Paradigm Change Research Articles

Comparative evaluation of methods for the prediction of protein–ligand binding sites

AbstractThe accurate identification of protein–ligand binding sites is of critical importance in understanding and modulating protein function. Accordingly, ligand binding site prediction has remained a research focus for over three decades with over 50 methods developed and a change of paradigm from geometry-based to machine learning. In this work, we collate 13 ligand binding site predictors, spanning 30 years, focusing on the latest machine learning-based methods such as VN-EGNN, IF-SitePred, GrASP, PUResNet, and DeepPocket and compare them to the established P2Rank, PRANK and fpocket and earlier methods like PocketFinder, Ligsite and Surfnet. We benchmark the methods against the human subset of our new curated reference dataset, LIGYSIS. LIGYSIS is a comprehensive protein–ligand complex dataset comprising 30,000 proteins with bound ligands which aggregates biologically relevant unique protein–ligand interfaces across biological units of multiple structures from the same protein. LIGYSIS is an improvement for testing methods over earlier datasets like sc-PDB, PDBbind, binding MOAD, COACH420 and HOLO4K which either include 1:1 protein–ligand complexes or consider asymmetric units. Re-scoring of fpocket predictions by PRANK and DeepPocket display the highest recall (60%) whilst IF-SitePred presents the lowest recall (39%). We demonstrate the detrimental effect that redundant prediction of binding sites has on performance as well as the beneficial impact of stronger pocket scoring schemes, with improvements up to 14% in recall (IF-SitePred) and 30% in precision (Surfnet). Finally, we propose top-N+2 recall as the universal benchmark metric for ligand binding site prediction and urge authors to share not only the source code of their methods, but also of their benchmark.Scientific contributionsThis study conducts the largest benchmark of ligand binding site prediction methods to date, comparing 13 original methods and 15 variants using 10 informative metrics. The LIGYSIS dataset is introduced, which aggregates biologically relevant protein–ligand interfaces across multiple structures of the same protein. The study highlights the detrimental effect of redundant binding site prediction and demonstrates significant improvement in recall and precision through stronger scoring schemes. Finally, top-N+2 recall is proposed as a universal benchmark metric for ligand binding site prediction, with a recommendation for open-source sharing of both methods and benchmarks.

Designing Culturally Competent Clinical Decision Support Systems to Reduce Health Disparities in Underserved Populations

Income inequality is associated with poor health. Both the cost of medical care and the utilization of services vary. The high expense of health care pushes a significant portion of Indian households into poverty. The surroundings in which people live, grow, work, and interact with one another are known as social determinants, and they have a big influence on people's well-being which can be reduced by computerized clinical decision support systems. In today's healthcare, computerized clinical decision support systems, or CDSS, represent a paradigm change. Clinicians can use CDSS to support them in making complicated decisions. Rapid advancements have been made in CDSS since they were used in the 1980s. Due to the growing worldwide usage of advanced electronic medical records, they are frequently administered using computerized clinical processes and electronic medical records.

Pre and Probiotics to Postbiotics: A Changing Paradigm

The relationship between microbiota and human health has long been stated by Hippocrates said, “Death sits in the bowls” in 400 B.C. With recent scientific advance ments, there is a growing understanding of the significance of microbiota in health and disease. The two-way communication between the host and the microbiota involves the production of various metabolites that play crucial roles in host energy metabolism, influence nervous system function and the gut- brain axis, immune maturation and homeostasis, maintenance of mucosal integrity, treatment of metabolic disorders, anti-obesity, cholesterol lowering, antioxidant, anticancer, antiproliferative and anti-inflammatory properties. Postbiotics are inanimate microorganisms or their compounds, including short-chain fatty acids, exopolysaccharides, vitamins, teichoic acids, bacteriocins, enzymes and peptides that provide health benefits to the host. Postbiotics can be stored under normal environmental conditions, have a prolonged shelf life, easy to transport, and handle and overcome the limitations of probiotic use. As a result, postbiotics have immense potential as a safe and effective means of promoting health and well-being.

The offender between penal policies and local practices: A history of individualised punishment

Like many other jurisdictions, the Danish criminal justice system has used pre-sentence reports for almost a century to be able to impose individualised sanctions. During this period, suspended sentences and a range of alternative sanctions have been developed, and the number of pre-sentence reports issued has increased dramatically accordingly. These changes are often explained in terms of shifting ideologies about the relation between crime, person and society during the 20th century. However, this article argues that the larger, paradigmatic changes within penal decision-making may be articulated quite differently in everyday institutional practices. Both current and former perceptions of ‘the criminal’ thus appear as hybrid forms in judges’, probation officers’ and other professionals’ contemporary practices feeding into sentencing. The penal history of pre-sentence reports as phenomenon thus enables us to raise awareness about contemporary, heterogeneous and anachronistic constructions of the defendant that influence their punishment.

Trends in home treatment and early discharge of patients with low-risk pulmonary embolism

Abstract Background A strategy of ambulatory treatment or early discharge (≤ 48 hours) of patients with acute low-risk pulmonary embolism (PE) has been adopted by the most recent guideline recommendations. However, the adoption of such a change of paradigm in PE care in the ‘real-world’ clinical setting, outside the concept of prospective cohort (management) studies, remains unknown. Aims To determine the proportion of patients with PE who fulfill eligibility criteria for home treatment or early discharge, to investigate in how many of them such a management strategy is actually followed, and to discover differences in early complications between early or later discharge among low-risk patients. Methods We used two nationwide databases, the US Nationwide Emergency Department Sample (NEDS) and Nationwide Readmission Database (NRD), to identify patients with low-risk PE (absence of the following at presentation: haemodynamic instability, cor pulmonale, tachycardia, dyspnea, hypothermia, altered mental status, and fulfilment of the Hestia critieria). We investigated the proportion of patients that were discharged entirely at home, or discharged early (hospital stay £ 2 days) and their association with predictor variables. We also studied the 90-day occurrence of venous thromboembolism recurrence and major bleeding. Results From 2016 to 2020, there were 2,099,390 emergency department visits for PE (NEDS Database), with 641,621 (30.6%) classified as low-risk. Home treatment was documented in 20.3% of all cases, with 31.5% of low-risk PE cases being treated at home and an increasing trend over time (Figure 1A). Factors associated with home treatment for low-risk PE included younger age, female sex, and absence of comorbidities; home treatment was more frequent at university hospitals, non-metropolitan hospitals, and those with higher emergency department volumes (Figure 2A). In the NRD Database, there were 1,950,708 PE hospitalizations during the same period with 481,321 classified as low-risk (24.7%). An early discharge strategy was followed in 22.6% of all cases, increasing to 45.9% for low-risk PE admissions, with a rising trend observed from 2016 (Figure 1B). Factors associated with early discharge for low-risk PE included younger age, male sex, and absence of comorbidities; here, university hospitals and metropolitan hospitals were less likely to implement early discharge (Figure 2B). The 90-day incidence of VTE recurrence among low-risk patients was lower with early discharge (1.3% vs. 1.8%, p<0.001), as was major bleeding (1.5% vs. 2.8%, p<0.001). Conclusion Our results reveal an increasing implementation of early discharge and home treatment for low-risk PE across recent years. Factors influencing these strategies are related to demographics and hospital type. Early discharge was associated with favourable outcomes in the real-world setting, thus supporting the results of previously performed prospective cohort studies and randomized trials.Figure 1Figure 2

The change of paradigm: high HDL-c levels could not mean a long lifespan

Abstract Background It is known that a low HDL-c level is associated with a high risk of overall mortality. Consequently, it was presumed that achieving higher levels of high-density lipoprotein cholesterol (HDL-c) would reduce the risk or even extend the lifespan. However, clinical trials with medical intervention failed to find clinical benefits. Aim We aimed to investigate the association between (HDL-c) levels and overall mortality using a prospective cohort from Portugal. Methods A prospective sub-study (2001-2022) was performed in a cohort of 1718 participants without coronary artery disease (CAD) of the control arm of the ongoing GENEMACOR study. The participants <65 years were followed during a mean follow-up of 7.0±5.7 years. All demographic, biochemical, and clinical data were collected. Participants were stratified into six levels of HDL-c. Kaplan-Meier estimated differences in the survival probability of each HDL-c level. Cox proportional analysis models (unadjusted and adjusted) were used to assess the association between HDL-c levels and overall mortality. Results The HDL-c levels with the lowest overall mortality rate were 60 to 70 mg/dl, set as the reference level. Total HDL-c strata were associated with overall mortality with a U-shaped relationship: in the control group, the first level (<40 mg/dl) was independently associated with increased risk of overall mortality (HR of 3.533; 95% CI: 1.738-7.178; p<0.0001). This risk drops and falls to the reference level (the lower risk) and rises again to an HR of 3.875 (95% CI: 1.472-10.201; p=0.006) in the very high HDL-c levels (≥80 mg/dl). Conclusions Our results, based on a large Portuguese cohort, suggest that very high HDL-c levels in the normal population may not represent a good prognosis, especially in women. Future research may confirm these findings and investigate the underlying mechanisms.

Polyphenol-treatment without preceding glutaraldehyde fixation: a potential paradigm change for bioprosthetic heart valves

Abstract Background Glutaraldehyde (GA) is the common fixative agent for bioprosthetic heart valves (BHVs). However, its chemical instability can expose calcium binding sites and, at commercially used concentrations, GA does not ensure effective immunological tolerance, triggering an immune response correlated to degeneration. Recently, polyphenols (PPs) achieved an almost complete xenoantigens inactivation in GA-fixed BHVs ensuring chemical stability of the treated tissue while improving mechanical characteristics and adding anti-infective and anti-thrombotic properties [1-4]. Purpose A new PP-based treatment has been introduced as a potential GA substitute in BHV manufacturing. The unique chemical properties of PPs permit them to interact with the tissue through stable chemical bonds without depolymerization over time, achieving several improvements that promise to extend the long-term durability of BHVs (Fig.1). Methods The study compared the effects of two cross-linking methods on bovine pericardial tissue: (1) traditional fixation in GA, and (2) treatment with PPs without GA. The type of chemical interaction between PPs and tissue was evaluated through nuclear magnetic resonance. The xenoantigens inactivation was quantified in-vitro by ELISA test and in-vivo in a humanized mouse animal model. Biomechanical properties were assessed through uniaxial stress-strain tests and cross-link density through the shrinkage temperature test. The protective effect against bacterial adhesion was evaluated against a strain of S aureus, while the inhibition of thrombosis was evaluated in-vivo in a pig animal model and in-vitro in a blood-loop using bovine blood with radio-labeled platelets. Results PPs effectuated multiple chemical bonds with and within the pericardium including cross-links based on covalent and hydrogen bonds, stacking, and electrostatic interactions. The inactivation of over 90% of surface-xenoantigens of the treated tissue allowed for superior biocompatibility (compared to <50% by commercial GA concentrations). The increase in elongation exhibited by PP-treated tissue confirmed excellent biomechanical features (Fig.2) while a sufficient degree of cross-linking was demonstrated through an adequate shrinkage temperature. Furthermore, a significant degree of bacterial adhesion (86% inhibition evaluated with S. aureus) and thrombus formation (Fig.2, up to 90% inhibition) were observed. Conclusion There is a real clinical need for improved chemical stability, calcification resistance, and immunological tolerance of current BHVs (surgical and transcatheter). PP technology may substitute the use of GA extending their performance and durability, thereby opening trans-catheter heart valves to younger patients. Reducing the need for mechanical heart valves would also address the associated risks of lifelong anticoagulation therapy.Figure 1Figure 2

Correlation Hyperspectral Imaging

Hyperspectral imaging aims at providing information on both the spatial and the spectral distribution of light, with high resolution. However, state-of-the-art protocols are characterized by an intrinsic trade-off imposing to sacrifice either resolution or image acquisition speed. We address this limitation by exploiting light intensity correlations, which are shown to enable overcoming the typical downsides of traditional hyperspectral imaging techniques, both scanning and snapshot. The proposed approach also opens possibilities that are not otherwise achievable, such as sharper imaging and natural filtering of broadband spectral components that would otherwise hide the spectrum of interest. The enabled combination of high spatial and spectral resolution, high speed, and insensitivity to undesired spectral features shall lead to a paradigm change in hyperspectral imaging devices and open up new application scenarios. Published by the American Physical Society 2024

Autonomy of the will: evolution of juridical doctrine and legal norms

In the article on the basis of statistical methods, the use of the term “autonomy of will” in judicial acts by the law enforcement officer is characterized. It is noted that the meaning of the relevant legal category is not sufficiently defined, which is the reason for its relatively rare (in comparison with “freedom of contract”) use in the texts of court rulings. Amendments made to civil legislation concerning decisions of assemblies, pre-contractual relations and the procedure for changing and terminating multilateral agreements are interpreted as the result of a change in the legal paradigm supported by a legislator. Deeply realized over the years of the functioning of the market economy, reinforced by data from related fields of scientific knowledge, the ability to regulate public relations in a decentralized manner by the will of many people has changed the ideas about the nature of the autonomy of participants in civil turnover, the nature of centralized regulation of public relations and the meaning of legal norms.

Paradigm changes in research: Kuhn meets socio-ecological transition theory

Recent research indicates that disruptiveness in science has decreased, triggering discussions about the reason for this. Earlier Thomas Kuhn discussed why revolutions in science are slow but inevitable processes. To better understand transition processes within a scientific discipline, this article draws on a novel transition concept. The concept combines ideas about the structure of scientific revolutions with the concept of adaptive cycles. Combining these two approaches facilitates theorization of the reasons for the reduced disruptiveness at the scientific discipline (system) level. To elucidate the interplay between individuals and the scientific discipline, and thus their role in processes of scientific paradigm shifts, the new model further integrates resilience theory. Factors determining the resilience of an adaptive system explain resistance to change at individual and system levels, as well as the interplay between these two levels. The discourse between environmental and ecological economics is used to illustrate the theoretical discussion and apply the novel transition concept to a specific case. The analysis shows that institutionalization, providing better answers to anomalies, and uncovering maladaptation are key in the transition process.

The effect of congruent emotional context on semantic memory during discourse comprehension

ABSTRACT This study examined the effect of emotional context on the semantic memory of subsequent emotional words during discourse comprehension in two eye-tracking experiments. Four-sentence discourses were used as experimental materials. The first three sentences established an emotional or neutral context, while the fourth contained an emotional target word consistent with the preceding emotional context's valence. The discourses were presented twice using the text change paradigm, where the target words were replaced with strongly - or weakly-related words during the second presentation. Thus, four conditions were included in the present study: Emotional-strongly-related, Emotional-weakly-related, Neutral-strongly-related and Neutral-weakly-related. In Experiment 1, negative contexts and negative target words were used, whereas in Experiment 2, positive contexts and positive target words were used. The results revealed a semantic relatedness effect, whereby the strongly-related words have lower change detection accuracy, longer reading times and more fixations in both Experiments 1 and 2. Furthermore, across both experiments, the magnitude of the semantic relatedness effect was greater in the emotionally congruent contexts than in the neutral contexts. These results suggest that emotional context could increase efforts to change the discrimination of subsequent words and demonstrate an important role of emotional context on semantic memory during discourse processing.

Social Inclusion for People with Intellectual Disability and on the Autism Spectrum through Assistive Technologies: Current Needs and Future Priorities

Context Contemporary technologies, such as mainstream and specialised Assistive Technologies (ATs), are seen as effective. However, there is a noticeable gap between technological progress and the ability to customise these technologies to meet the unique needs and characteristics of neurodivergent individuals, particularly those on the Autism Spectrum and people with Intellectual Disability (pwID). Purpose The goal of this study is to investigate the present requirements and future priorities acknowledged by specialists in the field regarding the progress of social inclusion for this population, making use of ATs. Methods and results A qualitative survey involving 24 international experts, and its respective thematic analysis reveals challenges in social inclusion, emphasizing communication and physical accessibility, awareness gaps, and stigma. Concurrently, issues surrounding ATs include limited access, insufficient training, and a lack of awareness and skills, with individuals, and families being inadequately involved. Conclusion and implications The study proposes strategies for overcoming these challenges, with a focus on accessibility, awareness, skills, family involvement, and customization. Identified research needs encompass scientific development, inclusive approaches, and changes in technological development paradigms.

Evolving Treatment Landscape for Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma.

This review highlights advances and recent changes in the treatment paradigm for advanced esophageal adenocarcinoma (EAC) and gastroesophageal junction adenocarcinoma (GEJAC). Chemotherapy remains the backbone of treatment for advanced EAC/GEJAC. New targets/agents include immunotherapy, HER-2, claudin18.2, and FGFR2b, with various mechanisms (CAR-T, bispecific mAB, ADCs) altering the treatment landscape against these targets. The approaches to these targets may act together, in sequence, and even synergistically to improve outcomes. Herein, we review the state of the field, including highlighting ongoing clinical trials and additional emerging agents and approaches.

The Public Interest in the Digital Age: Exploring the Emerging Roles and Governance Models of the AI as a Common Good

With the continuous development of artificial intelligence, we are living through the era of digital transformation, and the fourth Industrial Revolution is a paradigm change with unprecedented speed, scale, scope and complexity, and is fundamentally transforming production, consumption and society as a whole. As the basic unit of public management research, data has established a strong connection between the promotion of digital revolution and the change of public management research paradigm. The rise of AI technologies has enhanced AI governance and brought unprecedented help to policymakers. This study has used a cross-sectional quantitative design to capture perception and attitude towards AI as common good from a sample of 400 Chinese responders coming from diverse age, group and occupation categories. The key factors which measured were public awareness of AIGC, the extent of its utilization in government policy, public attitudes toward AIGC, and public participation in policy development. The findings indicated that public understanding and trust are paramount to successfully integrate Ai as common good in governance framework. Public enthusiasm and participations are highly affected by trust and public understanding. To deliver policies without much resistance, heightened awareness, participations and trust becomes essential.

Revolutionizing Patient Safety: Machine Learning and AI for the Early Detection of Adverse Drug Reactions and Drug-Induced Toxicity

Adverse drug reactions and drug-induced toxicity provide significant issues in drug research, jeopardizing patient safety and driving up healthcare costs. Toxicity has a greater potential impact than infectious diseases since it is less visible. Early diagnosis of these difficulties is critical to determining a drug's safety and viability profile. The combination of machine learning and artificial intelligence has marked a watershed moment in the identification of early adverse drug reactions and toxicity. These computational approaches enable rapid, extensive, and precise prediction of likely adverse drug reactions and toxicity even before practical drug manufacture, preclinical testing, and clinical trials. This paradigm change strives to create more efficient and safe drugs, lowering the likelihood of drug withdrawal. This comprehensive review investigates the critical role of machine learning and artificial intelligence in quickly detecting adverse drug reactions and toxicity, including approaches from data mining to deep learning. It lists essential databases, modelling techniques, and software that may be used to model and predict a wide range of toxicities and adverse drug reactions. This review provides a comprehensive overview, outlining recent developments and projecting future opportunities in machine learning and artificial intelligence-driven rapid identification of adverse drug reactions and drug-induced toxicity. It highlights the capabilities of these technologies and their enormous potential to improve patient safety and revolutionize medication discovery.

Van der Waals semiconductor InSe plastifies by martensitic transformation.

Inorganic semiconductor materials are crucial for modern technologies, but their brittleness and limited processability hinder the development of flexible, wearable, and miniaturized electronics. The recent discovery of room-temperature plasticity in some inorganic semiconductors offers a promising solution, but the deformation mechanisms remain controversial. Here, we investigate the deformation of indium selenide, a two-dimensional van der Waals semiconductor with substantial plasticity. By developing a machine-learned deep potential, we perform atomistic simulations that capture the deformation features of hexagonal indium selenide upon out-of-plane compression. Unexpectedly, we find that indium selenide plastifies through a martensitic transformation; that is, the layered hexagonal structure is converted to a tetragonal lattice with specific orientation relationship. This observation is corroborated by high-resolution experimental observations and theory. It suggests a change of paradigm, where the design of new plastically deformable inorganic semiconductors can focus on compositions and structures that facilitate phase transformations, going beyond the conventional dislocation slip.

Interactions of forest carbon sink and climate change in the hormesis paradigm

Interactions of forest carbon sink and climate change in the hormesis paradigm

Project Technologies in the Practical Course of the Russian Language in the Formation of Research Qualities of University Students

Nowadays, the role of science in the learning process of students is becoming more and more important. This is due to the fact that in recent years there has been an increase in the volume of research work, and there has been a change in the educational paradigm, in which the basic academic knowledge is no longer the only necessary capital, which leads to an increase in self-development in professional activities. Research work of students is one of the most important means of improvement of quality of education and training of specialists with higher education, capable of creative application in practice of the latest achievements of scientific, technical and cultural progress in modern conditions. Project technologies develop cognitive skills of students, their ability to independently construct their knowledge, ability to navigate in the information space, critical and creative thinking. In the article the authors define the importance of the use of the project method for the development of research activity of students. The stages and steps of implementation of this method are also given.

What drives paradigm change? Analogy, deponency, and verbal aspect in the history of dati / dajati / davati

What drives paradigm change? Analogy, deponency, and verbal aspect in the history of dati / dajati / davati

Changes of Paradigm in Private International Law of Contracts – A high-level comparison between 1989 and 2024, with tribute to the Unidroit Principles, the development of arbitration law and to Simplified Global Contracting

The article on German private law of contracts compares the state of private international law in Germany in 1989 with its state today, in 2024. It demonstrates a change of paradigm by looking at six selected parameters of relevance: (i) the respect of constitutional rights and European fundamental freedoms, (ii) the unitarian European character of private international law of contracts, subject to treaties, (iii) the dissemination of the CISG, (iv) the emergence of the the Unidroit Principles as a sound system of general principles and rules of international commercial contracts, (v) the development of international arbitration, and (vi) the emergence of internet and data platform based comparative legal research. Regarding the traditional private international law of contracts, as applied by European courts (of member states of the European Union), the author observes that more European uniformity has come at the cost of complexity. At the same time, the emergence and dissemination of the Unidroit Principles – described as “the biggest achievement of the international legal society since the year 534” – has enabled Simplified Global Contracting (i.e. the choice of the Unidroit Principles in combination with an arbitration clause) and thereby more freedom on a global level.