyte lysates, and the levels of PE in erythrocyte membranes by thin layer chro-matography. Results: Erythrocytes of NAFLD patients exhibit lower levels of arginase-1 and TSP-1 (p<0.01). Erythrocyte-bound TSP-1 levels correlated with the levels of erythrocyte surface CD47. Phosphatidylethanolamine was increased in erythrocytes of NASH patients and was accompanied by increased release, indicating exposure. Conclusion: Our results imply reduced TSP-1 binding by erythrocytes which could allow free TSP-1 molecules to act on macrophages, enhancing erythrophagocytosis. Increased PE which could amplify inflammation after efferocytosis, while downregulation of arginase-1 could lead to defective efferocytosis.

Recently, Gohar et al. introduced a novel, local, and well-behaved fractional calculus. It possesses all the classical properties, and Its locality imposes simplicity and accuracy in modeling fractional order systems. In this article, we further develop the definitions and extend the classical properties of Gohar fractional calculus to address some of the open problems in Calculus. The fractional Gronwall's integral inequality, Taylor power series expansion, and Laplace transform are defined and applied to overcome some of the limitations in the classical integer-order calculus. The fractional Laplace transform is applied to solve Bernoulli-type logistic and Bertalanffy nonlinear fractional differential equations, and the criteria under which it can be applied to solve linear differential equations are investigated.

Background/Objectives: The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Cardiovascular disease (CVD) is the leading cause of mortality in MASLD patients, therefore, the therapeutic interventions for MASLD should improve coronary risk factors such as obesity, diabetes and dyslipidemia, in addition to improving liver function. The evidence on effect of sodium-glucose cotransporter 2 inhibitors (SGLT2is) which have beneficial pharmacological properties for MASLD, especially the long-term effects, on the progression of MASLD in Asian population is very limited. Methods: The retrospective longitudinal study was performed by using the medical records at the National Center for Global Health and Medicine, Kohnodai Hospital, Japan. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between April 1, 2014 and March 31, 2018. We collected the data on metabolic parameters, including blood tests and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results: During the observation period, 324 patients had taken SGLT2is for 3 years. The 3-year-SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein-cholesterol, triglyceride and non-high-density lipoprotein-cholesterol (HDL-C) and significantly increased HDL-C. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions: Considering that the development of CVD determines the prognosis of MASLD patients, the long-term SGLT2is treatment may be an ideal therapy for MASLD patients.

fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF). Join us on a journey that unravels the mysteries of molecular intricacies, delves into advanced imaging techniques, and sheds light on therapeutic pathways. Unveiling the role of cardiac amyloidosis, particularly sub-clinical isolated cardiac amyloidosis (ICA), the narrative unfolds the heightened risk of AF in the elderly. State-of-the-art imaging techniques like cardiac magnetic resonance (CMR) and molecular imaging step into the spotlight, unraveling diagnostic and prognostic nuances of AF and HFpEF. Embarking on the molecular voyage, the article navigates through next-generation sequencing and comprehensive genomic profiling, shedding light on genetic alterations shaping the AF-HFpEF landscape. This molecular compass lays the groundwork for personalized medicine, illuminating pathways to identify therapeutic bullseyes and biomarkers. In the realm of medical strategies, the discussion homes in on the promising notes struck by SGLT2 inhibitors, particularly dapagliflozin, orchestrating a reduction in AF burden. Characters like spironolactone and dronedarone make appearances, each weaving a distinct tale, revealing their potential roles in steering the ship for AF- HFpEF patients. The subplot involving obesity in HFpEF unfolds, with the LEGACY study portraying the benefits of weight reduction. The pivotal intervention of catheter ablation emerges as the hero, boasting positive outcomes in reducing hospitalization rates and overall mortality for AF-HFpEF patients. However, cautionary tales echo about its impact on left atrial function, adding layers of complexity that beckon careful consideration and monitoring. Amidst the narrative, critical discussions unfold about the limitations of current research, echoing the need to define acute heart failure, refine imaging techniques, and tailor management strategies. The narrative passionately advocates for a personalized touch in addressing AF-HFpEF, recognizing the unique blend of clinical and molecular personas. In essence, this review paints a vivid mural of AF-HFpEF, skillfully bridging the realms of molecular intricacies and the artistry of clinical management.

This review paper presents a flashback on the evolution of the disease throughout the centuries, describes in summary pathophysiologic mechanisms, discusses briefly the mechanism of action of the diuretics, presents their role in decongesting heart failure patients and unfolds the data behind ultrafiltration in the management of acutely or chronically decompensated heart failure (ADHF), focusing on all the available data and advancements in this field. Acutely decompensated heart failure (ADHF) presents a critical clinical condition characterized by worsening symptoms and signs of heart failure, necessitating prompt intervention to alleviate congestion and improve cardiac function. Diuretics have traditionally been the mainstay for managing fluid overload in ADHF. Mounting evidence suggests that due to numerous causes, such as coexisting renal failure or chronic use of the loop diuretics, an increasing rate of diuretic resistance is noticed and needs to be addressed. There has been a series of trials that combined diuretics of different categories, without the expected results. Emerging evidence suggests that ultrafiltration may offer an alternative or adjunctive approach.

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of ZST316, an arginine analogue with inhibitory activity towards dimethylarginine dimethylaminohydrolase 1 (DDAH1) and vasculogenic mimicry, and its active metabolite L-257 in a xenograft model of triple negative breast cancer (TNBC). The method proved to be reproducible, precise, and highly accurate for the measurement of both compounds in plasma and tumour tissue following acute and chronic (five days) intraperitoneal administration of ZST316 (30mg/Kg daily) in six-week-old SCID mice inoculated with MDA-MB-231 TNBC cells. ZST316 was detected in tumour tissue and plasma after 1 hour (6.47 and 9.01M, respectively) and 24 hours (0.13 and 0.16M, respectively) following acute administration, without accumulation during chronic treatment. Similarly, the metabolite L-257 was found in tumour tissue and plasma after 1 hour (15.06 and 8.72M, respectively) and 24 hours (0.17 and 0.17M, respectively) following acute administration of ZST316, without accumulation during chronic treatment. The half-live after acute and chronic treatment ranged between 4.4-7.1hrs (plasma) and 4.5-5.0hrs (tumour) for ZST316, and 4.2-5.3hrs (plasma) and 3.6-4.9hrs (tumour) for L-257. The results of our study demonstrate the a) capacity to accurately measure ZST316 and L-257 concentrations in plasma and tumour tissue in mice using the newly developed HPLC-MS/MS method, b) rapid conversion of ZST316 into L-257, c) good intra-tumour penetration of both compounds, and d) lack of accumulation of both ZST316 and L-257 in plasma and tumour tissue during chronic administration. The new HPLC-MS/MS method is useful to investigate the in vivo effects of ZST316 and L-257 on vasculogenic mimicry, tumour mass, and metastatic burden in xenograft models of TNBC.

Diabetes mellitus (DM) and chronic kidney disease (CKD) are common in middle aged and elderly individuals. DM may accelerate the aging process, and the age-related declines in the estimated Glomerular Filtration Rate (eGFR), can pose a challenge to diagnose diabetic kidney disease (DKD) using standard diagnostic criteria especially with absence of severe albuminuria among the elderly. In the presence of CKD and DM, elderly patients may need multidisciplinary care due to susceptibility to various health issues e.g., cognitive decline, auditory or visual impairment, various comorbidities, complex medical regimens, and increased sensitivity to medication adverse effects. As a result, it can be challenging to apply recent therapeutic advancements for the general population to the elderly. We review the evidence that the benefits from these newer therapies apply equally to elderly and non-elderly patients and propose a framework for the management of DKD by discussing the nonpharmacological measures and pharmacological management with renin angiotensin system inhibitors (RASi), Sodium Glucose Co-Transporter two inhibitors (SGLT2i), non-steroidal mineralocorticoids receptor antagonists (MRAs), and Glucagon Like Peptide 1 Receptor Agonists (GLP1-RAs).

The uterine leiomyoma is the most common benign tumor in women of childbearing age. It may lead to problem of conception or complications during gestational period. The methods of treatment can be surgical (myomectomy and hysterectomy, embolization of arteries) and therapeutic treatment (Ulipristal acetate, Leuprolide acetate, Cetrorelix, Goserelin, Mifeprestone). Both approaches are efficient, but are incompatible with pregnancy planning. Therefore, there is a call for medical practice in developing therapeutical means of preventing leiomyoma onset in patients planning on pregnant. Based on the analysis of GWAS data on the search for mononucleotide polymorphisms associated with the risk of leiomyoma, meta-transcriptomic and meta-methylomic studies, target proteins have been proposed. Prospective therapeuticals of leiomyoma may be based on chemical compounds, humanized recombinant antibodies, vaccines based on markers of the uterine leiomyoma cells that are absent in the adult organism, DNA and RNA preparations. Three different nosological forms of the disease associated with driver mutations in the MED12, HMGA2 and FH genes should be considered when developing or prescribing drugs. E.g. synthetic inhibitors and vaccines based on matrix metalloproteinases MMP11 and MMP16 are expected to be effective only for the prevention of the occurrence of MED12-dependent nodules.

The RNA-binding protein Human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. The protein has been progressively recognized as a relevant therapeutic target for several pathologies like cancer, neurodegeneration, as well as inflammation. Inhibitors of mRNA binding to HuR might thus be beneficial against a variety of diseases. Here we present the rational identification of structurally novel HuR inhibitors. In particular, by combining chemoinformatics approaches, high throughput virtual screening and RNA–protein pull-down assays, we show that the 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand exhibits dose-dependent HuR inhibition in binding experiments. Importantly, the chemical scaffold is new with respect to the so-far known HuR inhibitors, opening up a new avenue for the design of pharmaceutical agents targeting this important protein.

Targeted cancer therapy has grown exponentially in the last decade, representing the largest frontier in the modern concept of precision medicine. This renaissance is largely due to our rapidly evolving ability to biochemically harness our immune systems to target cancer-specific antigens. Combined with an increasing armamentarium of surgical and non-invasive techniques for cancer mitigation we have upgraded cancer therapy from a non-specific assault on cell-division to a multi-modal, targeted approach. This renaissance has resulted in an increase in the perioperative footprint of patients with advanced cancer. The scope of the perioperative clinician has evolved from one of passive/reactive management of complications to a proactive approach that starts in the preoperative optimization phase and continues into the postoperative period. The perioperative world should not exist in a silo, and thus involvement of the oncology team is paramount. To provide safe oncologic care, it is essential to be up to date in newer cancer therapies, lest we act on erroneous and/or outdated information. Oncologists should weigh in on immune status, recent chemotherapeutic exposures, and potentially evolving toxicities. These might involve critical changes to perioperative infectious prophylaxis, steroid administration, and coagulopathy management. First, patients living beyond the typical life-expectancy for their cancer will carry a high burden of cancer-related downstream effects. General metabolic issues will include malnutrition, cachexia, and gastric outlet obstruction. Severe protein-calorie malnutrition, as well as hepatic and renal dysfunction can impact the metabolism and clearance of drugs. The cardiovascular, endocrinologic, pulmonary, and central nervous system implications of new cancer therapies will be discussed extensively below. Second, we have to enhance our ability to manage a cancer population who may be experiencing increasing novel chemotherapeutic toxicities. Newer agents differ from historical agents, which were blunt-force tools aimed at nonspecific destruction of cell-division. These drugs are efficacious but physiologically costly. Newer immunogenic therapies have a slightly improved acute safety profile, and a more complex chronic toxicity profile that may be overt or insidious. Chronic toxicities can present overtly or as a smoldering undertone to other active medical conditions such as sepsis, pneumonia, failure to thrive, or renal failure. The new therapies discussed in this review occur in the context of an overall increasingly multi-faceted cancer care machine. An example is screening for esophageal cancer in patients with Barrett's esophagus, or periodic chest CTs for patients with a strong history of tobacco use. These interventions are more likely to detect disease while it is still resectable, and resections will commonly accompany neo-adjuvant therapy. These approaches commonly involve new immunotherapies whose efficacy is higher-yield with a lower disease burden. In a recent example, the immune-checkpoint inhibitors (ICIs) ipilimumab plus nivolumab have significantly increased survival rate for squamous cell esophageal cancer when combined with standard chemotherapy. Surgical resection has evolved to one that often accompanies neoadjuvant chemo and radiation. The increasing efficacy of this approach may de-necessitate many major resections, and increase the number of sub-anatomic resections and minimally invasive procedures. Improved techniques - notably for hepatectomy, whipple procedure, prostatectomy, nephrectomy - have increased the safety profile and decreased the perioperative physiologic burden. This has enabled a broader subset of patients (due to cancer burden or due to medical comorbidities) to qualify for the operation, and increased the involvement of anesthesia and their perioperative services. With an increase in surgical candidacy comes an increase in post-surgical complications, and post-surgical maintenance such as drains, embolizations, imaging studies, etc. In the non-OR anesthesia realm, there have been considerable advancements in cancer “micro-treatments” such as hepatic metastasis embolization, tumor ablation, and peri-tumor vascular embolization. There are an ever-increasing number of IR-guided embolizations for bleeding tumors, aspiration of malignant effusions, and drainage of abscesses. This review serves to provide insight into new categories of chemotherapy and their perioperative implications.

Background: This study analyzes sex-based differences in renal structure and response to the Angiotensin-Converting Enzyme (ACE) inhibitor enalapril in a mouse model of atherosclerosis. Methods: ApoE-/- mice (8 weeks old) received enalapril (5 mg/kg/day, subcutaneous) or PBS as a control for an additional 14 weeks. Each group consisted of six males and six females. Results: Females exhibited elevated LDL-cholesterol levels, while males presented higher creatinine levels and proteinuria. Enalapril effectively reduced blood pressure in both groups, but proteinuria decreased significantly only in females. Plaque size analysis and assessment of kidney inflammation revealed no significant sex-based differences. However, males displayed more severe glomerular injury, with increased mesangial expansion, mesangiolysis, glomerular foam cells and activated parietal epithelial cells (PECs). Enalapril mitigated mesangial expansion, glomerular inflammation (particularly in females), and the hypertrophy of PECs in males. Conclusion: This study demonstrates sex-based differences in the response to enalapril in a mouse model of atherosclerosis. Males exhibited more severe glomerular injury, while enalapril provided renal protection, particularly in females. These findings suggest potential sex-specific considerations for ACE inhibitor therapy in chronic kidney disease and atherosclerosis cardiovascular disease. Further research is needed to elucidate the underlying mechanism behind these observations.

Skin melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Thus, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis identified two potent drugs (Cialis and Finasteride) that can efficiently inhibit AKT1 and MDM2 protein signatures respectively, and with better therapeutic properties. We proposed that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma.

Histone Lysine Specific Demethylase 1 (LSD1) is overexpressed in many cancers and become a new target for anticancer drugs. In recent years, the small molecule inhibitors with various structures targeting LSD1 have been reported. Here we report the binding interaction modes of a series of thieno[3,2-b]pyrrole-5-carboxamides LSD1 inhibitors using molecular docking, three dimensional quantitative structure-activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA q²=0.783, r²=0.944, r²_pred=0.851) and Comparative molecular similarity indices analysis (CoMSIA q²=0.728, r²=0.982, r²_pred=0.814) were used to establish 3D-QSAR models, which had good verification and prediction capabilities. Based on the contour maps and the information of molecular docking, 8 novel small molecules were designed in silico, among which compounds D4, D5 and D8 with high predictive activity were subjected to further molecular dynamics simulations (MD), and their possible binding modes were explored. It was found that Asn535 plays a crucial role in stabilizing the inhibitors. Furthermore, the ADME and bioavailability prediction for D4, D5 and D8 were carried out. The results would provide valuable guidance for designing new reversible LSD1 inhibitors in the future.

Penicillium digitatum is the major postharvest pathogen of citrus fruit under Mediterranean climate conditions. In the present work, we have addressed the study of the role of P. digitatum’s proteases in virulence following two complementary approaches. In a first approach, we have undertaken the functional characterization of the P. digitatum prtT gene, which codes for a transcription factor previously shown to regulate extracellular proteases in other filamentous fungi. Deletion of prtT caused a significant loss in secreted protease activity during in vitro growth assays. However, there was no effect on virulence. Gene expression of the two major secreted acid proteases was barely affected in the ΔprtT deletant during infection of citrus fruit. Hence, no conclusion could be drawn on the role of these secreted acidic proteases on the virulence of P. digitatum. In a second approach, we have studied the effect of different protease inhibitors and chelators in virulence. Co-inoculation of citrus fruit with P. digitatum conidia and a cocktail of protease inhibitors resulted in almost a complete absence of disease development. Analysis of individual inhibitors revealed that the metalloprotease inhibitor 1,10-phenanthroline was responsible for the observed effect. The application of metal ions reverted the protective effect caused by the metallopeptidase inhibitor. These results may set the basis for the development of new alternative treatments to combat this important postharvest pathogen.

Compounds with tyrosinase inhibitory efficacy could be effective as depigmenting agents. Although a large number of natural and synthetic tyrosinase inhibitors have been reported, few of them are used as skin-whitening agents due to poor activity and safety concerns. 3-(2,4-Dihydroxyphenyl)propionic acid (DPPA), a naturally occurring compound isolated from Ficus carica, was previously discovered as a moderate tyrosinase inhibitor. In this study, the structure-activity relationship study of DPPA was conducted. Compound 3g, with the 2,4-resorcinol subunit and terminal hydrophobic di-butylamino group, was identified with low nanomolar enzymatic IC₅₀ value. Additionally, compound 3g could effectively reduce melanin levels in B16-F10 melanoma cells treated with α-melanocyte-stimulating hormone (α-MSH) without affecting cell viability and proliferation. All these results indicated that compound 3g could be considered as a promising candidate for the treatment of diseases associated with hyperpigmentation.

Background: Virtual Reality (VR) is an emerging tool in the management of anxiety, one of the most disturbing symptoms of Alcohol Use Disorder (AUD), which often leads to relapse. Still, patients with Alcohol Use Disorder frequently have a history of Acute Symptomatic Seizures, and they are subsequently excluded from studies using VR because of the hypothesized fear of inducing photosensitive seizures. The first part of this narrative review explores the pathophysiological mechanisms of seizures associated with AUD, specifically acute symptomatic seizures. In contrast, the second part explores virtual reality’s safe use in seizure-prone individuals, highlighting that the current state-of-the-art is based on a biased per-ception and old epidemiological data from studies conducted on photosensitive seizures in the late 90s. VR exposure has yet to be reported as triggering seizures within known pharmacovigilance databases. Significance: The implications weigh heavily on VR research currently associated with this significant adverse event. Further studies are necessary to address the risk of seizures triggered by VR in patients predisposed to developing seizures, like alcohol use disorder patients with a history of acute symptomatic seizures. Such research is essential to ensure that the potential benefits of Virtual Reality as a tool for managing anxiety in individuals with alcohol use disorder and acute symptomatic seizures are not unduly restricted. Furthermore, AUD can also serve as an intervention model feasible to de-bias attitudes toward the current lack of evidence base concerning the significant adverse events of VR-induced seizures, therefore facilitating the clinical implementation of this unharnessed digital treatment interface.