Although there are several access control systems in the literature for flexible policy management in multi-authority and multi-domain environments, achieving interoperability & scalability, without relying on strong trust assumptions, is still an open challenge. We present HMBAC, a distributed fine-grained access control model for shared and dynamic multi-authority and multi-domain environments, along with Janus, a practical system for HMBAC policy enforcement. The proposed HMBAC model supports: (a) dynamic trust management between different authorities; (b) flexible access control policy enforcement, defined at domain and cross-domain level; (c) a global source of truth for all entities, supported by an immutable, audit-friendly mechanism. Janus implements the HMBAC model and relies on the effective fusion of two core components. First, a Hierarchical Multi-Blockchain architecture that acts as a single access point that cannot be bypassed by users or authorities. Second, a Multi-Authority Attribute Based Encryption protocol that supports flexible shared multi-owner encryption, where attribute keys from different authorities are combined to decrypt data distributedly stored in different authorities. Our approach was implemented using Hyperledger Fabric as the underlying blockchain, with the system components placed in Kubernetes Docker container pods. We experimentally validated the effectiveness and efficiency of Janus, while fully reproducible artifacts of both our implementation and our measurements are provided.

Classical and optimal control architectures for motion mechanics with fusion of noisy sensors use different algorithms and calculations to perform and control any number of physical demands, to varying degrees of accuracy, precision, and cost. Their performances are tested for the purpose of comparison through the means of a Monte Carlo simulation that simulates how different parameters might vary under noise, representing real-world imperfect sensors. We find that improvements in one figure of merit often come at a cost in the performance in the others, especially depending on the presence of noise in the system sensors. If sensor noise is negligible, open-loop optimal control performs the best. However, in the overpowering presence of sensor noise, using a control law inversion patching filter performs as the best replacement, but has significant computational strain.

Proton exchange membrane water electrolyzers (PEMWEs) for water electrolysis have received tremendous attention due to their immediate response, high proton conductivity, low ohmic losses and gas crossover rate. However, design high activity, economical and long-term durable electrocatalysts in an acidic environment is still the bottleneck to realize the large-scale commercialization of PEMWEs. Iridium-based materials represent one of the most promising classes of oxygen evolution reaction (OER) catalysts due to their intrinsic stability in acid media over ruthenium-based counterparts. However, only a few innovative approaches have been developed to synthesizing iridium-based catalysts (IBCs) in the past decade, mainly due to achieving high activity may deteriorate the stability of IBCs. Accordingly, various engineering strategies of optimizing IBCs have been proposed to address this issue, including doping engineering, morphology engineering, crystal phase engineering and support engineering. Herein, a critical overview focusing on various synthesis and modulation strategies of IBCs is presented, based on an in-depth understanding of the relationship between electronic structures, charge redistribution and activity as well as stability of the electrocatalysts. In addition, the unprecedented achievements in PEMWEs are summarized. The reaction mechanisms and future perspectives are critically discussed to inspire more rational design of IBCs toward practical applications.

Fluorescence microscopy is an important tool for disease diagnosis, often requiring costly optical components, such as fluorescence filter cubes and high-power light sources. Due to its high cost, conventional fluorescence microscopy cannot be fully exploited in low-income settings. Smartphone-based fluorescence microscopy becomes an interesting low-cost alternative, but raises challenges in the optical system. We present the development of a low-cost inverted laser fluorescence microscope, that uses a smartphone to visualize the fluorescence image of biological samples. Our fluorescence microscope uses a laser-based simplified optical filter system, that provides analog optical filtering capabilities of a fluorescence filter cube. Firstly, we validated our inverted optical filtering by visualizing microbeads labeled with three different fluorescent compounds or fluorophores, commonly used for disease diagnosis. Secondly, we validated the disease diagnosis capabilities, by comparing the results of our device with those of a commercial fluorescence microscope. We successfully detected and visualized Trypanosoma cruzi parasites, responsible of the Chagas infectious disease, and the presence of Antineutrophil cytoplasmic antibodies of the ANCA non-communicable autoimmune disease. The samples were labeled with the fluorescein isothiocyanate (FITC) fluorophore, one of the most commonly used for disease diagnosis. Our device provides a 400 X magnification and is at least two orders magnitude cheaper than conventional commercial fluorescence microscopes.

Nature-based solutions (NbS) - working with and enhancing nature to address societal challenges - are increasingly being featured in climate change adaptation policy and plans. While there is growing evidence that NbS can reduce vulnerability to climate change impacts in general, there is a lack of understanding on the mechanisms through which this can be achieved, particularly in the Global South. To address this, we analyse 85 nature-based interventions in rural areas across the Global South, and factors mediating their effectiveness, based on a systematic map of peer-reviewed studies encompassing a wide diversity of ecosystems, climate impacts, and intervention types. We develop and apply an analytical framework of people’s social-ecological vulnerability to climate change, in terms of six pathways of vulnerability reduction: social and ecological exposure, sensitivity, and adaptive capacity. Most cases (95%) report a reduction in vulnerability, primarily by lowering ecosystem sensitivity to climate impacts (73% of interventions), followed by reducing social sensitivity (52%), reducing ecological exposure (36%), increasing social adaptive capacity (31%), increasing ecological adaptive capacity (19%) and/or reducing social exposure (14%). An analysis of mediating factors shows that social dimensions are equally important as technical factors in NbS to achieving equitable and effective outcomes. Attention to the distinct social and ecological pathways through which vulnerability is reduced helps to harness the multiple benefits of working with nature in a warming world.

Reliable quantification of pulmonary arterial pressure is essential in the diagnostic and prognostic assessment of a range of cardiovascular pathologies including rheumatic heart disease, yet an accurate and routinely available method for its quantification remains elusive. This work proposes an approach to infer pulmonary arterial pressure based on scientific machine learning techniques and non-invasive, clinically available measurements. A 0-D multicompartment model of the cardiovascular system was optimized using several optimization algorithms, subject to forward-mode automatic differentiation. Measurement data were synthesized from known parameters to represent the healthy, mitral regurgitant, aortic stenosed and combined valvular disease situations with and without pulmonary hypertension. Eleven model parameters were selected for optimization based on 95 % explained variation in mean pulmonary arterial pressure. A hybrid Adam and limited-memory Broyden-Fletcher-Goldfarb-Shanno optimizer yielded the best results with input data including valvular flow rates, heart chamber volume changes and systematic arterial pressure. Mean absolute percentage errors ranged from 1.8 % to 3.78 % over the simulated test cases. The model was able to capture pressure dynamics under hypertensive conditions with pulmonary arterial systole, diastole, and mean pressure average percentage errors of 1.12 %, 2.49 % and 2.14 %, respectively. The relatively low errors highlight the potential of the proposed model to recover pulmonary pressures for diseased heart valve and pulmonary hypertensive conditions.

Previous research has either neglected to consider misbehaviour or misconduct in the virtual workplace during the current COVID-19 pandemic or highlighted some challenges encountered with remote working or work from home but in isolation, e.g., misbehaviours or ethical concerns associated with improper use of technology when accessing clients’ confidential information, without understanding their aetiology and context in a holistic manner. This has impacted the ability of existing research in providing recommendations organisations can practically implement to improve the sustainability and productivity of the virtual workplace, especially as they seek to navigate the current pandemic and prepare for the global business environment in the next decade. Instead, this study, for the first time, proposes a novel holistic methodology to identify the aetiologies of ethical and performance challenges with focus to the Information Technology consulting sector, as well as developing a set of recommendations companies can adopt to manage such behavioural and productivity challenges. Thus, this study illustrates the key issues associated with remote working implemented to respond to the current COVID-19 pandemic, which mine not only the individual performance in an organisation but also its overall productivity, as well as suggests the main performance and reward management strategies that can be leveraged to mitigate them. Tailored strategies are described and discussed as referred to this industry to help in navigating a more unstable yet competitive market to manage the virtual employees’ misbehaviours in the workplace and drive growth for individuals and organisations alike.

Coronavirus Disease-19 (COVID-19) is presently wreaking havoc on public health and socio-economic development. Besides the upper and lower respiratory tract involvement, gastrointestinal symptoms are also reported in COVID-19 patients through gut-lung axis. Finding its way through the feces of infected individuals and other sources, the genetic material of SARS-CoV-2 (ssRNA) is reported widely in wastewater and is being used as a fingerprint for its detection. With millions of cases arriving every day, there is a need to level up the testing speed efficiency. Due to the restricted sampling potential of testing laboratories, clinical testing is unable to track all the symptomatic and asymptomatic cases. Wastewater-based epidemiology (WBE) bestows an auxiliary monitoring tool that will contribute in community level screening. Sample collection, concentration, RNA extraction, quantification and data analysis are the main steps involved in implementation of WBE that can be relied upon as an alarm call for an upcoming wave, emergence of a new variant or any future pandemic. WBE can be a cheaper and more practical alternative to high end and sophisticated clinical testing for community transmission detection. Worldwide, there are more than 300 reports entailing the occurrence of SARS-CoV-2 in wastewater exhibiting unique temporal trends with five of them in India. This review aims to address the present knowledge on surveillance of SARS-CoV-2 in wastewater and its implications.

Premature ventricular contraction (PVC) is one of the common ventricular arrhythmias, which may cause stroke or sudden cardiac death. Automatic long-term electrocardiogram (ECG) analysis algorithms could provide diagnosis suggestion even early warning for physicians, however, they are mutually-exclusive in terms of robustness, generalization and low complexity. In this study, a novel PVC recognition algorithm that combines deep learning-based heartbeat template clusterer and expert system-based heartbeat classifier is proposed. Long short-term memory-based auto-encoder (LSTM-AE) network was used to extract features from ECG heartbeats for K-means clustering. Thus, the templates were constructed and determined based on clustering results. Finally, the PVC heartbeats were recognized based on a combination of multiple rules, including template matching and rhythm characteristics. Three quantitative parameters, sensitivity (Se), positive predictive value (P+) and accuracy (ACC), were used to evaluate the performances of the proposed method on the MIT-BIH Arrhythmia database and the St. Petersburg Institute of Cardiological Technics database. Se on the two test databases was 87.51% and 87.92%, respectively; P+ was 92.47% and 93.18%, respectively; and ACC was 98.63% and 97.89%, respectively. The PVC scores on the 3rd China Physiological Signal Challenge 2020 training set and hidden test set were 36,256 and 46,706, respectively, which could rank first in the open-source codes. The results showed that the combination strategy of expert system and deep learning can provide new insights for robust and generalized PVC identification from long-term single-lead ECG recordings.

Emotions or affective states recognition in farm animals is an underexplored research domain. Despite significant advances in the animal welfare research, the animal affective computing through the development and application of devices and platforms that can not only recognize but interpret and process the emotions, are in nascent stage. By capitalizing on the immense potential of biometric sensors, the artificial intelligence enabled big data methods substantially offers advancement of animal welfare standards and meet the urgent need of caretakers to respond effectively to maintain the wellbeing of their animals. Farm animals, numbering over 70 billion worldwide, are increasingly managed in large-scale, intensive farms. With both public awareness and scientific evidence growing that farm animals experience suffering, as well as affective states such as fear, frustration and distress, there is an urgent need to develop efficient and accurate methods for monitoring their welfare. At present, there are no scientifically validated ‘benchmarks’ for quantifying transient emotional (affective) states in farm animals, and no established measures of good welfare, only indicators of poor welfare, such as injury, pain and fear. Conventional approaches to monitoring livestock welfare are time consuming, interrupt farming processes and involve subjective judgments. Biometric sensors data enabled by Artificial Intelligence are an emerging smart solution to unobtrusively monitoring livestock, but their potential for quantifying affective states and groundbreaking solutions in their application are yet to be realized. This review provides innovative methods for collecting big data on farm animal emotions, which can be used to train artificial intelligence models to classify, quantify and predict affective states in individual pigs and cows. Extending this to the group level, social network analysis can be applied to model emotional dynamics and contagion among animals. Finally, ‘digital twins’ of animals capable of simulating and predicting their affective states and be-havior in real time are a near-term possibility.

In this paper we try to demonstrate that the classical model of certainty factos for dealing with innacurate knowledge can be efficiently implemented in a quantum environment. For this, we assume that certainty factors are strongly correlated with the quantum probability. We first explore the certainty factors approach for inexact reasoning from a classical point of view. Next, we introduce some basic aspects of quantum computing, and we pay special attention to quantum rule-based systems. We then build a use case: an inferential network to be implemented in both, the classical approach and the corresponding quantum circuit. Both implementations have been used to compare the behavior of the classical and the quantum approaches when confronted with the same hypothetical case. We analyze three different situations: (1) Only Imprecision (which refers to inaccuracy in declarative knowledge or facts) is present in the use case, (2) Only Uncertainty (which refers to inaccuracy in procedural knowledge or rules) is present in the use case, and (3) Both Imprecision and Uncertainty are present in the use case. Finally, we analyze the results to reach a conclusion about the eventually intrinsic probabilistic nature of the certainty factors model and to pave the way for future quantum implementations of this method for handling inaccurate knowledge.

Background: Serious games are conceptualized as a broad topic and overlap segments of more modern forms of education: e-learning, edutainment, game-based learning, and digital game-based learning. Serious Games aligns with digitalization and the modern era and creates novel opportunities for learning and assessment in medical education. Escape rooms, a type of serious games, merge mental and physical aspects to reinforce critical skills useful in daily life. It challenges logic and reasoning and demands careful analysis of situations to correlate and solve different stages of the escape room under pressurized, timed conditions. Furthermore, it serves as an adequate environment to build problem-solving skills, communication skills, and leadership skills through the collaboration of people to achieve a common goal. The aim of this study was to investigate the applications of escape rooms in Medical Education. Method: This study investigated the applications of escape rooms in medical education. Serious games are expanding in education and have attained great relevance due to their intriguing and intrinsically motivating attributes. Within serious games, we focused on escape rooms in which participants are locked in a room, faced with puzzles that must be solved to ‘escape the room’. Compiling the data from the first 100 hits of medical application of escape rooms, we found 72 cases and categorized them by year, specialty, participants structure, simulation experience, and design. Results: We reported on escape rooms in medical education by the year in which they were reported, the medical specialty, the participant structure, grouped or individual, the experience design; real, hybrid, or digital, and the modality of the delivery. 72% of the escape rooms focused on four main areas: nursing education (25.0%), emergency medicine (22.2%), pharmacy (12.5%), and interprofessional education (12.5%). Most of the escape rooms had a group-based physical design and little attention was given to provide a detailed description of the design considerations, such as the pathway type (linear, semi-linear, open). Conclusion: Escape rooms are applied in a wide range of medical education areas. In Medical Education, group-based on-site escape rooms with a focus on nursing, emergency medicine, pharmacy and interprofessional education dominates the implementation landscape. To further advance the field, stronger emphasis on making explicit the design considerations will advance the research and inform implementations.

The use of Information Communication Technologies (ICT) in education brings up new possibilities of promoting the learning and health experiences. In this sense, education contexts of 21st century must consider these two areas of knowledge, especially their integration. This article presents learning practices developed with mobile devices and games, in order to improve learning and well-being in children and adolescents undergoing cancer treatment in non-formal educational setting. The methodology is based on qualitative case studies with content-based data analysis, involving informal interviews and observation methods. The study considers data from 5 patients who participated in the research between 2015 and 2019. The results demonstrate a positive influence of the practices with mobile technologies and games in terms of learning and in the well-being feeling of patients during the treatment.

This paper provides a concise review of remote sensing of ocean fronts and its applications in marine ecology and fisheries, with a particular focus on the most popular front detection algorithms/techniques: Canny (1986), Cayula and Cornillon (1990, 1992, 1995), Miller (2004, 2009), Shimada et al. (2005), Belkin and O’Reilly (2009), and Nieto et al. (2012). A case is made for feature-based approach in marine ecology and fisheries that emphasizes fronts as major structural and circulation features of the ocean realm that play key roles in various aspects of marine ecology.

Nature-based Solutions (NbS) have rapidly been gaining traction across the research, policy, and practice spheres, touted as transformative actions to jointly address biodiversity loss and climate change. However, there are multiple, alternative ways to imagine NbS in those three spheres. To inform the NbS discourses across these three spheres, we critically reflect on the prevailing framing of NbS and consider the potential of a different framing of NbS to support transformations towards regenerative relationships between humans and nature. Such reflection is urgently needed to ensure that research, policy, and practice delivers on the transformative ambitions of NbS. We propose a novel “core framing” of NbS, charting two pathways for how such a framing can support a human value-based transformation – first through influencing individual beliefs and values, and second through the communication and application of the NbS concept in research, policy, and practice. We argue that for NbS to support transformation, it must support a reframing of human-nature relationships, one where the interdependencies between people and nature are recognized as essential for social and environmental well-being. We elaborate on how such a framing is key to support inclusivity and collaboration between diverse research perspectives, policy objectives across scales, and implementation practices, to deliver successful NbS.

The ongoing COVID-19 pandemic has raised numerous questions concerning the shape and range of state interventions whose goals are to reduce the number of infections and deaths. The lockdowns, which have become the most popular response worldwide, are assessed as being an outdated and economically inefficient way to fight the disease. However, in the absence of efficient cures and vaccines, there is a lack of viable alternatives. In this paper we assess the economic consequences of the epidemic prevention and control schemes that were introduced in order to respond to the COVID-19 pandemic. The analyses report the results of epidemic simulations that were obtained using the agent-based modelling methods under the different response schemes and their use in order to provide conditional forecasts of the standard economic variables. The forecasts were obtained using the DSGE model with the labour market component.

The global use of alcohol based hand sanitizers (ABHS) as a means of controlling the transmission of infectious disease increased dramatically in 2020 as governments and public health agencies across the world advocated hand hygiene as a preventative measure during the COVID-19 pandemic. Although the performance of these products is most commonly defined as a function of their alcohol concentration, they are multifaceted products in which an interplay of several factors is important in determining efficacy. The hand sanitizer tetrahedron, is a novel concept that considers both ABHS formulation factors and product performance factors from a multi-dimensional perspective. The four faces of the tetrahedron represent input/formulation factors: 1) the type and amount of alcohol, 2) inactive ingredients, 3) the type of formulation/delivery system and 4) manufacturing practices. The four corners of the tetrahedron represent output/product performance factors: 1) efficacy, 2) sensory characteristics, 3) usage, usability and compliance and 4) product safety/adverse effects. All factors are of importance to ensuring the effectiveness and utility of these products.

Gene editing tools such as CRISPR-Cas9 have created unprecedented opportunities for genetic studies in plants and animals. We designed a course-based undergraduate research experience (CURE) to train introductory biology students in the concepts and implementation of gene editing technology as well as develop their soft skills in data management and scientific communication. We present two versions of the course that can be implemented with twice-weekly meetings over a five-week period. In the remote-learning version, students perform homology searches, design guide RNAs and primers, and learn the principles of molecular cloning. This version is appropriate when access to laboratory equipment or in-person instruction is limited, such as closures that have occurred in response to the Covid-19 pandemic. In the in-person version, students design guide RNAs, clone CRISPR-Cas9 constructs, and perform genetic transformation of the model plant Arabidopsis thaliana. The highly parallel nature of the CURE makes it possible to target dozens to hundreds of genes, depending on the number of course sections available. Applying this approach in a sensitized mutant background enables focused reverse genetic screens for genetic suppressors or enhancers. The course can be readily adapted to other organisms or projects that employ gene editing.

In recent years, team-based learning (TBL) is gaining popularity as a student-centered active collaborative learning strategy in healthcare education. This paper reports the design, implementation, and impact of a "hybrid team-based learning" (H-TBL) for one respiratory lecture in year two undergraduate physiotherapy program in 2019. A retrospective study was conducted, including 136 second-year undergraduate physiotherapy students using H-TBL design for one respiratory lecture topic. Student engagement was evaluated based on the percentage of completion for pre-class work, attendance to classroom session, and submission of formative creative assignment. Student' performance on formative creative tasks was evaluated based on thinking and learning rubric. Student perceptions were assessed based on the student's feedback using "Mentimeter." 109/ 136 (80%) students attended the COPD 2 session. 90/109 (82%) students engaged in COPD 1 (web-based) and tRAT in COPD 2 session. 54/109 (50%) students provided feedback and 67/90 (74%) students submitted formal formative creative assignment on completion of COPD 2 session. This study confirms that H-TBL enhances student's active engagement, creativity, and equilibration of their subject knowledge. Future randomized studies are mandated to explore the validity and specificity of H-TBL in diverse physiotherapy curriculum to evaluate the long-term student engagement and academic performance.

Adaptive bitrate (ABR) algorithms optimize the quality of streaming experiences for users in client-side video players especially in unreliable or slow mobile networks. Several rule-based heuristic algorithms can achieve stable performance, but they sometimes fail to adapt properly to changing network conditions. Fluctuating bandwidth may cause algorithms to default to behavior that creates a negative experience for the user. ABR algorithms can be generated with reinforcement learning, a decision-making paradigm in which an agent learns to make optimal choices through interactions with an environment. Training reinforcement learning algorithms for bitrate streaming requires building a simulator for an agent to experience interactions quickly; training an agent in the real environment is infeasible due to the long step times in real environments. This project explores using supervised learning to construct a world-model, or a learned simulator, from recorded interactions. A reinforcement learning agent trained inside of the learned model, rather than a simulator, can outperform rule-based heuristics. Furthermore, agents trained inside the learned world-model can outperform model-free agents in low sample regimes. This work highlights the potential for world-models to quickly learn simulators, and to be used to generate optimal policies.

The advance of the medical field in the 21st century has influenced the development of many innovations, including in medical education. PBL (problem-based learning) is one of the pedagogical approaches that has been studying and implementing worldwide to attract medical students’ attention with their learning style and learning environment. China is the most significant “receiver” country of foreign students in Asia, and clinical medicine is one of the most chosen majors for undergraduate. In China, PBL has been implementing in some schools, but mostly with the local students and only a few implementations to the international students. International medical students in China faced a variety of challenges during their studies. In this review paper, we give the solution to adapt to the challenges by focusing on the implementation the integrated organ/system curriculum/syllabus with the PBL method to the school system with the support of the school stakeholders and students’ role.

In the present work, the state of the art of the most common additive manufacturing (AM) technologies used for the manufacturing of complex shape structures of graphene-based ceramic nanocomposites, ceramic and graphene-based parts is explained. A brief overview of the AM processes for ceramic, which are grouped by the type of feedstock used in each technology, is presented. The main technical factors that affect the quality of the final product were reviewed. The AM processes used for 3D printing of graphene-based materials are described in more detail; moreover, some studies in a wide range of applications related to these AM techniques are cited. Furthermore, different feedstock formulations and their corresponding rheological behaviour were explained. Additionally, the most important works about the fabrication of composites using graphene-based ceramic pastes by Direct Ink Writing (DIW) are disclosed in detail and illustrated with representative examples. Various examples of the most relevant approaches for the manufacturing of graphene-based ceramic nanocomposites by DIW are provided.

The major stress-inducible Hsp70 (HSPA1A) is overexpressed in the cytosol of many highly aggressive tumor cells including glioblastoma multiforme and presented on their plasma membrane. Depending on its intracellular or membrane localization, Hsp70 either promotes tumor growth or serves as a target for NK cells. The kinetics of the membrane Hsp70 (mHsp70) density on human glioma cells (U87) was studied after different irradiation doses to define the optimal therapeutic window for Hsp70-targeting NK cells. To maintain the cells in the exponential growth phase during a cultivation period of 7 days different initial cell counts were seeded. Although cytosolic Hsp70 levels remained unchanged on days 4 and 7 after a sublethal irradiation with 2 Gy, 4 Gy and 6 Gy, a dose of 2 Gy resulted in an upregulated mHsp70 density in U87 cells which peaks on day 4 and starts to decline on day 7. Higher radiation doses (4 Gy, 6 Gy) resulted in an earlier and more rapid onset of the mHsp70 expression on days 2 and 1, respectively, followed by a decline on day 5. Membrane Hsp70 levels are higher in G2/M than in G1, however, an irradiation-induced cell cycle arrest on days 4 and 7, was not associated with an increase in the mHsp70 density. Extracellular Hsp70 concentrations increased significantly compared to sham (0 Gy) irradiated cells on days 4 and 7 but not on day 1. Functionally, elevated mHsp70 densities were associated with a significantly better lysis by Hsp70-targeting NK cells. In summary, the kinetics of changes in the mHsp70 density upon irradiation on tumor cells is time- and dose-dependent.

Prediction of stock groups values has always been attractive and challenging for shareholders. This paper concentrates on the future prediction of stock market groups. Four groups named diversified financials, petroleum, non-metallic minerals and basic metals from Tehran stock exchange are chosen for experimental evaluations. Data are collected for the groups based on ten years of historical records. The values predictions are created for 1, 2, 5, 10, 15, 20 and 30 days in advance. The machine learning algorithms utilized for prediction of future values of stock market groups. We employed Decision Tree, Bagging, Random Forest, Adaptive Boosting (Adaboost), Gradient Boosting and eXtreme Gradient Boosting (XGBoost), and Artificial neural network (ANN), Recurrent Neural Network (RNN) and Long short-term memory (LSTM). Ten technical indicators are selected as the inputs into each of the prediction models. Finally, the result of predictions is presented for each technique based on three metrics. Among all algorithms used in this paper, LSTM shows more accurate results with the highest model fitting ability. Also, for tree_based models, there is often an intense competition between Adaboost, Gradient Boosting and XGBoost.

Visual Patient technology is a situation awareness–oriented visualization technology that translates numerical and waveform patient monitoring data into a new user-centered visual language. Vital sign values are converted into colors, shapes, and rhythmic movements—a language humans can easily perceive and interpret—on a patient avatar model in real time. In this review, we summarize the current state of the research on the Visual Patient, including the technology, its history, and its scientific context. We also provide a summary of our primary research and a brief overview of research work on similar user-centered visualizations in medicine. In several computer-based studies under various experimental conditions, Visual Patient transferred more information per unit time, increased perceived diagnostic certainty, and lowered perceived workload. Eye tracking showed the technology worked because of the way it synthesizes and transforms vital sign information into new and logical forms corresponding to the real phenomena. The technology could be particularly useful for improving situation awareness in settings with high cognitive demand or when users must make quick decisions. This comprehensive review of Visual Patient research is the foundation for an evaluation of the technology in clinical applications, starting with a high-fidelity simulation study in early 2020.

UAVNs (unmanned aerial vehicle networks) may become vulnerable to threats and attacks due to their characteristic features such as high mobility, highly dynamic network topology, and open-air wireless environments. Since previous work has focused on classical and metaheuristic-based approaches, none of these approaches have a self-adaptive approach. In this article, we examine the challenges of cyber detection methods to secure UAVNs and review exiting security schemes proposed in the current literature. Furthermore, we propose an agent-based self-protective method (ASP-UAVN) for UAVNs that is based on the Human Immune System (HIS). In ASP-UAS, the safest route from the source UAV to the destination UAV is chosen according to a self-protective system. In this method, a multi-agent system using an Artificial Immune System (AIS) is employed to detect the attacking UAV and choose the safest route. In the proposed ASP-UAVN, the route request packet (RREQ) is initially transmitted from the source UAV to the destination UAV to detect the existing routes. Then, once the route reply packet (RREP) is received, a self-protective method using agents and the knowledge base is employed to choose the safest route and detect the attacking UAVs. The method is evaluated here via extensive simulations carried out in the NS-3 environment. The experimental results of four scenarios demonstrated that the ASP-UAS increases the Packet Delivery Rate (PDR) by more than 17.4, 20.8, and 25.91%, and detection rate by more than 17.2, 23.1, and 29.3%, and decreases the Packet Loss Rate (PLR) by more than 14.4, 16.8, and 20.21%, the false-positive and false-negative rate by more than 16.5, 25.3, and 31.21% those of SUAS-HIS, SFA and BRUIDS methods, respectively.

As of today, 20 disease modifying drugs (DMD) have been approved for the treatment of relapsing multiple sclerosis (MS) and, based on their efficacy, they can be grouped into moderate-efficacy DMDs and high-efficacy DMDs. The choice of the drug mostly relies on the judgement and experience of neurologists and the evaluation of therapeutic response can only be obtained by monitoring clinical and magnetic resonance imaging (MRI) status during follow up. In an era where therapies are focused on personalization, the aim of this study is to develop a modeling infrastructure to predict the evolution of relapsing MS and the response to treatments. We built a computational modeling infrastructure named UISS (Universal Immune System Simulator) able to simulate the main features and dynamics of the immune system activities. We extended UISS to simulate all the underlying MS pathogenesis and its interaction with the host immune system. This simulator is a multi-scale, multi-organ, agent based simulator with an attached module capable of simulating the dynamics of specific biological pathways at the molecular level. We simulated six MS patients with different relapsing-remitting courses. These patients were characterized on the basis of their age, sex, presence of oligoclonal bands, therapy and MRI lesion load at onset. The simulator framework is made freely available and can be used following the links provided in the availability section. Even though the model can be further personalized employing immunological parameters and genetic information, based on the available data we generated a few simulation scenarios for each patient, including those who matched the real clinical and MRI history. Moreover, for two patients, the simulator anticipated the timing of subsequent relapses, which really occurred, suggesting that UISS may have the potential to assist MS specialists in predicting the course of the disease and the response to treatment.

Community-engaged research is understood as existing on a continuum from less to more community engagement, defined by participation and decision-making authority. It has been widely assumed that more is better than less engagement. However, we argue that what makes for good community engagement is not simply the extent but the fit or alignment between the intended approach and the various contexts shaping the research projects. This article draws on case studies from three Community Engagement Cores (CECs) of NIEHS-funded Environmental Health Science Core Centers (Harvard University, UC Davis and University of Arizona,) to illustrate the ways in which community engagement approaches have been fit to different contexts and the successes and challenges experienced in each case. We analyze the processes through which the CECs work with researchers and community leaders to develop place-based community engagement approaches and find that different strategies are called for to fit distinct contexts. We find that alignment of the scale and scope of the environmental health issue and related research project, the capacities and resources of the researchers and community leaders, and the influences of the socio-political environment are critical for understanding and designing effective and equitable engagement approaches. These cases demonstrate that the types and degrees of alignment in community-engaged research projects are dynamic and evolve over time. Based on this analysis, we recommend that CBPR scholars and practitioners select a range of project planning and management techniques for designing and implementing their collaborative research approaches and both expect and allow for the dynamic and changing nature of alignment.

The sensor nodes have limited computation, sensing, communication capabilities and generally operated by batteries in a harsh atmosphere with non-replenish able power sources. These limitations force the sensor network subject to failure because most of the energy is spent on sensing, computing and data transmission. This paper introduces an Energy Efficient Clustering and Shortest-Path Routing Protocol (EECSRP) to assist Wireless Sensor Networks (WSNs) by (a) extending the lifespan of the network (b) effectively using the battery power (c) decreasing the network overhead and (d) ensuring a high packet transmission ratio with minimal delay. The delay time-based Cluster Head (CH) is elected based on the node degree, residual energy and Received Signal Strength (RSS) to accomplish the goal. Additionally, the RSS-based network partitioning is implemented to evaluate the gradient based on demand routing between source (sensing node) and destination (BS). Whenever the current CH residual energy goes under the threshold level, the proposed protocol performs the clustering process, reducing the exchange of control packets. However, the BS periodically gathers the data from every single CH which helps to reduce the collision and Medium Access Control (MAC) layer conflict. From the simulation results, it is the evident that the proposed protocol performance in terms of average end-to-end latency, packet delivery ratio, average energy consumption and control overhead is better than the well-known current protocols.

This study presents a path planning method for a mobile robot to be effectively operated through a multi-objective decision-making problem. Specifically, the proposed Fuzzy analytic hierarchy process (FAHP) determines an optimal position as a sub-goal within the multi-objective boundary. The key features of the proposed FAHP are evaluating the candidates according to the fuzzified relative importance among objectives to select an optimal solution. In order to incorporate FAHP into path planning, an AHP framework is defined, which includes the highest level (goal), middle level (objectives), and the lowest level (alternatives). The distance to the target, robot’s rotation, and safety against collision between obstacles are considered as objective functions. Comparative results obtained from the artificial potential field and AHP/FAHP simulations show that FAHP is much preferable for the mobile robot’s path planning than typical AHP.

This study assessed bio-equivalence of high-quality, plant-based protein blends versus Whey Protein Isolate (WPI) in healthy, resistance-trained men. The primary endpoint was incremental area under the curve (iAUC) of blood essential Amino Acids (eAAs) 4 hours after consumption of each product. Cmax and Tmax of blood leucine were secondary outcomes. Subjects (n=18) consumed three plant-based protein blends and WPI (control). Analysis of Variance model was used to assess for bio-equivalence of total sum of blood eAA concentrations. The total blood eAA iAUC ratios of the three blends were: [90% CI]: #1: 0.66 [0.58-0.76]; #2: 0.71 [0.62-0.82]; #3: 0.60 [0.52-0.69], not completely within the pre-defined equivalence range [0.80-1.25], indicative of 30-40% lower iAUC versus WPI. Leucine Cmax of the three blends was not equivalent to WPI, #1: 0.70 [0.67-0.73]; #2: 0.72 [0.68-0.75]; #3: 0.65 [0.62 – 0.68], indicative of a 28-35% lower response. Leucine Tmax for two blends were similar to WPI (#1: 0.94 [0.73-1.18]; #2: 1.56 [1.28-1.92]; #3: 1.19 [0.95-1.48]). The plant-based protein blends were not bio-equivalent. However, blood leucine kinetic data across the blends approximately doubled from fasting concentrations whereas blood Tmax data across two blends was similar to WPI. This suggests evidence of rapid hyperleucinemia, which correlates with a protein’s anabolic potential.

Failure of various weight-loss programs and long-term maintenance of favorable body composition in all kinds of people is high, since the majority go back to old dietary patterns. Many studies have documented the efficacy of a plant-based diet (PBD) for body mass management, but there are opinions that maintaining a PBD is difficult. We aimed to evaluate the long-term success of a whole-food plant-based (WFPB) lifestyle program. We investigated the differences in the obesity indices and lifestyle of 151 adults (39.6 ± SD 12.5 years), who were on our program for short (0.5–<2 years), medium (2–<5 years), or long term (5–10 years). Body-composition changes were favourable for all three groups, both genders and all participants. There were no differences in relative body-composition changes (BMI, body fat percentage and muscle mass index (MMI)) between the three groups. All participants improved their BMI (baseline mean pre-obesity BMI range (kg/m²): 26.4 ± 5.6 to normal 23.9 ± 3.8, p < 0.001), decreased body mass (–7.1 ± 8.3 kg, p < 0.001) and body fat percentage (–6.4 ± 5.6 % points, p < 0.001). Those with the highest BMI at baseline lost the most of: a) BMI units, b) total body mass and c) body fat (a) (kg/m²) (–5.6 ± SD 2.9, –2.4 ± 1.8 and –0.9 ± 1.5), b) (kg) (–16.1 ± SD 8.8, –7.1 ± 5.4 and –2.5 ± 4.5) and c) (% points) (–9.5 ± SD 5.7, –6.6 ± 4.6 and –4.7 ± 5.3) for participants who had baseline BMI in obese, overweight and normal range, respectively; p_{baseline vs. current} < 0.001 for all). 85.6% (101 out of 118) of parents of underage children (< 18 years), introduced WFPB lifestyle to their children. WFPB lifestyle program provides long-term lifestyle changes for reversal of obesity and is effective transferred to the next generation.

Aquaporin-3 (AQP3) is one of the aquaglyceroporins, which is expressed in the basolateral layer of the skin membrane. Studies have reported that human skin squamous cell carcinoma overexpresses AQP3 and inhibition of its function may alleviate skin tumorigenesis. In the present study, we have applied a virtual screening method that encompasses filters for physicochemical properties and molecular docking to select potential hit compounds that bind to the Aquaporin-3 protein. Based on molecular docking results, the top 20 hit compounds were analyzed for stability in the binding pocket using unconstrained molecular dynamics simulations and further evaluated for binding free energy. Furthermore, examined the ligand-unbinding pathway of the inhibitor from its bound form to explore possible routes for inhibitor approach to the ligand-binding site. With a good docking score, stability in the binding pocket, and free energy of binding, these hit compounds can be developed as Aquaporin-3 inhibitors in the near future.

Public access to high quality green environments has become a key issue for city managers and a matter of environmental justice. Remnants of natural ecosystems allow citizens a direct contact with nature, but conversely the presence of people contributes further to the existing disturbances. Urban pressures on ecosystem remnants may act to favour the expansion of some invasive species in cities. Whilst the negative impacts of invasive species on ecosystem function is well documented little is known how invasive species influence the use of green spaces by people. Here, we examined one of the few remnants of urban riparian forests in Europe, the Vistula river valley in Warsaw which has recently become an attractive recreation site. Despite their high ecological value, the poplar and willow forests have been increasingly taken over by the invasive tree species Acer negundo. We examined the status of the invasion process and the relationship between recreational ecosystem services and the characteristics of the tree stands – tree species, tree density and age and NDVI values. We found the willow forest to be more susceptible to invasion by A. negundo than the poplar forest, which was revealed in significantly higher share of the maple individuals and their greater volume per unit area. Presence of A. negundo affected biodiversity resulting in decreased undergrowth density and number of species. The use intensity by the public, assessed on the basis of trampling intensity and the density of existing informal tracks, were negatively correlated to the presence of A. negundo. This study highlights the need to integrate invasive species management into green infrastructure planning and management.

This study aimed to evaluate the impact of selected pregnancy pathologies statistically depending on overweight/obesity and excessive maternal weight gain during pregnancy on women who gave birth in the years 2013–2015 at the Second Department of Gynecology and Obstetrics at the University Hospital in Bratislava, Slovakia. In a retrospective study, we analyzed data gathered from the sample, which consisted of 7,122 women. Our results indicate a positive statistical dependency of the groups of women with overweight and obesity and gestational hypertension (adjusted odds ratio [AOR]=15.3; 95% CI 9.0−25.8 for obesity), preeclampsia (AOR=3.4; 95% CI 1.9−6.0 for overweight and AOR=13.2; 95% CI 7.7−22.5 for obesity), and gestational diabetes mellitus (AOR=1.9; 95% CI 1.2−2.9 for overweight and AOR=2.4; 95% CI 1.4−4.0 for obesity). A higher incidence of pregnancies terminated by cesarean section was observed in the group of obese women. Gestational weight gain above the IOM (the Institute of Medicine) recommendations was associated with a higher risk of pregnancy terminated by C-section (AOR=1.2; 95% CI 1.0−1.3), gestational hypertension (AOR=1.7; 95% CI 1.0−2.7), and infant macrosomia (AOR=1.7; 95% CI 1.3−2.1). Overweight and obesity during pregnancy significantly contribute to the development of pregnancy pathologies and increased incidence of cesarean section. Systematic efforts to reduce weight before pregnancy through pre-pregnancy dietary counseling, regular physical activity, and healthy lifestyle should be the primary goal.

Research on bidirectional human-machine interfaces will enable the smooth interaction with robotic platforms in contexts ranging from industry to tele-medicine and rescue. This paper introduces a bidirectional communication system to achieve multisensory telepresence during the gestural control of an industrial robotic arm. We complement the gesture-based control by means of a tactile-feedback strategy grounding on a spiking artificial neuron model. Force and motion from the robot are converted in neuromorphic haptic stimuli delivered on the user’s hand through a vibro-tactile glove. Untrained personnel participated in an experimental task benchmarking a pick-and-place operation. The robot end-effector was used to sequentially press six buttons, illuminated according to a random sequence, and comparing the tasks executed without and with tactile feedback. The results demonstrated the reliability of the hand tracking strategy developed for controlling the robotic arm, and the effectiveness of a neuronal spiking model for encoding hand displacement and exerted forces in order to promote a fluid embodiment of the haptic interface and control strategy. The main contribution of this paper is in presenting a robotic arm under gesture-based remote control with multisensory telepresence, demonstrating for the first time that a spiking haptic interface can be used to effectively deliver on the skin surface a sequence of stimuli emulating the neural code of the mechanoreceptors beneath.

Educating for Sustainability involves promoting sustainable competences in students. Not in vain, wider societal changes that ensure a balance between economic growth, respect for the environment and social justice must start with individual actions, implying knowledge, capacity and willingness to act. However, and although there is wide consensus that education should promote the development of competences for life, putting this theoretical tenet into may entail more problems. Competence is most often expressed in general terms without a specific definition of the intervening elements (knowledge, skills, values, attitudes), which may collide with the necessity of teachers – as learning planners - concrete entities on which to base their process of design. So that, in this work we propose a series of indicators that serve to characterize the four dimensions of scientific competence – contents of science, contents about science, value of science and utility of science-. Although they are primarily intended to be used to filter multimedia resources in an educational platform, this proposal of indicators can be extrapolated to the management and selection of a variety of resources and activities, and for sharing the objectives and evidences for the acquisition of competencies.

Vanadium titano-magnetite is a significant resource in China, and in this study, we characterize its isothermal reduction mechanisms in the mixture of H₂, CO, and N₂ where the variables considered here include reduction time, reduction temperature, gas composition, and pellet size. The kinetics of the reduction process are mainly studied, which follows a shrinking core model. The results indicate that the reduction degree of oxidized VTM pellets increases with the increase of reduction time, reduction temperature but decreases with the increase of pellet size. Moreover, we found that an increase of H₂/(H₂+CO) ratio induces an increase of the reduction degree. Then the transformation of main Ti-bearing mineral phases is discussed, and the most probable reaction mechanism is revealed. In the whole reduction process, the kinetic results confirm the existence of an early stage and a latter stage, which are controlled by interface chemical reaction and diffusion, respectively. Furthermore, the results show that the diffusion-control step can be observably shortened with the decrease of pellet size because a thinner product layer is formed during the reduction process. Our study thus provides a valuable technical basis on the VTM industrial application.

Low carbon cities are increasingly forming a distinct strand of sustainability literature. Models have been developed to measure the performance of low carbon cities. The purpose of this paper is to formulate a strategy-based model to evaluate current performance and predict future conditions of low carbon cities. It examines the dynamic interrelationships between key performance indicators (KPIs), induces changes to city plan targets and then instantly predicts the outcome of these changes. Designed generic and flexible, the proposed model shows how low carbon targets could be used to guide the transformation of low carbon cities under four strategies: (1) passive intervention, (2) problem solving, (3) trend modifying and (4) opportunity seeking. Further, the model has been applied to 17 cities and then tested on 5 cities: London, New York, Barcelona, Dubai and Istanbul. The paper concludes with policy implications to realign city plans and support low carbon innovation.

"The wisdom of crowd'' is so often observed in social discourses and activities around us. The manifestations of it are, however, so intrinsically embedded and behaviorally accepted that an elaboration of a social phenomenon evidencing such wisdom is often cheered as a discovery; or at least an astonishing fact. One such scenario is explored here, namely conceptualization and modeling of a food safety system, a system directly related to social cognition. Food safety is an area of concern these days. Models representing the food safety systems are recently published to study the effect of interactions between important entities of the system. For example, Knowles’s model finds conditions leading to a more efficient and dependable system of entities like consumers, regulators and stores with specific focus on regulators behavior and their impact on the food safety. The first contribution of this paper is reevaluation of Knowles’s model towards a more conscious understanding of ``the wisdom of crowd'' effects on inspection and consuming behaviors. The second contribution is augmenting of the model with social networking capabilities, which acts as a medium to spread information about stores and help consumers find stores which are not contaminated. Simulation results reveal that stores’ respecting social cognition improve effectiveness of the food safety system for consumers and stores both. Simulation findings also reveals that an active society has a capability to self-organize effectively even in the absence of any regulatory compulsion.

Intersectoral and intermunicipal cooperation are still underdeveloped spheres of public and economic development policies. Academic discussions are invariably focused on pro-competitive activities, the economic efficiency of which is not always sufficient. In this paper the authors attempt to identify factors leading to cooperation between local government authorities and economic entities, focusing on examples from the forest and wood-based sector in Poland. These processes are analysed in the framework of the New Institutional Economy, both in the theoretical and practical context.

Efficient member revocation and strong security against attacks are prominent requirements in group signature schemes. Among the revocation approaches Verifier-local revocation is the most flexible and efficient method since it requires to inform only the verifiers regarding the revoked members. The verifier-local revocation technique uses a token system to manage members’ status. However, the existing group signature schemes with verifier-local revocability rely on weaker security. On the other hand, existing static group signature schemes rely on a stronger security notion called, full-anonymity. Achieving the full-anonymity for group signature schemes with verifier-local revocation is a quite challenging task. This paper aims to obtain stronger security for the lattice-based group signature schemes with verifier-local revocability, which is closer to the full-anonymity. Moreover, this paper delivers a new key-generation method which outputs revocation tokens without deriving from the users’ signing keys. By applying the tracing algorithm given in group signature schemes for static groups, this paper also outputs an efficient tracing mechanism. Thus, we deliver a new group signature scheme with verifier-local revocation that satisfies a stronger security from lattices.

In this article, management control has been studied from the perspective of intention towards sustainable development of companies. The main idea focuses on the analysis of relations between sustainable management control and the system of performance appraisal using as a reference the resource-based theory. These relations have been assessed both theoretically by reviewing literature in the field, and empirically based on data collected in a questionnaire from top management, as well as data from Annual Reports from the main segment of Bucharest Stock Exchange. The authors have shown that financial performance has a significant influence on management control, and the return on capital employed is one of the most recommended indicators. The sustainable nature attributed to management control is the result of institutional theory evolution, provisions of Directive 2014/95/EU and Guide of Global Management Accounting Principles (2015) using stewardship. Consequently, profits are not the main element any more in the assessment of financial „health” of a company. To ensure the sustainable success, sustainable balanced scorecard is one of real measures for managing financial and non-financial performance.

Modern mobile devices are replete advanced sensors that expand the array of possible methods of locating users. This is often viewed in a positive light, as a tool to gather and use spatial information, but it also brings with it the problem of “geosurveillance” in which the “Location” becomes a product in itself. In the realm of software developers, this has been reduced and discretized to a set of coordinates, devoid of human experiences and meanings. To function in such digitally augmented realities, people need to adopt specific attitudes, often accompanied with anxiety. We explored attitudes toward locational data collection practices using questionnaire surveys (n = 280) from Poznan and Edinburgh. The prevailing attitude is neutral with a strong undertone of resignation, in which surrendering personal locational information is viewed as a digital currency. A smaller number of people had stronger, emotional views, either very positive or very negative, based on uncritical technological enthusiasm or fear of privacy violation. Such a wide spectrum of attitudes is not only produced by interaction with technology but can also be viewed as a result of different perceptions and values associated with space and place itself.

Orbit and clock products are used in real-time GNSS precise point positioning without knowing their quality. This study develops a new approach to detect orbit and clock errors through comparing geometry-free and geometry-based wide-lane ambiguities in PPP model. The reparameterization and estimation procedures of the geometry-free and geometry-based ambiguities are described in detail. The effects of orbit and clock errors on ambiguities are given in analytical expressions. The numerical similarity and differences of geometry-free and geometry-based wide-lane ambiguities are analyzed using different orbit and clock products. Furthermore, two types of typical errors in orbit and clock are simulated and their effects on wide-lane ambiguities are numerically produced and analyzed. The contribution discloses that the geometry-free and geometry-based wide-lane ambiguities are equivalent in terms of their formal errors. Although they are very close in terms of their estimates when the used orbit and clock for geometry-based ambiguities are precise enough, they are not the same, in particular, in the case that the used orbit and clock, as a combination, contain significant errors. It is discovered that the discrepancies of geometry-free and geometry-based wide-lane ambiguities are coincided with the actual time-variant errors in the used orbit and clock at the line-of-sight direction. This provides a quality index for real-time users to detect the errors in real-time orbit and clock products, which potentially improves the accuracy of positioning.

The software industry has adopted component-based software development (CBSD) to rapidly build and deploy large and complex software systems with significant savings at minimal engineering effort, cost, and time. However, CBSD encounters issues on security trust, mainly with respect to dependability attributes. A system is considered dependable when it can produce the outputs for which it was designed with no adverse effect on its intended environment. Dependability consists of several attributes that imply availability, confidentiality, integrity, reliability, safety, and maintainability. Dependability attributes must be embedded in a CBSD model to develop dependable component software. Motivated by the importance of these attributes, this paper pursues two objectives: to design a model for developing a dependable system that mitigates the vulnerabilities of software components, and to evaluate the proposed model. The model proposed in this study is labelled as developing dependable component-based software (2DCBS). To develop this model, the CBSD architectural phases and processes must be framed and the six dependability attributes embedded according to the best practice method. The expert opinion approach was applied to evaluate 2DCBS framing. In addition, the 2DCBS model was applied to the development of an information communication technology (ICT) portal through an empirical study method. Vulnerability assessment tools (VATs) were employed to verify the dependability attributes of the developed ICT portal. Results show that the 2DCBS model can be adopted to develop web application systems and to mitigate the vulnerabilities of the developed systems. This study contributes to CBSD and facilitates the specification and evaluation of dependability attributes throughout model development. Furthermore, the reliability of the dependable model can increase confidence in the use of CBSD for industries.

Objective Hypertension is one of the most common chronic diseases, affecting more than 20 % of the population. The side effects experienced due to antihypertensive medications such as tired-ness, muscle pain, and insomnia are often a significant predictor of poor adherence to therapy. The goal of the current study is to present the frequency, type, seriousness, and severity of adverse drug reactions reported to the BDA via Individual Case Safety Reports (ICSR) and following differentiation of messages found in more than one patient. Methods We conducted a retrospective analysis of the reported adverse drug reactions (ADR) reported in the Bulgarian Drug Agency database after treatment with antihyperlipidemic medicines, angiotensin-converting enzyme (ACE) - inhibitors, and sartans for the period 2017-2021. Each ICSR form was observed and data for suspected medicine and type of adverse reaction was analyzed. Results The total number of processed notifications for adverse drug reactions (ADR) included in the database is 142. The highest number of ADRs was reported for ARB (58), followed by antihyperlipidemic medicines (55) and ACE inhibitors (29.) Most of the assessed adverse events experienced by more than one patient fall into the probable and related categories based on Global Introspection method classification. Therefore, they have been investigated and are consistent with exposure in the population. Conclusion Cardiovascular medicines from the groups of ACE inhibitors, sartans and statins are with high share of reported ADRs in the BDA system. Some of them are severe and need further investigation.

Background and objective: Iliopsoas abscess (IPA) is a rare condition with varied symptomology and etiology. Less than one-third of patients with IPA present on the emergency department (ED) admission with the traditional triad of fever, back pain, and restricted hip motion (or limp), leading to delays in diagnosis and management. This case report aims to bring awareness among healthcare professionals regarding the atypical presentation and introduce a potential differential diagnosis when evaluating patients with fever and back pain. The intention is to provide insights into the signs and symptoms that may indicate the presence of an iliopsoas abscess and prompt additional investigations. Case report: Here, we describe a case of primary iliopsoas abscess associated with drug-induced acute liver failure in our ED. The patient complained of pain in the left lumbar region and fatigue that started two weeks before this presentation, claiming that, during the previous night, the pain suddenly worsened. She had a fever, pain at palpation in the right hypochondriac and left lumbar regions, accompanied by fever and vomiting, jaundiced skin, and sclera at the examination in ED. On abdominal ultrasonography, the diagnosis of acute cholangitis was suspected. The laboratory test shows leukocytosis with neutrophilia, thrombocytosis, hepatocytolysis syndrome, and hyperbilirubinemia with the predominance of indirect bilirubin. We performed then abdominal and pelvic computed tomography, which confirmed the diagnosis of cholelithiasis observed with the diameter of the bile duct within normal limits but also showed an abscess-like collection fused to the interfibrillar level of the left iliopsoas muscle; a diagnosis we most likely would have been missed. After that, the patient was hospitalized in the General Surgery Department, and surgery drainage of the abscess was performed. The patient's evolution was excellent; she was discharged after 11 days. Conclusions: The case presented here exemplifies how iliopsoas abscess, a rare cause of back pain, can quickly go unrecognized, especially in the emergency department. Our experiences will raise awareness among doctors in emergency departments about this uncommon but essential diagnosis. With advancements in diagnostic tools and techniques, we aspire that more cases of iliopsoas abscess will be accurately diagnosed.

Introduction: A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). Material and Methods: The study analysed articles published in JCR journals from 2019 to 2024, including retrospective, prospective, case-control, or cross-sectional studies. It combined MESH and free terms for "Epileptogenesis" and "Neuroinflammation" and included searches for biomarkers previously reported in narrative reviews. Results: The study analysed 243 articles related to epileptogenesis and neuroinflammation, with 356 from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 52 evaluated by authors. 21 articles were included in the qualitative evaluation, including 18 case-control studies, 2 case series, and 1 prospective study. This systematic review provides acceptable support for five biomarkers: TNF-a and some of its soluble receptors (sTNFr2), HMGB1 and TLR-4, CCL2 and IL-33. Discussions: Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control levels of epileptic patients. Their value will be better defined by future studies.

Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor ac-tivity in combination with the commonly used six anticancer drugs namely cyclophosphane, fluorouracil, etoposide, cysplatine, ribomustine with different mechanisms of action was investi-gated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting on the С6 rat glioma model cells.

Among nonsteroidal anti-inflammatory drugs, ibuprofen, diclofenac, and celecoxib have been frequently used in multimodal analgesia. Recent studies challenge the conventional theory that they exhibit activity and toxicity by acting on cyclooxygenase selectively. We compared their membrane interactions that may be associated with analgesic and gastrointestinal toxic effects. Biomimetic membranes suspended in buffers of different pH were prepared with 1-palmitoyl-2-oleoylphosphatidylcholine, sphingomyelin, and cholesterol to mimic neuronal membranes and with 1,2-dipalmitoylphosphatidylcholine to mimic gastrointestinal mucosae. The membrane interactivity was determined by measuring fluorescence polarization. At pH 7.4, the drugs interacted with neuro-mimetic membranes to decrease membrane fluidity at pharmacokinetically-relevant 0.5–100 μM. Celecoxib was most potent, followed by ibuprofen and diclofenac. At pH 4.0 and 2.5, however, the drugs increased the fluidity of 1,2-dipalmitoylphosphatidylcholine membranes at 0.1–1 mM corresponding to gastroduodenal lumen concentrations after administration. Their membrane fluidization was greater at gastric pH 2.5 than at duodenal pH 4.0. Low-micromolar ibuprofen, diclofenac, and celecoxib structure-specifically decrease neuronal membrane fluidity, which hypothetically could affect signal transmission of nociceptive sensory neurons. Under gastroduodenal acidic conditions, high-micromolar ibuprofen, diclofenac, and celecoxib induce fluidity increases of membranous phosphatidylcholines that are hypothetically associated with gastrointestinal toxic effects, which would enhance acid permeability of protective mucosal membranes.

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases’ progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop of new, disease-modifying drugs to treat AD and PD, thereby decreasing the social and economic burdens linked to these NDs.

Non-coding RNAs have been described as crucial regulators of gene expression and guards for cellular homeostasis. Some recent papers are focused on vault RNAs, one of the classes of non-coding RNA, and their role in cell proliferation, tumorigenesis, apoptosis, cancer response to therapy, and autophagy, which made them potential therapy targets in oncology. In the human genome, four vault RNA paralogues can be distinguished. They are associated with vault complexes, considered the largest ribonucleoprotein complex. The protein part of these complexes consists of a major vault protein (MVP) and two minor vault proteins (vPARP and TEP1). The name of the complex, as well as vault RNA, comes from the hollow barrel-shaped structure that reminds a vault. Their sequence and structure are highly evolutionary conserved and show many similarities in comparison with different species, but vault RNAs show various roles. Vaults were discovered in 1986, and their functions remained unclear for many years. Although not much is known about their contribution to cell metabolism, it has become clear that vault RNAs are involved in various processes and pathways associated with cancer progression and modulating cell functioning in normal and pathological stages. In this review, we discuss known functions of the human vault RNAs in the context of cellular metabolism, emphasizing processes related to cancer and cancer therapy efficacy.

Sheep’s milk is a significant source of nucleotides monophosphate (NMPs) but can also contain undesirable residues from veterinary drugs, posing a potential human health risk. This study introduces a novel application of 2D-LC, in heart-cutting mode, for the simultaneous determination of nucleotides and veterinary drug residues in sheep’s milk. Two-dimensional liquid chromatography (2D-LC) allows for the separation of these compounds in a single chromatographic run despite their differing physicochemical properties. The proposed method separates six veterinary drug residues and five NMPs in a single injection. The compounds were separated using a C18 reversed-phase column in the first dimension and a Primesep SB analytical column in the second dimension. The method performance was evaluated in terms of linearity range, detection and quantification limits, matrix effects, precision, and accuracy. The results demonstrated good linearity and sensitivity, with quantification limits allowing for the quantification of veterinary drugs at the maximum residue level and nucleotides at typical levels found in milk samples. The method has been successfully applied to the analysis of sheep’s milk samples acquired from local supermarkets, with recoveries within a range of 70-119 % and 82-117 % for veterinary residues and NMPs, respectively.

This study investigated the presence, distribution, and antimicrobial resistance profiles of extend-ed-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in a dairy herd located in Northern Italy. A questionnaire was administered, and the feces of clinically healthy pre-weaned dairy calves, their mothers, and the cows treated for mastitis, waste milk, water, and environmental samples, were collected and inoculated on Chromagar ESBL™ medium. The questionnaire identi-fied several risk factors including administration of waste milk to male calves, lack of routine cleaning of calf feeding and housing equipment, and blanket dry cow therapy. Escherichia coli was identified by MALDI-TOF MS in the feces of 28 of 37 (75.67%) calves, 2 of 3 (66.67%) treated cows, 8 of 14 (57.15%) environmental samples, and the waste milk. Six of 14 (42.85%) environmental samples were also positive for ESBL Acinetobacter baumannii, while all fecal samples were negative. ESBL production was confirmed for all E. coli isolates based on the double disk susceptibility test (DDST), while none were carbapenemase producers. Upon minimal inhibitory concentration (MIC) analysis, all of them showed multiple resistances and were categorized as multi-drug resistant (MDR). This study confirms the widespread presence of MDR, ESBL-E. coli in dairy calves and highlights their diffusion in the farm environment.

Transdermal drug delivery systems (TDDS) are designed to administer a consistent and effective dose of medication through the patient's skin. These pharmaceutical preparations are self-contained, discrete dosage forms designed to be placed topically on intact skin to release the active component at a controlled rate by penetrating the skin barriers. This medication provides a continuous and prolonged administration of a substance at a consistent rate. TDDS, or transdermal drug delivery system, has gained significant attention as a non-invasive method of administering drugs to vulnerable patient populations, such as pediatric and geriatric patients. This approach is considered easy to administer and helps overcome bioavailability issues associated with conventional drug delivery, which can be hindered by poor absorption and metabolism. TDDS has various advantages compared to conventional methods of drug administration. It is less intrusive, more patient-friendly, and can circumvent first-pass metabolism and the corrosive acidic environment of the stomach that happens when medications are taken orally. Multiple methodologies have been devised to augment the transdermal permeability of diverse pharmaceutical substances. Recent advancements in transdermal drug delivery systems have facilitated the precise delivery of medications to the intended site of action by improving the penetration of drugs through the outermost layer of the skin, known as the stratum corneum, resulting in enhanced drug availability throughout the body. This review seeks to provide a concise overview of the several methods employed in the production of TDDS, as well as their evaluation, therapeutic uses, clinical considerations, and current advancements. These advancements have resulted in the development of intelligent, biodegradable, and highly efficient transdermal drug delivery systems.

This narrative review delves into the evolving landscape of fertility preservation techniques with a particular focus on their use in patients undergoing oncology treatment that carries a risk of ovarian insufficiency. Advances in established methods such as cryopreservation of oocytes and embryos are highlighted and the increasing use of gonadotropin-releasing hormone (GnRH) agonists is discussed. The review also addresses the complexities and controversies associated with these approaches, such as the 'flare-up' effect associated with GnRH agonists and the potential of GnRH antagonists to reduce the risk of ovarian hyperstimulation syndrome. Despite advances in fertility preservation, the report highlights the challenges we face, including the need for personalized treatment protocols and management of associated risks. It calls for continued research and collaboration between healthcare professionals to refine these techniques and ultimately improve reproductive outcomes for patients facing the prospect of fertility-impairing treatment.

Recently, nanotechnologies have become increasingly prominent in the field of bone tissue engineering (BTE), offering substantial potential to advance the field forward. These advancements manifest in two primary ways: the localized application of nanoengineered materials to enhance bone regeneration and their use as nano-vehicles for delivering bioactive compounds. Despite significant progress in the development of bone substitutes over the past few decades, it is worth noting that the quest to identify the optimal biomaterial for bone regeneration remains a subject of intense debate. Ever since its initial discovery, poly(lactic-co-glycolic acid) (PLGA) has found widespread use in BTE due to its favorable biocompatibility and customizable biodegradability. This review provides an overview of contemporary advancements in the development of bone regeneration materials using PLGA polymer. The review covers some of PLGA properties with a special focus on modifications of these properties towards bone regeneration. Furthermore, we delve into the techniques for synthesizing PLGA nanoparticles (NPs), the diverse forms in which these NPs can be fabricated, and the bioactive molecules that exhibit therapeutic potential for promoting bone regeneration. Additionally, we addressed some of the current concerns regarding the safety of PLGA NPs, and PLGA-based products available in the market. Finally, we briefly discussed some of the current challenges and proposed some strategies to functionally enhance the fabrication of PLGA NPs towards BTE. We envisage that the utilization of PLGA NP holds significant potential as a potent tool in advancing therapies for intractable bone diseases.

Background Candida auris is an emerging multidrug-resistant fungal pathogen that represents a serious threat to healthcare settings currently. Objective: Its objective was to determine the prevalence of C. auris in the hospital since its initial detection in late 2019. Methods: Using an adapted risk assessment tool, we reviewed the charts. and medical files of all suspected? and confirmed cases of C. auris cases reported at King Khalid University Hospital, Riyadh between November 2019 and December 2022. Anonymized data were retrieved in a pre-established datasheet and analyzed to determine the epidemiological characteristics of C. auris infection in our facility. We established our initial prevalence by age, gender, risk factors, and according to sampling source. Results: Of the 53 confirmed cases positive for C. auris during the study period, 33 (62%) were males. Their ages ranged between 15 and 98; most positive cases occurred in 50 and above. Only one of the confirmed cases was hospital-acquired. All patients had at least one risk factor, and Urine samples yielded the greatest number of positive cases while admission to healthcare facilities constituted the highest risk in our study. Conclusion: Establishing a local prevalence could serve as our baseline/benchmark to compare with regional and international benchmarks.

Drug-target affinity (DTA) prediction is crucial for understanding molecular interactions and aiding drug discovery and development. While various computational methods have been proposed for DTA prediction, their predictive accuracy remains limited, failing to delve into the structural nuances of interactions. With increasingly accurate and accessible structure prediction of targets, we developed a novel deep learning model, named S2DTA, to accurately predict DTA by fusing sequence and structural knowledge of drugs, targets, and pockets using heterogeneous models based on graph and semantic networks. Experimental findings underscored that complex feature representations imparted negligible enhancements to the model’s performance. However, the integration of heterogeneous models demonstrably bolstered predictive accuracy. In comparison to three state-of-the-art methodologies, the supremacy of S2DTA became strikingly apparent. It showcased a noteworthy 25.2% reduction in Mean Absolute Error (MAE) and an impressive 20.1% decrease in Root Mean Square Error (RMSE). Furthermore, S2DTA exhibited substantial advancements in other pivotal metrics, including Pearson Correlation Coefficient (PCC), Spearman, Concordance Index (CI), and R2. These metrics experienced remarkable increments of at least 19.6%, 17.5%, 8.1%, and a remarkable 49.4%, respectively. Finally, we conducted interpretability analysis on the effectiveness of S2DTA by bidirectional self-attention mechanism, fully proving that S2DTA is a valuable and accurate tool for predicting DTA. For further exploration, the source data and code repository can be accessed at https://github.com/dldxzx/S2DTA.

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.

The emergence of drug-resistant strains of M. tuberculosis (Mtb) and the phenomenon of phe-notypic tolerance to drugs challenge the goal of tuberculosis (TB) elimination worldwide. By using the ex vivo cultures of alveolar macrophages obtained from lung tissues of TB patients after intensive antimicrobial chemotherapy before surgery, different subpopulations of multi-drug-tolerant Mtb with a spectrum of phenotypic and growth features were identified in the same TB lesions. Our results indicative of not only passive mechanisms generating nonheritable resistance of Mtb to antibiotics, which are associated mainly with a lack of Mtb growth, but also some active mechanisms of Mtb persistence, such as cell wall and metabolic pathway remod-eling. In one of the subpopulations, non-acid-fast Mtb have undergone significant repro-gramming with the restoration of acid-fastness, lipoarabinomannan expression and replication in host cells of some patients after withdrawal of anti-TB drugs. Our data indicate the universal stress protein Rv2623 as a clinically relevant biomarker of Mtb that have lost acid-fastness in human lungs. The studies of Mtb persistence, dormancy, and resumption and the identification of biomarkers characterizing these phenomena are very important to develop vaccines and drug regimens with the individualized management of patients for overcoming the re-sistance/tolerance crisis in anti-TB therapy.

Objectives: Studies on the association between non-steroidal anti-inflammatory drugs (NSAIDs) and major adverse cardiovascular events (MACE) in the Arabian Gulf are scarce. The aim of this study was to evaluate the association between NSAIDs use and MACE in acute coronary syndrome (ACS) patients in the Arabian Gulf region. Methods: Data was analyzed from 3,007 consecutive patients diagnosed with ACS admitted to 29 hospitals in four Arabian Gulf countries from January 2012 to January 2013 as well as being on prior NSAIDs use during the index admission. MACE included stroke/transient ischemic attacks (TIAs), myocardial infarction (MI), all-cause mortality and readmissions for cardiac reasons. Results: The overall mean age of the cohort was 62 ± 12 years and 9.6% (n = 290) of the patients were on prior NSAID use during the index admission. At 12-months follow-up, after adjusting for confounding factors, those on NSAIDs were significantly more likely to have had MACE (adjusted OR (aOR), 1.89; 95% confidence interval (CI): 1.44-2.48; p < 0.001). Specifically, the higher event rates observed were stroke/TIA (aOR, 2.50; 95% CI: 1.51-4.14; p < 0.001) and readmissions for cardiac reasons (aOR, 2.09; 95% CI: 1.59-2.74; p < 0.001) but not MI (aOR, 1.26; 95% CI: 0.80-1.99; p = 0.320) and all-cause mortality (aOR, 0.79; 95% CI: 0.46-1.34; p = 0.383). Conclusions: NSAIDs use was associated with significant stroke/TIA events as well as readmissions for cardiac reasons. However, NSAIDs were not associated with increased MI or all-cause mortality rates in ACS patients in the Arabian Gulf.

HIV-associated cognitive dysfunction during combination antiretroviral therapy (cART) involves mitochondrial dysfunction, but the impact of contemporary cART on chronic metabolic changes in the brain and in latent HIV infection is unclear. We interrogated mitochondrial function in a human microglia (hμglia) cell line harboring inducible HIV provirus, and in SH-SY5Y cells, after exposure to individual antiretroviral drugs or cART, using the MitoStress assay. cART-induced changes in protein expression, reactive oxygen species (ROS) production, mitochondrial DNA copy number, and cellular iron were also explored. Finally, we evaluated the ability of ROS scavengers or plasmid-mediated overexpression of the antioxidant iron-binding protein, Fth1, to reverse mitochondrial defects. Contemporary antiretroviral drugs, particularly bictegravir, depressed multiple facets of mitochondrial function by 20-30%, with most pronounced effects in latently infected-HIV+ hμglia and SH-SY5Y cells. Latently HIV-infected hμglia exhibited upregulated glycolysis. Increases in total and/or mitochondrial ROS, mitochondrial DNA copy number, and cellular iron accompanied mitochondrial defects in hμglia and SH-SY5Y cells. In SH-SY5Y cells, cART reduced mitochondrial iron-sulfur-cluster-containing supercomplex and subunit expression and increased Nox2 expression. Fth1 overexpression or pre-treatment with N-acetylcysteine prevented cART-induced mitochondrial dysfunction. Contemporary cART impairs mitochondrial bioenergetics in hμglia and SH-SY5Y cells, partly through cellular iron accumulation; some effects differ by HIV latency.

Opium smoking for long hours and over many years is common in Iran, and the Covid-19 pan-demic and false beliefs about the protective effects of that opium against COVID-19 infection has caused the increasing of opium smoking during the pandemic. The aim of this study was to in-vestigate the relationship between non-ergonomic positions of traditional opium smoking in Iran with the occurrence of neck pain and disability, forward head posture and hyperkyphosis. In this cross-sectional and correlation study 120 people who smoke opium were selected based on the inclusion criteria and were interviewed about their addiction profile and evaluated for the pres-ence of pain and disability in the neck by Maudsley Addiction Profile, Leeds Dependence Ques-tionnaire, the Visual Analog Scale and Neck Disability Index. Also, they were evaluated about forward head posture (FHP) through side view photography and hyperkyphosis (HK) through flexible ruler. Data were analyzed by correlation coefficient tests and stepwise linear regression. There was a significant relation between homelessness, the duration of lifetime opium smoking (months), the duration of daily opium smoking (minutes) and drug dependence severity with the severity of neck pain, neck disability, forward head posture and hyperkyphosis. Homelessness is the strongest predictive variable of the possibility of neck pain and disability, FHP and HK, fol-lowed by ‘‘the number of months of opium smoking’’ and ‘‘the number of minutes of opium smoking in one day’’ respectively. Increasing the duration of sitting in non-ergonomic positions can lead to neck pain and disability, FHP and HK due to their non-neutral posture in opium smokers.

Antibiotic resistance has emerged as one of the major concerns to public human health due to issues in treatment and control of major infectious diseases. From discovery of penicillin in 1940, the antibiotic resistance originated and now developed the microorganisms as resistive strains to the major available antibiotics. Furthermore, studies on this captivating activity of the microbes provide insight into the complexities of microbial physiology and may offer some guidance in preventing the onset and consequent development of antibiotic resistance. Despite of initiatives taken in last few decades to overcome the issues, the trends of antibiotic resistance gained much peak. Antibiotic resistance appears to have emerged as a result of various factors including antibiotics being misused and overused in both the medical field and the agricultural sector. Important factors in the development of antibiotic resistance also include bacterial mutation, unplanned evolution, and horizontal gene transfers. In addition, antibiotics resistance imposed the financial consequences to public health and drug development research. Future advancements related to innovative antibiotics and molecular drug designing become challenge for researchers due to intensive multiple antibiotics resistance among human population. Many researches have been conducted on origin, evolutionary aspect of antibiotic resistance and mechanisms of antibiotics resistance, but its effect on future drug development is little understood. Therefore, the recent review will highlight the role of antibiotic resistance in drug designing and impacts of antibiotic resistance on drug development in future.

Unlike plants which have special gravity-sensing cells, such special cells in animals are yet to be discovered. However, microgravity, the condition of apparent weightlessness, causes bone, muscular and immune system dysfunctions in astronauts following spaceflights. Decades of investigations show correlations between these organ and system-level dysfunctions with changes induced at the cellular level both by simulated microgravity as well as microgravity conditions in outer space. Changes in single bone, muscle and immune cells include morphological abnormalities, altered gene expression, protein expression, metabolic pathways and signaling pathways. These suggest that human cells mount some response to microgravity. However, the implications of such adjustments on many cellular functions and responses are not clear. Here, we addressed the question whether microgravity induces alterations to drug response in cancer cells. We used both adherent cancer cells (T98G) and cancer cells in suspension (K562) to confirm known effects of microgravity and then treated the K562 cells with common cancer drugs (hydroxyurea and paclitaxel) following 48 hours of exposure to microgravity via a NASA-developed rotary cell culture system. Fluorescence-guided morphometry revealed microgravity-induced loss of the significant reduction (p &lt; 0.0l) to the nuclear to cytoplasm ratio of cancer cells treated with hydroxyurea. Our results call for more studies on impact of microgravity on cellular drug-response, in view of the growing need for space medicine, as space exploration grows.

Lung cancer is the leading cause of global cancer-related mortality resulting in ~1.8 million deaths annually. Systemic, molecular targeted, and immune therapies have provided significant improvements of survival outcomes for patients. However, drug resistance usually arises and there is an urgent need for novel therapy screening and personalized medicine. 3D patient-derived organoid (PDO) models have emerged as a more effective and efficient alternative for ex vivo drug screening than 2D cell culture and patient-derived xenograft (PDX) models. In this review, we performed an extensive search of lung cancer PDO-based ex vivo drug screening studies. Lung cancer PDOs were successfully established from fresh or biobanked sections/biopsy of lung tumors, PDXs, and pleural affusion. PDOs were subject to ex vivo drug screening with chemotherapy, targeted therapy and immune therapy agents. PDOs mainly recapitulated the genomic alterations, transcriptomic landscape and drug sensitivity of primary tumors. Although sample sizes of the previous studies were limited and some technical challenges remained, PDOs showed promise to screen novel therapy drugs. With the technical advance of high throughput, tumor-on-chip, combined microenvironment, and air-liquid interface (ALI), the drug screening using PDOs would serve better for precision care of lung cancer patients.

(1) Background: The emergence of antibiotic-resistant bacteria is a growing concern in the field of medicine. This has led to the need for alternative treatments for bacterial infections. (2) Methods: The present study aimed to investigate the synergistic effect of a water-based extract of S. fru-tescens and penicillin G on the growth of E. faecalis. (3) Results: The study found that the combina-tion of the plant extract and penicillin G had a synergistic effect on the inhibition of bacterial growth, with a significantly larger inhibition zone observed compared to penicillin G alone. The MIC and MBC tests also demonstrated that the combination of the plant extract and penicillin G was more effective against E. faecalis than penicillin G alone, with a dilution of 1 in 4 yielding 100% inhibition of growth. (4) Conclusion: Although the specific mechanism of action was not dis-cussed in the study, the results suggest that the combination of the plant extract and penicillin G may offer a promising alternative treatment for antibiotic-resistant infections. Further research is needed to determine the active compounds in the plant extract and to investigate the synergistic effect of the combination on other strains of bacteria.

Metformin (MeT) is an FDA-approved drug with a myriad of health benefits. Besides being used as an anti-diabetic drug, MeT is also effective against various cancers, liver-, cardiovascular-, and renal diseases. It has also been proven to demonstrate anti-ageing and neuroprotective effects. This study was undertaken to examine its unique potential as an anti-virulence drug against an opportunistic bacterial pathogen, Pseudomonas aeruginosa. Due to the menace of multidrug resistance in pathogenic microorganisms, many novel or repurposed drugs with anti-virulence prospects are emerging as next-generation therapies with the aim to overshadow the application of existing antimicrobial regimens. The quorum sensing (QS) mechanisms of P. aeruginosa are an attractive drug target for attenuating bacterial virulence. In this context, the anti-QS potential of MeT was scrutinized using biosensor assays. MeT was comprehensively evaluated for its effects on different motility phenotypes, virulence factor production (phenotypic and genotypic expression) along with biofilm development in P. aeruginosa in vitro. At sub-lethal concentrations, MeT displayed prolific quorum quenching (QQ) ability and remarkably inhibited AHL biosynthesis in P. aeruginosa. Moreover, MeT (1/8 MIC) effectively downregulated the expression levels of various QS- and virulence genes in P. aeruginosa, which coincided with a notable reduction in the levels of alginate, hemolysin, pyocyanin, pyochelin, elastase, and protease production. In silico analysis through molecular docking also predicted strong associations between the QS receptors of P. aeruginosa and MeT. MeT also compromised the motility phenotypes and successfully abrogated biofilm formation by inhibiting EPS production in P. aeruginosa. Hence, the QQ, anti-virulence, and anti-fouling potential of MeT was elucidated for the first time against P. aeruginosa.

Because of their high biocompatibility, stability, ability to negotiate biological barrier passage, and functionalization properties, biological nanoparticles have been actively investigated for many medical applications. Biological nanoparticles, including natural extracellular vesicles (EVs) and synthetic extracellular vesicle-mimetic nanovesicles (EMNVs) represent novel drug delivery vehicles that can accommodate different payloads. In this study, we investigated EVs and EMNVs for their physical, biological and delivery properties and we showed that EMNVs have similar delivery properties compared to EVs. In addition, these nanotherapeutics were analyzed for their cytostatic properties in combination with the FDA-approved drug hydroxychloroquine (HCQ), which increased their cytostatic thanks to its lysosome-destabilizing properties. Altogether, these data demonstrated that, at least in vitro, the use of synthetic biomimetic particles is comparable to the natural counterparts, while their synthesis is significantly faster and more cost effective. In addition, we highlighted the benefits of combining biological nanoparticles with a lysosome destabilizing agent that increased the delivery properties of the particles.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis and highlight various ways through which tumor cells reprogram normal cells including into phenotypes that are pro-tumorigenic including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to formation of new vascular networks in order to actively promote and sustain tumor growth via supply of oxygen and nutrients whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to targeting of tumor cells. Re-programming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centred therapies under investigations.

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

The neuroglial extracellular matrix (ECM) provides critical support and physiological cues for the proper growth, differentiation, and function of neuronal cells in the brain. However, in most in vitro settings that study neural physiology, cells are grown as monolayers on stiff surfaces that maximize adhesion and proliferation, and therefore lack the physiological cues that ECM in native neuronal tissues provides. Macromolecular crowding (MMC) is a biophysical phenomenon based on the principle of excluded volume that can be harnessed to induce native ECM deposition by cells in culture. Here, we show that MMC using two species of Ficoll with vitamin C supplementation significantly boosts deposition of relevant brain ECM by cultured human astrocytes. Dopaminergic neurons co-cultured on this astrocyte-ECM bed prepared under MMC treatment showed longer and denser neuronal extensions, a higher number of pre ad post synaptic contacts, and increased physiological activity as evidenced by higher frequency calcium oscillation, compared to standard co-culture conditions. When the pharmacological activity of various compounds was tested on MMC-treated co-cultures, their responses were enhanced, and for apomorphine, a D2-receptor agonist, it was inverted in comparison to control cell culture conditions, thus emulating responses observed in in vivo settings. These results indicate that macromolecular crowding can harness the ECM-building potential of human astrocytes in vitro forming an ultra-flat 3D microenvironment that makes neural cultures more physiological and pharmacological relevant.

Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress, decreased phagocytic activity, and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory drug developed for treating atopic dermatitis and known to inhibit toll-like receptor 4, on light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once a day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 protected against this decrease in retinal thickness and increase in ERG am-plitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregu-lation of C-C motif chemokine 2　by LPS stimulation was significantly inhibited by SIG-1451 treatment, and western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 protects photoreceptor cells by attenuating light damage progression through inhibiting inflammatory responses.

The purpose of this work was to evaluate the suitability of recent US Food and Drug Administration (US-FDA) approved and marketed oral liquid, powder, or granule products for children in North America, to identify the next group of Active Pharmaceutical Ingredients (APIs) that have high potential for development as commercially available FDA-approved finished liquid dosage forms , and to propose lists of compounded nonsterile preparations (CNSPs) that should developed as commercially available FDA-approved finished liquid dosage forms as well as those that pharmacists should continue to compound extemporaneously. Through this identification and categorization process, the pharmaceutical industry, government, and the professions are encouraged to continue to work together to improve the likelihood that patients will receive high quality standardized extemporaneous CNSPs and US-FDA-approved products.

Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient’s serum were cloned into the replication-competent HBV 1.2mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.

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.

Tuberculosis (TB) remains a global healthcare crisis with an estimated 10 million new cases and 1.4 million deaths per year TB is caused by infection with the major human pathogen Mycobacte-rium tuberculosis, which is difficult to rapidly diagnose and treat. There is an urgent need for new methods of diagnosis, sufficient in vitro models which capably mimic all physiological condi-tions of the infection, and high-throughput drug screening platforms. Microfluidic-based tech-niques provide single-cell analysis which reduces experimental time, the cost of reagents, and have been extremely useful for gaining insight into monitoring microorganisms. This review out-lines the field of microfluidics and discusses the use of this novel technique so far in M. tuberculo-sis diagnostics, research methods, and drug discovery platforms. The practices of microfluidics have promising future applications for diagnosing and treating TB.

Despite identical genetic constitution, a cancer cell population can exhibit phenotypic variations termed as non-genetic/non-mutational heterogeneity. Such heterogeneity – a ubiquitous nature of biological systems – has been implicated in metastasis, therapy resistance and tumour relapse. Here, we review the evidence for existence, sources and implications of non-genetic heterogeneity in multiple cancer types. Stochasticity/ noise in transcription, protein conformation and/or external microenvironment can underlie such heterogeneity. Moreover, the existence of multiple possible cell states (phenotypes) as a consequence of the emergent dynamics of gene regulatory networks may enable reversible cell-state transitions (phenotypic plasticity) that can facilitate adaptive drug resistance and higher metastatic fitness. Finally, we highlight how computational and mathematical models can drive a better understanding of non-genetic heterogeneity and how a systems-level approach integrating mathematical modelling and in vitro/in vivo experiments can map the diverse phenotypic repertoire, and identify therapeutic vulnerabilities of an otherwise clonal cell population.

This research aims to find out whether the synthetic 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with Candida albicans. Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a We are interested in using molecular docking and molecular dynamics modelling to investigate the interaction between the derivatives of 1, 2, 4-triazine and the resulting lanosterol 14 - demethylase (CYP51) of Candida albicans The inhibition of Candida albicans CYP51 is the main goal of our research. The 1, 2, 4-triazine and its derivatives have been docked to the CYP51 enzyme, which is involved in Candida albicans Multidrug Drug Resistance (MDR). Autodock tools were used to identifying the binding affinities of molecules against the target proteins. Compared to conventional fluconazole, the molecular docking results indicated that each drug has a high binding affinity for CYP51 proteins and forms unbound interactions and hydrogen bonds with their active residues and surrounding allosteric residues. The docking contacts were made using a 10 ns MD simulation with nine molecules. RMSD, RMSF, hydrogen bonds, and the Rg all confirm these conclusions. In addition, these compounds were expected to have a favorable pharmacological profile and low toxicity. The compounds are being offered as scaffolds for the development of new antifungal drugs and as candidates for future in vitro testing.

Transplant of human cancer cells into zebrafish larvae has emerged as a useful methodology in cancer research. Zebrafish have very low husbandry costs, are amenable to large-scale drug screening, and are unmatched for optical clarity in live animal imaging. However, there is currently no consensus on the ideal methods for xenograft of human cancer cells into zebrafish. Here, we have examined the effects of transplant site and housing temperature on both zebrafish larvae and human cancer cells using survival analyses, metabolomic approaches, and in vivo imaging. Our data show that while zebrafish larvae can adapt to the ideal conditions for mammalian cells, human cancer cells are highly sensitive to both temperature change and transplant site. Human cells housed in slightly cooler than physiologic temperatures had a significantly altered metabolism that resulted in changes in growth, survival, and response to chemotherapy. Cancer cells xenografted into the yolk of the larvae also had reduced proliferation and drug response compared to those xenografted into the soma, in part due to the differences in metabolites available at these sites. In total, temperature and transplant site can have profound effects on xenografted cells. Standardization of zebrafish xenograft methods will enhance data reproducibility between individual laboratories.

Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp) currently being used to manage COVID-19 in several countries. By acting as a substrate for RdRp, favipiravir gets incorporated into the nascent viral RNA and prevents strand extension. A high mutation rate of SARS-CoV-2 RdRp may facilitate antigenic drift as an answer to the host immune response, thereby generating resistance of virus to favipiravir. Therefore, it is extremely crucial to predict potential mutational sites in the RdRp and the emergence of structural modifications contributing to drug resistance. Here, we used high-throughput interface-based protein design to generate >100,000 designs and identify mutation hotspot residues in the favipiravir-binding site of RdRp. Several mutants had lower binding affinities to favipiravir, out of which hotspot residues with a high propensity to undergo positive selection were identified. The results showed that the designs retained an average of 97 to 98% sequence identity, suggesting that SARS-CoV-2 can develop favipiravir resistance with just a few mutations. Notably, we observed that out of 134 mutations predicted designs, 63 specific mutations were already present in the CoV-GLUE database, thus attaining ~47% correlation match with the clinical sequencing data. The findings improve our understanding of the potential signatures of adaptation in SARS-CoV-2 against favipiravir and management of COVID-19. Furthermore, they can help develop exhaustive strategies for robust antiviral design and discovery.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the chief concern of the international community in almost no time. As of May 9th, 2021, more than 150 million cases and 3.2 million deaths have been recorded. Considering the early struggle in treating COVID-19 patients, the researchers and clinicians have decided to try the previously available drugs according to their mechanisms of action. Hence, many antivirals, antibiotics, antiparasitics, and antipyretics have been proposed. Pregnant women, fetuses, and infants are known high-risk populations that are threatened during disease outbreaks. Therefore, this article reviews the safety of potential drugs for COVID-19 patients during pregnancy and breastfeeding.

One of the most used markers of cancer stem cells in several cancers, including colorectal cancer and breast cancer, is CD44. CD44 is a glycoprotein that traverses the cell membrane and binds to many ligands including hyaluronan resulting in activation of signaling cascades. Several reports have shown conflicting data on the expression of CD44 and that the expression depends on modes of investigations and subtypes of cancers. In addition, the correlation between CD44 expression and drug resistance, immune infiltration, EMT, metastasis and patients prognosis in several cancer types remains unclear. This study investigated CD44 expression in several cancers and explored its relationship with tumorigenesis using various publicly available databases, including The Cancer Genome Atlas, GEPIA, Oncomine, Genomics of Drug Sensitivity in Cancer and Tumor Immune Estimation Resource. Our analysis reveals that CD44 is differentially expressed in different cancers. CD44 expression is significantly associated with cancer patients’ survival in gastric, pancreatic and colorectal cancers. In addition, CD44 expression is closely linked with immune infiltration and immune suppressive features in pancreatic, colon adenocarcinoma and stomach cancer. High CD44 expression was significantly correlated with the expression of drug resistance-, EMT- and metastasis- linked genes. Tumors expressing high CD44 have higher mutation burden and afflict older patients than tumors expressing low CD44. Cell lines expressing high CD44 are more resistant to anti-cancer drugs compared to those expressing low CD44. Protein-protein interaction investigations and functional enrichment analysis showed that CD44 interacts with gene products related to cell-substrate adhesion, migration, platelet activation, and cellular response to stress. KEGG pathway analysis revealed that these genes play key roles in biological adhesion, cell component organization, locomotion, G-α-signaling and the response to stimulus. Overall, this investigation reveals that CD44 play significant roles in tumorigenesis, can be used as a prognostic biomarker in several cancers and can be therapeutically targeted in cancer therapy.

Neuroscience is a vast discipline that deals with the anatomy, biochemistry, molecular biology, physiology and pathophysiology of central and peripheral nerves. Advances made through basic, translational, and clinical research in the field of neuroscience have great potential for long-lasting and beneficial impacts on human health. The emerging field of biological therapy is intersecting with the disciplines of neuroscience and rheumatology, creating new horizons for interdisciplinary and applied research. Biological drugs, growth factors, neuropeptides and monoclonal antibodies are being developed and tested for the treatment of painful arthritic and rheumatic diseases. This concise communication focuses on the solutions provided by the fields of neuroscience and neuroimmunology for real-world clinical problems in the field of rheumatology, focusing on synovial joint pain and the emerging biological treatments that specifically target pathways implicated in osteoarthritis pain in peripheral nerves.

The outbreak of novel Coronavirus (SARS-COV-2 ) disease (COVID-19) in Wuhan has attracted worldwide attention. SARS-COV-2 known to share a similar clinical manifestation that includes various symptoms such as pneumonia, fever, breathing difficulty, and in particular, SARS-COV-2 also causes a severe in ammation state that leads to death. Consequently, massive and rapid research growth has been observed across the globe to elucidate the mechanisms of infections and disease progression in genotype and phenotype scale. Data Science is playing a pivotal role in in-silico analysis to draw hidden and novel insights about the SARS-COV-2 origin, pathogenesis, COVID-19 outbreak forecasting, medical diagnosis, and drug discovery. With the availability of multi-omics, radiological, biomolecular, and medical data urges to develop novel exploratory and predictive models or customise exiting learning models to t the current problem domain. The presence of many approaches generates the need for the systematic surveys to guide both data scientists and medical practitioners. We perform an elaborate study on the state-of-the-art data science method ologies in action to tackle the current pandemic scenario. We consider various active COVID-19 data analytics domains such as phylogeny analysis, SARS-COV-2 genome identication, protein structure prediction, host-viral protein interactomics, clinical imaging, epidemiological analysis, and most importantly (existing) drug discovery. We highlight types of data, their generation pipeline, and the data science models in use. We believe that the current study will give a detailed sketch of the road map towards handling COVID-19 like situation by leveraging data science in the future. We summarise our review focusing on prime challenges and possible future research directions .

Since its introduction, the Triangulation number has been the most successful and ubiquitous scheme for classifying spherical viruses. However, despite its many successes, it fails to describe the relative angular orientations of proteins, as well as their radial mass distribution within the capsid. It also fails to provide any insight into critical sites of stability, modifications or possible mutations. We show how classifying spherical viruses using icosahedral point arrays, introduced by Keef and Twarock, unveils new geometric rules and constraints for understanding virus stability and key locations for exterior and interior modifications. We present a modified fitness measure which classifies viruses in an unambiguous and rigorous manner, irrespective of local surface chemistry, steric hinderance, solvent accessibility or triangulation number. We then utilize these point arrays to explain the immutable surface loops of bacteriophage MS2, the relative reactivity of surface lysines in CPMV and the non-quasiequivalent flexibility of the HBV dimers. We explain how using sister and double point arrays can function as predictive tools for site directed modifications in other systems. This success builds on our previous work showing that viruses place their protruding features along the great circles of the asymmetric unit, demonstrating that viruses indeed adhere to these geometric constraints.

Background: Accurate prediction of patients’ response to therapy is clinically indispensable, howbeit challenging. With increased understanding of the human genome and malignancies, there is the renaissance of in silico pharmacogenomics with renewed interest in drug response predictability based on gene-drug interaction. Objective: Evidence-based transcript-proteome profiling is essential for synthesizing clinically applicable algorithms for predicting response to anticancer therapy, including immune checkpoint blockade (ICBT); thus, saving physicians’ time, reducing polypharmacy, and curtailing unnecessary treatment expense. In this study, we tested and validated the hypothesis that a selected proteomic signature in ICBT-naïve patients is sufficient for the prediction of response to ICBT. Methods: Using a multimodal approach consisting of computational pharmacogenomics, transcript-proteome analytics, mathematical modeling, and machine learning systems; we delineated therapy-sensitivity and stratified patients into graduated response groups based on their proteomic profile. Protein expression levels in our cohort tissue specimens were evaluated based on T cell- and non-T cell- inflamed phenotypes by immunohistochemistry. Results: We established β-catenin, PDL1, CD3 and CD8 expression-based ICBT response model. Statistical regression models validated the predictive association between our predefined algorithms and therapeutic outcome. Interestingly, our 4-gene prediction classifier was constitutively independent of tumor tissue origin, correctly stratified patients into high-, low-, and non- responders pre-treatment, with high prediction accuracy, and exhibited good association with patients’ performance status and prognosis (p < 0.01). Conclusion: Our findings demonstrate the possibility of accurate proteomics based ICBT response prediction and provide a putative basis for drug response prediction based on selective proteome profile in untreated cancer patients.

The release profiles of methotrexate, an anticancer drug, from the monoolein liquid crystalline cubic phases were studied. The cubic phases were used either in the form of a lipidic film deposited onto a glassy carbon electrode surface or in the dispersed form of magnetocubosomes, which are considered a prospective hybrid drug delivery system. Commonly, cubosomes or liposomes are employed, but not in the case of toxic methotrexate, known to block receptors responsible for folate transport into the cells. The release profiles of the drug from the lipidic films were monitored electrochemically and described using the Higuchi model. They were also modified via changes in temperature; the release was faster, although deviating from the model when the temperature was increased. Magnetocubosomes - cubic phase nanoparticles containing hydrophobic magnetic nanoparticles placed in an alternating magnetic field of low frequency and amplitude, stimulated drug release from the suspension, which was monitored spectroscopically. These new biocompatible hybrid materials are very promising, allowing to control the release of the drug at the appropriate sites, but do require further investigations into their in vitro cytotoxicity and in vivo biodistribution.

Owing to the complexity of neurodegenerative diseases, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted nanoemulsion) are available. Versatile small-molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly SR-BI), making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such LCM substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.

A review of different modelling techniques, specifically in the framework of carbon-based nanomaterials (CNMs, including nanoparticles as graphene and carbon nanotubes - CNTs) and the composites and devices that can be derived from them, is presented. The article highlights the multiscale nature of these types of materials and systems, which require different approaches depending on the type, size, internal structure/configuration of the material and properties of interest. Far from attempting to cover the entire spectrum of models, this review examines a wide range of analysis and simulation techniques, highlighting their potential use, some of their weaknesses and strengths, and presenting the latest developments and some application examples. Specifically, this paper shows how electronic, atomistic, mesoscopic, continuum and system models can be used to study and design CNMs, to predict different properties and responses of materials, or even to study devices such as sensors. This review has been performed within the framework of COST Action EsSENce (High-performance Carbon-based composites with Smart properties for Advanced Sensing Applications – CA19118).

Curd, a traditional fermented dairy product, is integral to various culinary traditions, cultural practices, and nutritional systems globally. This review offers an in-depth exploration of curd, encompassing its production methods, nutritional profile, health benefits, and cultural significance. We begin with a detailed examination of the fermentation process, focusing on the role of lactic acid bacteria and the factors affecting curd’s quality and sensory characteristics. The paper evaluates the microbial composition of curd and its potential health benefits, including a comparative analysis of its probiotic effects relative to yogurt. Additionally, we delve into curd-based beverages, assessing their production techniques, nutritional value, and health-promoting properties. The review also explores curd’s cultural and dietary importance, tracing its historical roots in Indian cuisine and traditional medicine, and contrasts its global culinary use with yogurt. By providing a comprehensive overview, this review aims to enhance the understanding of curd and curd-based beverages as functional foods, cultural symbols, and valuable sources of nourishment across diverse populations.

Background: Falls in older adults are prevalent and can result in an injury affecting their quality of life. Whether a fall is fatal or not, it has a high financial impact. Older adults with dementia are more likely to fall than their cognitively healthy counterparts, increasing their risk of serious injury or even death. This quality improvement project developed, implemented, and evaluated an evidence-based fall prevention bundle to reduce preventable falls in a long-term memory care unit.; Methods: The interventions that were implemented includes fall risk screening, physical exercise, vitamin D supplementation, purposeful hourly rounds, and post-fall huddles. Kurt Lewin’s force field analysis guided the project’s implementation. Nurses, healthcare providers, certified nursing assistants, restorative aides, and life enrichment staff from all shifts at a long-term memory care unit participated in the project. The participants implemented the evidence-based fall prevention bundle based on their scope of practice. They participated for 12 weeks. The frequency of falls was compared three months before, during, and after implementation. Paired t-test and independent samples t-test were used to analyze statistically significant differences between variables.; Results: Thirty staff members attended educational sessions, and 22 residents received interventions. Fall rates dropped 50% during the project's implementation but increased subsequently. The difference in the number of falls before, during, and after implementation was not statistically significant.; Conclusions: Staff working in a long-term care facility may help reduce fall rates using evidence-based interventions, but measures should be taken to sustain the initiative's implementation.

This study outlines the development and optimization of a Long Short-Term Memory (LSTM) network designed to analyze and classify time-series data from tribological experiments, with a particular emphasis on identifying stationary phases. The process of fine-tuning key hyperparameters was systematically optimized through Bayesian optimization, coupled with K-fold cross-validation, to minimize the inherent randomness associated with training neural networks. The refined LSTM network achieved a weighted average accuracy of 84%, demonstrating a high level of agreement between the network's identified stationary phases and those manually determined by researchers. This result suggests that LSTM networks can reliably mimic manual identification processes in tribological data, providing a promising avenue for automating data analysis. The study underscores the potential of neural networks to transcend their traditional role in predictive modeling within tribology, opening up new possibilities for their application across a broader spectrum of tasks within the field.

The use of educational robotics has become increasingly popular in STEM education, offering motivating and hands-on learning experiences. This paper explores the potential of educational robotics for teaching plane curves at the university level. Specifically, it investigates the development and implementation of a LEGO SPIKE Prime robot designed to draw various central trochoids, including epicycloids and hypocycloids. The robot’s construction and programming are described, emphasizing the relationship between the robot’s physical movements and the mathematical equations of the curves it produces. The study also examines the integration of dynamic geometry software, which allows for visualization of the curves and verification of the robot’s accuracy. The paper concludes that educational robotics can serve as a valuable tool for enhancing both theoretical and practical understanding of mathematical and engineering concepts, offering a more engaging and interactive approach to learning.

The discharge of industrial effluents containing toxic heavy metals in water sources has serious consequences for human health and the environment, and biosorption appears to be an environmental-friendly and cost-effective alternative that can be used for wastewater treatment. The use of different types of agricultural waste as biosorbents for the removal of toxic heavy metals, although an alternative, is quite difficult to apply in practice because these wastes have many other uses. Based on these considerations, in this study, soybean biomass (SB), soybean waste biomass obtained from oil extraction (SBW) and biochar obtained from soybean waste pyrolysis (BC-SBW) were testes as biosorbents form the removal of Pb(II) and Cd(II) ions, in batch systems. Under optimal conditions (pH = 5.4, 4.0 g biosorbent/L, room temperature (25 ± 1 C), contact time = 180 min), the biosorption capacity increase in the order: SB &lt; SBW &lt; BC-SBW for both metal ions, indicating that BC-SBW has the highest efficiency in removing toxic heavy metals. In addition, experiments on wastewater samples have shown that, in addition to significant reducing the content of heavy metals, BC-SBW also significant improved other quality indicators (such as: pH, TSM, CCO-Cr, CBO5), compared to the other biosorbents (SB and SBW). Quantitative evaluation of the biosorptive performance of each biosorbent (SB, SBW and BC-SBW) shows that BC-SBW has a real chance of being used on an industrial scale for wastewater treatment. All these aspects allowed the development of a circular approach for the use of soybean biomass in the removal processes of toxic heavy metals. This approach minimizes the shortcomings of using biomass as a biosorbent and increase the chance of using these materials in industrial practice.

With the increasing use of automatic transmissions in passenger vehicles, there is a growing need for improved gear shifting control strategies that aim to enhance performance and fuel efficiency. This paper introduces a knowledge-based fuzzy control system designed specifically for automatic transmissions in light vehicles. The proposed system utilizes a fuzzy inference system as the controller, enabling the emulation of the driver’s perceptions during the gear shifting process. Consequently, the input signal consists of variables that are either sensitive to or observable by the driver, while the output represents the selected gear. The paper evaluates three distinct control strategies, each based on different inputs. These inputs include the longitudinal velocity of the vehicle, the angular velocity of the engine, or a combination of both, along with the time-derivative of the throttle valve opening. Through the evaluation, it is observed that the combination of inputs yields significantly improved performance. Therefore, the methodology presented in this paper demonstrates that the combined input approach is more effective for gear shifting control.

According to current forecasts, global heating is likely to exceed 2,8°C by the end of the century. This makes substantial adaptation measures necessary to secure a broad basis for livelihoods provision and the conservation of biodiversity. While the implementation of top-down and technocratic adaptation efforts is the majority, related adaptation shortcomings of socio-economic and ecological nature are becoming more and more apparent. Community-based adaptation (CBA) with its participatory, inclusive and needs-based bottom-up approach offers a promising and powerful alternative. This article uses a semi-systematic literature review approach to screen the current literature and identify core issues of CBA. Linking communality, locality, multidimensionality, power imbalances, transformative potential, localisation, the triad of adaptation metrics and adaptation with nature to corresponding potential actions for practical implementations provides a more holistic conceptualisation and broadens the horizons for further learnings, research and improved application.

The Gulf of Mannar, a UNESCO World Biosphere Reserve, faces severe overfishing and habitat degradation threats. In this study, we investigate the pivotal role of ecosystem services in sustaining local livelihoods and overall well-being. By conducting a comprehensive survey of 480 respondents across two districts, we gathered extensive data on demographics, livelihoods, fishing practices, reliance on ecosystem services, and community management participation. The analysis reveals a critical dependence on the Gulf's resources (income, food security, traditions) with gender disparities (men fish, women in pre/post-harvest), but fishing is only allowed in the 10km buffer zone (not the core zone). The findings emphasize the promise of community-based strategies, such as Marine Protected Areas and reviving co-management committees, for achieving sustainable fisheries management. However, we also identify gaps, including the need for more nuanced well-being indicators and improved models for community management participation. To address these challenges, we advocate for sustainable fishing practices, tackling social inequities, especially gender disparities in resource access and decision-making, and investing in healthcare, education, and social safety nets for fishing communities. Promoting alternative livelihoods can alleviate pressure on fish stocks, and empowering local communities through capacity building and community-based management initiatives is crucial for ensuring the long-term sustainability of both the Gulf of Mannar ecosystem and the well-being of its dependent communities. This multifaceted approach holds significant promise for balancing ecological health with human prosperity.