Rational Approach Research Articles

Probing the Chemical Space of Guanidino-Carboxylic Acids to Identify the First Blockers of the Creatine-Transporter-1.

The creatine transporter-1 (CRT-1/SLC6A8) maintains the uphill transport of creatine into cells against a steep concentration gradient. Cellular creatine accumulation is required to support the ATP-buffering by phosphocreatine. More than 60 compounds have been explored in the past for their ability to inhibit cellular creatine uptake, but the number of active compounds is very limited. Here, we show that all currently known inhibitors are full alternative substrates. We analyzed their structure-activity relation for inhibition of CRT-1 to guide a rational approach to the synthesis of novel creatine transporter ligands. Measurements of both, inhibition of [3H]creatine uptake and transport associated currents, allowed for differentiating between full and partial substrates and true inhibitors. This combined approach led to a refined understanding of the structural requirements for binding to CRT-1, which translated into the identification of three novel compounds - i.e. compound 1 (2-(N-benzylcarbamimidamido)acetic acid), and MIPA572 (=carbamimidoylphenylalanine) and MIPA573 (=carbamimidoyltryptophane) that blocked CRT-1 transport, albeit with low affinity. In addition, we found two new alternative full substrates, namely MIP574 (carbamimidoylalanine) and GiDi1257 (1-carbamimidoylazetidine-3-carboxylic acid), which was superior in affinity to all known CTR-1 ligands, and one partial substrate, namely GiDi1254 (1-carbamimidoylpiperidine-4-carboxylic acid). Significance Statement The creatine transporter-1 (CRT-1) is required to maintain intracellular creatine levels. Inhibition of CRT-1 has been recently proposed as a therapeutic strategy for cancer, but pharmacological tools are scarce. In fact, all available inhibitors are alternative substrates. We tested existing and newly synthesized guanidinocarboxylic acids for CRT-1 inhibition and identified three blockers, one partial and two full substrates of CRT-1. Our results support a refined structural understanding of ligand binding to CRT-1 and provide a proof-of-principle for blockage of CRT-1.

The Photoredox Paradox: Electron and Hole Upconversion as the Hidden Secrets of Photoredox Catalysis.

Although photoredox catalysis is complex from a mechanistic point of view, it is also often surprisingly efficient. In fact, the quantum efficiency of a puzzlingly large portion of photoredox reactions exceeds 100% (i.e., the measured quantum yields (QYs) are >1). Hence, these photoredox reactions can be more than perfect with respect to photon utilization. In several documented cases, a single absorbed photon can lead to the formation of >100 molecules of the product, behavior known to originate from chain processes. In this Perspective, we explore the underlying reasons for this efficiency, identify the nature of common catalytic chains, and highlight the differences between HAT and SET chains. Our goal is to show why chains are especially important in photoredox catalysis and where the thermodynamic driving force that sustains the SET catalytic cycles comes from. We demonstrate how the interplay of polar and radical processes can activate hidden catalytic pathways mediated by electron and hole transfer (i.e., electron and hole catalysis). Furthermore, we illustrate how the phenomenon of redox upconversion serves as a thermodynamic precondition for electron and hole catalysis. After discussing representative mechanistic puzzles, we analyze the most common bond forming steps, where redox upconversion frequently occurs (and issometimes unavoidable). In particular, we highlight the importance of 2-center-3-electron bonds as a recurring motif that allows a rational chemical approach to the design of redox upconversion processes.

SOCIO-LEGAL CHALLENGES OF INDIGENOUS LAND IN WEST KALIMANTAN: CUSTOMARY PRACTICES AND NATIONAL LAW

Customary law in the national legal system is undoubtedly fundamental to maintaining existence because customary law can also be applied to resolve conflicts in society. This research uses socio-legal methods, and the data obtained is based on data in the field through an interview process with several related parties. In contrast, for legal problems in this society, only some things can be resolved through a customary law approach. For example, in the Dayak indigenous community, several legal problems cannot be resolved according to custom, especially regarding unregistered land rights. These problems certainly cannot be solely resolved using a customary law approach. This certainly shows that customary law cannot necessarily accommodate the interests of Indigenous peoples because this is also closely related to legal certainty. Because they relate to legal certainty, they must be resolved through a positive legal approach, such as submitting a request to the court or an application to the relevant agency. This certainly happens because the legal awareness of regional communities in Indonesia is currently not very good; this leads to legal issues within indigenous communities that cannot be resolved through customary law.

Neoadjuvant immunotherapy for dMMR and pMMR colorectal cancers: therapeutic strategies and putative biomarkers of response.

Approximately 15% of locally advanced colorectal cancers (CRC) have DNA mismatch repair deficiency (dMMR), resulting in high microsatellite instability and a high tumour mutational burden. These cancers are frequently sensitive to therapy with immune-checkpoint inhibitors (ICIs) in the metastatic setting. This sensitivity seems to be even more pronounced in locally advanced disease, and organ preservation has become a realistic aim in ongoing clinical trials involving patients with dMMR rectal cancer. By contrast, metastatic CRCs with proficient DNA mismatch repair (pMMR) are generally resistant to ICIs, although a proportion of locally advanced pMMR tumours seem to have a high degree of sensitivity to ICIs. In this Review, we describe the current and emerging clinical evidence supporting the use of neoadjuvant ICIs in patients with dMMR and pMMR CRC, and the potential advantages (based on a biological rationale) of such an approach. We discuss how neoadjuvant 'window-of-opportunity' trials are being leveraged to progress biomarker discovery and we provide an overview of potential predictive biomarkers of response to ICIs, exploring the challenges faced when evaluating such biomarkers in biopsy-derived samples. Lastly, we describe how these discoveries might be used to drive a rational approach to trialling novel immunotherapeutic strategies in patients with pMMR CRC, with the ultimate aim of disease eradication and the generation of long-term immunosurveillance.

The root cause of disruptive NTMs and paths to stable operation in DIII-D ITER baseline scenario plasmas

Abstract Analyses of the DIII-D ITER Baseline Scenario database support that the disruptive m,n=2,1 magnetic islands are pressure gradient driven, non-linear instabilities seeded in a sequence of stochastic transient magnetic perturbations, and that the current profile relaxation does not affect the m,n=2,1 island onset rate. At low torque, these Neoclassical Tearing Modes are most commonly seeded by non-linear 3-wave coupling when the differential rotation between the q=1 & q=2 rational surfaces approaches zero. Lack of statistically significant difference between the current profiles of stable and unstable states, as well as lack of correlation between the tearing mode onset rate and the current profile relaxation both reject causality between the current profile evolution and the 2,1 magnetic island onsets in these plasmas. These support that preserving the differential rotation between the q=1 and q=2 rational surfaces is key to long pulse stable operation in the plasma scenario planned for ITER, while optimization of the current profile within the explored parameter space may lead to much weaker improvements than sustaining the differential rotation.

A Machine Learning Algorithm Suggests Repurposing Opportunities for Targeting Selected GPCRs.

Repurposing utilizes existing drugs with known safety profiles and discovers new uses by combining experimental and computational approaches. The integration of computational methods has greatly advanced drug repurposing, offering a rational approach and reducing the risk of failure in these efforts. Recognizing the potential for drug repurposing, we employed our Iterative Stochastic Elimination (ISE) algorithm to screen known drugs from the DrugBank database. Repurposing in our hands is based on computer models of the actions of ligands: the ISE algorithm is a machine learning tool that creates ligand-based models by distinguishing between the physicochemical properties of known drugs and those of decoys. The models are large sets of "filters" made out, each, of molecular properties. We screen and score external sets of molecules (in our case- the DrugBank molecules) by our agonism and antagonism models based on published data (i.e., IC50, Ki, or EC50) and pick the top-scoring molecules as candidates for experiments. Such agonist and antagonist models for six G-protein coupled receptors (GPCRs) families facilitated the identification of repurposing opportunities. Our screening revealed 5982 new potential molecular actions (agonists, antagonists), which suggest repurposing candidates for the cannabinoid 2 (CB2), histamine (H1, H3, and H4), and dopamine 3 (D3) receptors, which may be useful to treat conditions such as neuroinflammation, obesity, allergic dermatitis, and drug abuse. These sets of best candidates should now be examined by experimentalists: based on previous such experiments, there is a very high chance of discovering novel highly bioactive molecules.

The natural law and positivist approaches to legal understanding in the context of revealing the category of legal personality of professional participants in capital markets

This article aims to analyze the main philosophical concepts used in understanding the legal category of legal personality and to conduct a descriptive study of the concepts related to this category that prevail in domestic science. The author of the article substantiates the position that the approaches to the theoretical and legal developments of the category of universal legal personality of legal entities should be based on the natural law type of legal understanding. At the same time, the article analyzes domestic authors’ approaches to understanding the legal category of legal personality and compares these approaches with those prevailing in Western countries. Furthermore, the author attempts to justify the expediency of distinguishing exclusive legal personality, given the positivist approach that underlies the construction of the model of the exclusive type of legal personality of professional participants in capital markets. In our opinion, establishing the exclusive legal personality of legal entities is a state-imposed limitation on their universal legal capacity, such as the ability to participate in certain civil-law relations, considering the social importance of the type of activity carried out by these entities. After all, the proper functioning of capital markets is crucial to the financial stability of the country. Capital markets, along with commodity markets, directly influence the formation of exchange rates by attracting foreign investment into the country’s economy. They can also act as a catalyst for economic growth by accumulating financial resources from the population to create capital-intensive productions with high value-added end products. However, achieving such results depends on the balanced state policy in the field of regulating the activities of professional participants in capital markets. To limit the speculative nature of such entities and ensure sustainable economic development, the scope of their legal capacity is narrowed by directly specifying in the law the types of activities they are permitted to engage in.

Deter, detect, disrupt. An analysis of Nottinghamshire Police’s knife crime team

Nottinghamshire Police established the only dedicated team in the UK outside London, proactively locating those at higher likelihood of involvement in Knife-enabled crime. The team uses a mix of tactics under the banner of ‘deter, detect, and disrupt’ through intelligence-led and problem-oriented policing approaches. This article examines those tactics and assesses the effectiveness thereof as a case study, using a mix of statistics and wider academic research to identify potential benefits. It concludes that the approaches have reaped positive rewards, alongside other, softer, prevention and partnership approaches. There remains however a need to better define the team’s aims and purpose.

Decent work and work fulfilment: The mediating role of work engagement and the moderating role of psychological ownership

This study explores the well-being (engagement) and work fulfilment of 628 blue-collar workers as outcomes of decent work, based on the Psychology of Working Theory and its target group. It takes a positive preventative approach and demonstrates the motivational role of work engagement and psychological ownership in contributing to the work fulfilment of blue-collar workers experiencing decent work. Data was collected from a South African-owned trailer manufacturing company. The results show a positive relationship between decent work and work fulfilment, with work engagement mediating this relationship. Additionally, psychological ownership positively moderates the relationship between decent work and work engagement. This study adds insights into the underlying mechanism (work engagement) that elucidates how decent work relates to work fulfilment. This study sheds light on how decent work contributes to work fulfilment through work engagement. Furthermore, suggesting that this relationship is stronger for blue-collar workers with higher levels of psychological ownership.

Exploring Egalitarianism: A Conceptual and Methodological Review of Egalitarianism and Impacts on Positive Intergroup Relations.

Considerable research on intergroup relations emphasizes attitudes, motivations, and emotions that lead to the reduction of prejudice. While factors that actively promote positive intergroup interactions have been emerging, a central theoretical framework has not been formally proposed. To address this gap, we engaged a positive psychology lens to explore how researchers have defined key indicators and consider the positive counterparts of traditional prejudice-reduction models to begin building a new framework of egalitarianism. After scanning 16,840 records that emerged in PsycInfo using keywords "egalitarian", "non-prejudice", and "intergroup", we assessed 158 articles for eligibility. Among the relevant articles (N = 54), we analyzed authors' definitions, methods of measurement, types of processes, and outcomes associated with egalitarian values as they related to intergroup behavior. Overall, there was notable variability in how researchers conceptualized and studied egalitarianism. We discuss the five broad categories of egalitarianism (prejudice reduction, universal orientation, concern for others, positive expression, and low social dominance orientation) and how they relate to positive or negative and approach or avoidant outcomes. Through these findings, we urge scholars to utilize a centralized model for studying egalitarianism in intergroup contexts moving forward.

Unleashing potential: how alpha female status shape extra-role performance across life's stages and marital roles

PurposeThe present study examines the interplay between age, marital status, alpha female status and various adaptive performance dimensions among a cohort of 380 female professionals.Design/methodology/approachThis study adopts a positivist approach to collect and analyse the data, utilizing appropriate statistical techniques to explore the relationships between the variables of interest.FindingsThe study elucidates the significant role of alpha female status in predicting adaptive performance. It finds that alpha females possess distinct competencies, particularly in learning and training, indicative of proactive behaviour and self-efficacy. While older participants tend to demonstrate higher performance levels, the study reveals no significant correlation between age and alpha female status, suggesting that leadership traits may develop independently of age. Furthermore, marital status exerts a modest influence on adaptive performance. The interplay of age and marital status significantly affects adaptive performance, potentially due to the Cumulative Advantage Paradigm, which is the accumulation of advantages or disadvantages throughout an individual's life course.Originality/valueThis study contributes to the existing literature by providing a nuanced understanding of how demographic factors converge to influence adaptive performance in professional settings. It highlights the importance of recognising and nurturing alpha females in organizations and considering the interactions between age and marital status when designing career development programmes and support systems.

EcoClimate and ESG Disputes: Practice, Risks, Prospects

The ecoclimate or «green» agenda, largely constituted through the concept of «sustainable development» and the system of ESG standards, has captured the world and is changing society, generating new social patterns, and ceasing business and management models. This encourages rethinking the legal superstructure, adapting new regulatory arrays to the current legal taxonomy, which is not always possible, taking into account the positivist approach to law and a significant amount of «soft» law rules and sources of non-state regulation within the framework of «green» regulation. The ecoclimate agenda has a number of dimensions in the context of law and jurisprudence, one of which is the practice of ecoclimate and ESG disputes, often of a cross-border nature. Very little attention is paid to this issue in the Russian research space, while the volume of relevant lawsuits in the world is growing rapidly. The object of the study within the framework of this work covers the risk-oriented nature of the above-mentioned issues, the licensing risks of mainly cross-border contracts, the assessment of companies’ activities in the field of sustainable development in the context of possible judicial or arbitration proceedings. The paper provides a classification of ecoclimate and ESG disputes, gives examples of judicial and arbitration practice, and makes some conclusions regarding mitigation of litigation risks generated by the companies’ activities.

Development of Meaningful Learning from Family-School Integration

The research shows the results of a study carried out on family-school integration as a foundation for meaningful learning in secondary basic education students, belonging to the official sector in the Colombian Caribbean region. The type of research was descriptive, with a deductive rationalist approach and a mixed or complementary paradigm. The sample was made up of sixty-four (64) students in their final year of high school and twenty-four (24) parents and/or guardians, to whom a survey was applied, eleven (11) teachers and one (1) director of the educational institution, consulted through an interview. Once the information was obtained, the triangulation technique was used to cross-reference the opinions, perceptions and beliefs of the actors involved in the comprehensive training of the students. As a result, it was possible to characterize the factors that favor family-school integration, including emotionality, participation, communication, attention and motivation of parents in accompanying their children's academic activities. For their part, schools must organize spaces that promote integration relationships, which represents an alternative to face the dilemmas of the educational context and promote the development of meaningful learning.

Enhancement of interlayer exchange coupling via intercalation in 2D magnetic bilayers: towards high Curie temperature.

Two-dimensional magnetic materials are considered as promising candidates for developing next-generation spintronic devices by providing the possibility of scaling down to nanometers. However, a low Curie temperature is a crucial problem for practical applications, being intimately related to weak interlayer exchange coupling. Here, by using density functional theory calculations, we show that interlayer exchange coupling can be enhanced by intercalating 3d transition metals (Sc to Zn) into a bilayer of CrI3 and NiI2. It is found that intercalated Ni and Cr atoms exhibit strong antiferromagnetic coupling with the CrI3 and NiI2 host layers, respectively. This enhances the ferromagnetic interlayer exchange coupling between the host layers by many folds compared to pristine CrI3 and NiI2 bilayers. Moreover, both intercalated compounds show out-of-plane magnetic anisotropy with half metallic nature, which makes them ideal candidates for spintronics applications. Thereby our work provides a rational approach to raise the Curie temperature of non-metallic two-dimensional magnets by intercalation.

Adsorption behavior and mechanism of NH2-MIL-101(Cr)@COFs@SA composite adsorbent for tetracycline removal

Herein, we employed a rational approach to develop a hydrogel composite material by encapsulating NH2-MIL-101(Cr)/covalent organic frameworks (COFs) in sodium alginate (SA) to effectively capture of tetracycline (TC). Experimental tests and various characterizations (including Fourier-transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron spectroscopy (SEM), Brunauer-Emmett-Teller (BET), and X-ray photoelectron spectroscopy (XPS)) confirmed that the NH2-MIL-101(Cr)@COFs@SA composite exhibited a more robust, multilayer pore structure with abundant active functional groups. Under conditions of 298 K and pH = 7, the NH2-MIL-101(Cr)@COFs@SA adsorbent demonstrated remarkable TC adsorption capability, achieving a removal rate of 96.38 % in 120 min and a qmax of 252.6 mg/g at 298 K by Langmuir model. Kinetic analysis indicated that the interaction between TC and NH2-MIL-101(Cr)@COFs@SA follows a pseudo-second-order model, suggesting that chemisoption governs the process. The Langmuir model and thermodynamic analysis suggested that TC adsorption follows a monolayer sorption pattern and is spontaneous and exothermic. Even in the presence of other ions, NH2-MIL-101(Cr)@COFs@SA maintained high efficiency for TC adsorption, demonstrating superior selectivity. NH2-MIL-101(Cr)@COFs@SA demonstrated remarkable recyclability, with only a minimal reduction in the removal efficiency (85.5 % and 142 mg/g) after 10 cycles of adsorption and regeneration. Various analytical techniques, including FTIR spectroscopy, SEM, EDX, XPS, and density functional theory (DFT) calculations of adsorption energy were used to elucidate the TC adsorption mechanisms by NH2-MIL-101(Cr)@COFs@SA. The adsorption process primarily involved π-π stacking, hydrogen bonding, electrostatic interactions, and complexation.

Tecnología financiera al servicio del cliente: percepción sobre herramientas digitales bancarias en Lima

The scientific study aims to establish the perception of banking customers in a district of Lima, Peru, regarding the effect of digital tools on the quality of service and customer care in the banking sector. It is based on a positivist approach, adopting a quantitative paradigm through a descriptive, non-experimental, and cross-sectional field method. The research employs a probabilistic random sampling method to select a representative sample of 350 banking customers in Lima, Peru. Data collection is conducted through surveys using a 21-question questionnaire. Before its implementation, the questionnaire underwent a pilot test and was evaluated by a panel of five experts. The reliability of the questionnaire was verified using Cronbach's alpha coefficient, obtaining an index of 0.87. The data were analyzed using SPSS v.27 statistical software and presented in the form of tables and graphs. The results revealed a positive perception among banking customers about the impact of digital tools applied in the banking sector on the quality of service and customer care. Additionally, the study highlights the importance of understanding individual user expectations and ensuring a regulatory framework that fosters customer trust. The research concludes by emphasizing the positive perception of banking customers regarding the impact of financial technology on the quality of service and customer care in the banking sector.

Integration of Open Metal Sites in an Amino-Functionalized Sm(III)-Organic Framework toward Enhanced Third-Order Nonlinear Optical Property.

A variety of new inorganic and organic materials have emerged to advance laser technologies and optical engineering. A rational design approach can contribute significantly to fabricating nonlinear optically active metal-organic frameworks (MOFs) by considering the underlying structure-property linkage. Here, it has been embarked on a study of novel samarium(III) MOF, ([Sm2(ata)3(DMF)4]·DMF (ata2-: 2-aminoterephthalate), abbreviated as NH2-Sm-MUM-4) with enhanced nonlinear optical (NLO) properties. The crystal structure of this MOF represents a 6-connected framework with a pcu topology and distinctive characteristics, including open metal sites, free amine groups, and great stability, making it suitable for third-order NLO activity. The nonlinear index of refraction (n2) revealed the self-focusing impacts of NH2-Sm-MUM-4 at different incident intensities. The highest value of n2 and β related to 10 mw power of incident intensity are 5.15 cm2/W and 2.65 cm/W, respectively. As far as the authors know, this is the first study examining the potential systematic structural-property associations in Sm-MOFs considering improved third-order NLO properties.

Unlocking Success: Strategies for Preventing and Managing Complications in Chronic Total Occlusion Percutaneous Coronary Intervention Procedures

Complications in percutaneous coronary intervention (PCI), particularly in chronic total occlusion (CTO) cases, pose notable challenges, with a mortality rate of approximately 0.4% during hospitalization, mainly due to issues like perforation and tamponade. While risk assessment tools can aid in evaluating periprocedural complication risk, prevention and preparedness take precedence. Guided by the "3 Ps" framework—prevention, preparedness, and planning—we navigate the complexities of managing complications in CTO PCI procedures. This emphasizes the importance of comprehensive patient discussions, adherence to appropriateness use criteria, and ensuring a well-trained team equipped with standardized equipment. Furthermore, it is crucial to extract valuable insights from encountered complications, turning potential setbacks into invaluable learning opportunities. This positive approach not only fosters individual growth but also contributes to the advancement of CTO PCI practices. Various complications specific to CTO PCI are addressed, including donor vessel injury, equipment loss/entrapment, radiation injury and coronary perforation.

Mouse cursor trajectories capture the flexible adaptivity of predictive sentence processing.

Recent psycholinguistic findings raise fundamental questions about comprehenders' ability to rationally adapt their predictions during sentence processing. Two mouse cursor tracking experiments (each N = 85) assessed this adaptivity by manipulating the reliability of verb-based semantic cues. In Experiment 1, predictive mouse cursor movements to targets (e.g., bike) versus distractors (e.g., kite) were measured while participants heard equal proportions of nonpredictive (e.g., "spot … the bike"), predictive (e.g., "ride … the bike"), and antipredictive (e.g., "fly … the bike") sentences. In Experiment 2, participants heard equal proportions of nonpredictive and antipredictive sentences. Participants were observed to flexibly adapt their predictions, such that they disengaged prediction in Experiment 1 when verb-based cues were unreliable and as likely to be disconfirmed as confirmed, while they generated adapted predictions in Experiment 2 when verb-based cues were reliably disconfirmed. However, links to individual differences in cognitive control were not observed. These results are interpreted as supporting rational theoretical approaches. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Characterization of DNA damage repair pathway utilization in high-grade serous ovarian cancers yields rational therapeutic approaches

While poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have improved the prognosis of ovarian high-grade serous carcinoma (HGSC) tumors that are homologous recombination (HR) deficient (HRD), new therapeutic strategies are needed for tumors that are HR proficient (HRP) because they demonstrate greater resistance to current treatments and thus have poorer clinical outcomes. Additionally, clinical precautionary statements regarding potential risks associated with PARPi, such as myelodysplastic syndrome, highlight the need for combinatorial approaches that can lessen the dose and duration of PARPi treatment to reduce toxicities. Here, we evaluated DNA double-strand damage repair pathways in HRD and HRP ovarian cancer cell lines and found that in HRD cell lines, PARPi therapy reduced non-homologous end joining (NHEJ)-mediated repair, specifically due to decreased theta-mediated end-joining. The combination of PARPi with ATM serine/threonine kinase inhibitor (ATMi) suppressed both NHEJ and HR pathways in HRD and HRP cell lines, with synergistic increases in apoptosis and decreases in cell viability and colony formation. Interestingly, PARPi plus ATMi also decreased NF-κB p65 phosphorylation, which was not observed when PARPi was combined with inhibition of the ATR kinase (ATRi). These findings indicate that PARPi plus ATMi is a promising strategy for HGSC independent of underlying tumor HR status.