Search Results (153)

The replacement of ionizable functional groups that are predominantly charged at physiological pH with neutral bioisosteres is a common strategy in medicinal chemistry; however, its impact on binding affinity is often context-dependent. Here, we investigated a series of amide derivatives of a glycomimetic E-selectin ligand, in which the carboxylate group of the lead compound is substituted with a range of amide and isosteric analogs. Despite the expected loss of the salt-bridge interaction with Arg97, several amides retained or even improved the binding affinity. Co-crystal structures revealed conserved binding poses across the series, with consistent interactions involving the carbonyl oxygen of the amide and the key residues Tyr48 and Arg97. High-level quantum chemical calculations ruled out a direct correlation between carbonyl partial charges and affinity. Instead, a moderate correlation was observed between ligand binding and the out-of-plane pyramidality of the amide nitrogen, suggesting a favorable steric adaptation within the binding site. Molecular dynamics (MD) simulations revealed that high-affinity ligands exhibit enhanced solution-phase pre-organization toward the bioactive conformation, likely reducing the entropic penalty upon binding. Further analysis of protein–ligand complexes using Molecular mechanics/Generalized born surface area (MM-GB/SA) decomposition suggested minor lipophilic contributions from amide substituents. Taken together, this work underscores the importance of geometric and conformational descriptors, beyond classical electrostatics, in driving affinity in glycomimetic ligand design and provides new insights into the nuanced role of amides as carboxylate isosteres in protein–ligand recognition. Full article

The 17 sustainable development goals advocated by the United Nations have played a big role in focusing the minds of policy makers in terms of sustainability issues and have also highlighted the issue of social inclusion and the need to make society more equitable. As well as referencing the sustainable development goals, attention is given to the planetary health concept as it is known to deepen our understanding of the ecological interdependence brought about by cultural, environmental and socio-economic factors, which have relevance in terms of mankind achieving the sustainable development goals. This paper addresses the following question: How can a framework to foster global partnerships leading to sustainable development be underpinned by a philosophical argument that strengthens the case for social inclusion? Consequently, a wide body of literature is reviewed, with key concepts such as collaboration being placed in context and reinforced through stakeholder theory. A philosophical discussion is entered into embracing Moore’s open question argument regarding the reliance on Intuitionism to explain how actions can be coined as immoral or moral. Such arguments are useful for raising moral issues that often end in moral disagreements, and which raise and help solve ethical problems. To effectively deal with the complexity involved, policy makers should support the use of frameworks that can be used to support and encourage social inclusion. In adopting this viewpoint, we put forward a sustainable partnership framework that provides guidance to policy makers and their advisors in terms of tackling the issue of social inclusion. In order to achieve social inclusion, policy makers need to understand the role that symbolic representation plays and how the influence of major influencers generates collaborative knowledge that is reappraised through philosophical argument. The outcome of the philosophical argument is a change in a nation’s cultural value system and the implementation of social inclusion policy. Full article

Background/Objectives: This study aimed to assess whether income was associated with dental caries experience and dental care levels among 12-year-old children in two contrasting economic contexts, Sri Lanka (lower-middle-income) and Wales (high-income), regardless of national income status. Methods: An ecological study design was used with published data. For Sri Lanka, the income parameters used included household income, mean per capita income, and the Gini coefficient. For Wales, the Welsh Index of Multiple Deprivation was used. Dental caries was assessed using the DMFT index and its components (DT, MT, FT), while dental care was assessed using the care index, restorative index, and treatment index. Pearson correlations were used to explore associations between income measures and both caries experience and dental care indices across districts in Sri Lanka and unitary authorities in Wales. Results: The mean DMFT for 12-year-old children was 0.6 in both Sri Lanka and Wales, with caries prevalence of 30.4% and 29.6%, respectively. In Sri Lanka, both mean household income and per capita income showed moderate, statistically significant positive correlations with DMFT (r = 0.47, p = 0.01). Income inequality, measured by the Gini coefficient, was positively associated with caries experience (r = 0.42, p = 0.03). In Wales, higher deprivation (lower income) was moderately associated with increased DMFT, in areas within the 20% (r = 0.54, p < 0.01), 30% (r = 0.53, p < 0.01), and 50% (r = 0.61, p < 0.01) deprived quintiles. The dental care indices showed no clear association with income in either of the countries. Conclusions: Income-related disparities in dental caries were evident in both countries. Prevention strategies should focus on higher-income groups in Sri Lanka and on deprived populations in Wales. However, as this was an ecological study, the results are subject to ecological fallacy and should therefore be interpreted with caution. Full article

The environmental crisis demands transformative solutions on both technological and societal levels. Bioinspired approaches, which draw from the principles of natural systems, have emerged as a promising interdisciplinary framework to address these challenges. These approaches not only drive technological innovation but also provoke critical philosophical and ethical discourse, particularly in the field of biomimicry. Philosophical and ethical questions include: How can we ethically justify drawing inspiration from nature without exploiting it? How might a shift toward a bioinspired perspective alter our relationship with nature? How could a reorientation toward nature influence ethical frameworks and guide human behavior toward the environment? This narrative review systematically examines key philosophical and ethical perspectives within biomimicry, while focusing on potentials as well as limitations of these approaches to the environmental crisis. In doing so, it explores key perspectives such as “biomimetic ethics”, the “ontology of nature”, “bioinclusivity”, and the “naturalistic fallacy”. Full article

Our proposal is aimed at analyzing a series of sacred forms that question that initial hallmark of the general theory of secularization which, based on a teleological conception, postulated a movement from the sacred to the profane, from the religious to the secular. These new sacred forms describe a different pattern that goes from the secular to the religious, as new forms of sacralization. In this sense, we analyze, first, the historical emergence of the grand narrative of secularization in Europe, which describes a unidirectional process from the religious to the secular. Second, we carry out a genealogical critique of the narrative of secularization. Third, we analyze the other direction in that dynamic tension that goes from the secular to the religious. Fourthly, we analyze new forms of sacralization that emerged in the French Revolution, in American “civil religion”, in post-war Europe, in the commemorations of Memorial Day or Veteran’s Day, in the Coronation Ceremony of Queen Elizabeth II, in the proto-event of 11 September 2001, in the sacralization of the person and in the sacralization of the child. “See to it that no one enslaves you through the vain fallacy of a philosophy, founded on human traditions, according to the elements of the world and not according to Christ.” (Saint Paul, Epistle to the Colossians 2: 8); “In the imagination of the simple patriot, the nation is not a society but the Society. Although its values are relative, they appear, from his naive perspective, as absolute. The nation is always endowed with an aura of sacredness, which is the reason why religions, which claim universality, are so easily captured and domesticated by national sentiment, religion and patriotism converging in such a process.” (Reinhold Niebuhr); “Everyone can only choose for himself who for him is God and who is the devil because with respect to values, in fact, it is always and everywhere not only a matter of alternatives, but of an irreconcilable fight to the death, between ‘god’ and the ‘devil’.” (Max Weber). Full article

Over the past two decades, cardiovascular disease (CVD) prevention guidelines have progressively lowered LDL-C targets to <70 mg/dL for high-risk individuals based on the assumption of a linear relationship between LDL-C levels and CVD risk. However, the available evidence challenges this premise. Multiple studies demonstrate a weak or inconsistent association between LDL-C levels and atherosclerosis progression at the individual patient-level. Systematic reviews supporting the linearity assumption have notable limitations, including extrapolation beyond observed LDL-C ranges and potential ecological fallacy, as meta-regression analyses rely on study-level data, while patient-level data within the same trials often show no association between LDL-C reduction and CVD outcomes. Moreover, randomized controlled trials explicitly designed to assess LDL-C targets have yielded inconclusive and biased results. LDL-C itself is a heterogeneous marker, with particle size and composition influencing its atherogenicity. The cardiovascular benefits of lipid-lowering therapies may arise in part from pleiotropic effects unrelated to LDL-C lowering. Additionally, several studies indicate that higher LDL-C levels are paradoxically associated with longevity in elderly populations that is equal to or even greater than that of the general population. Collectively, this body of evidence raises questions about the validity of current LDL-C targets < 70 mg/dL in high-risk patients. Full article

Cognitive bias is widespread, hidden, and difficult to deal with. It impacts each and every aspect of the justice and legal systems, from the initial engagement of police officers attending the crime scene, through the forensic examination, and all the way to the final outcome of the jurors’ verdict and the judges’ sentencing. It impacts not only the subjective elements in the justice and legal systems but also the more objective scientific elements, such as forensic fingerprinting and DNA. The impact of bias on each of these elements has mainly been researched and considered in silo, neglecting the biasing interactions and how bias cascades and snowballs throughout the justice and legal systems. These should happen rarely, as the Swiss cheese model shows that such errors in the final outcome rarely occur because they require that the shortcomings in each element be coordinated and aligned with the other elements. However, in the justice and legal systems, the different elements are not independent; they are coordinated and mutually support and bias each other, creating and enabling hidden bias cascade and bias snowball effects. Hence, minimizing bias requires not only taking measures to reduce bias in each of the elements but also a wider perspective that addresses bias cascade and bias snowball effects. Full article

This article discusses the nature of self-talk, characterizing it as a psycholinguistic activity consisting of the performance of speech acts directed to oneself. More specifically, it examines negative speech acts as embedded in behavioral and emotional reasoning, the performance of which creates behavioral and emotional disturbances for the agent, such as anxiety, depression, guilt, and anger. This characterization has important implications for psychotherapy, namely, that helping clients to identify these speech acts and replacing them with ones that have antidotal properties can be therapeutic. According to Logic-Based Therapy (LBT), a popular form of philosophical counseling, cardinal or key self-destructive speech acts can be counteracted by uplifting philosophical speech acts when the latter resonate with clients. This means that philosophical psychotherapies, such as LBT, can potentially have significant therapeutic value. Based on this premise, this article introduces and discusses an AI-generated “Toolbox” of philosophical antidotes created by the Institute for Logic-Based Therapy and Consultation in the United States to help clients find suitable, resonant philosophical antidotes to their self-destructive speech acts. Full article

The apparel industry significantly contributes to climate change through its carbon emissions, excessive water usage, and waste accumulation, leading to environmental degradation and social issues such as modern slavery and poor working conditions. Amid increasing customer awareness and demands from international organizations for transparency, traceability has emerged as a critical concept, especially with advancements in technology. This study employs an interpretive case study approach, drawing early observations from a pilot project focused on traceability implementation within an apparel manufacturer and its chain-of-custody. This exploration is timely, as numerous similar initiatives are underway globally. Our research reveals that, even with the best technologies and intentions, achieving true transparency through traceability remains a challenge, often distancing stakeholders from meeting sustainability goals. Developing six (6) propositions along the way, we identify the fallacies of sustainable supply chain arising in relation to the notion of chain-of-custody. This study underscores the necessity of a collaborative approach among stakeholders to enhance traceability efforts and contribute meaningfully to sustainable practices in the apparel sector. Full article

According to the free will theodicy of hell, the damned agent freely chooses to suffer in hell, or equivalently, to reject God. Against this view, Thomas Talbott argues that it is impossible for the agent to freely reject God because doing so is not rational. The aim of this essay is to critically respond to Talbott’s argument that it is not rational to reject God, rather than offering a full defense of the free will theodicy of hell itself. Drawing on recent work on rationality, I argue that not only does Talbott’s argument commit the fallacy of equivocation, but its two premises are also indefensible. I also explain what the reasons are for rejecting God: when the agent’s happiness consists of an incoherent combination of attitudes, it is both structurally and substantively rational for her to reject God. Full article

One salient feature of Logic-Based Therapy (LBT), a form of philosophical counseling based on Rational–Emotive Behavior Therapy (REBT), is its inclusion of a set of guiding virtues that provide transcendent goals in overcoming self-destructive forms of thinking called “cardinal fallacies”. This paper discusses modes of interconnectivity between these virtues and some prominent types of cardinal fallacies and between each virtue and each fallacy. In comparison to other psychotherapeutic approaches, such as Acceptance and Commitment Therapy (ACT) and Positive Psychology, it shows how clients who embrace these virtues can transcend matching fallacies that create states of negative emotions, such as anxiety and depression, and how these virtues can, in turn, interconnect human beings and promote positive growth. Full article

Biological systems learn from past experiences by establishing relationships between two simultaneously occurring events, a phenomenon known as associative learning. This concept has promising applications in modern AI (Artificial Intelligence) and ML (Machine Learning). To leverage it effectively, a precise electrical model that can simulate associative learning observed in biological systems is essential. The paper focuses on modeling Pavlov’s famous experiment related to the drooling of dogs at the sound of bell after associating the food with the bell during training. The study addresses limitations in existing circuit designs that fail to accurately replicate associative learning in dogs, particularly when the sequence of food and bell signals deviates from a specific pattern. We propose a novel design using a few CMOS (Complementary Metal Oxide Semiconductor) transistors and memristor models that produces an output corresponding to the dogs drooling only when food and bell signals are associated, mirroring real-life training conditions. The results section first discusses simulations using the standard TiO₂ (Titanium Oxide) memristor model, followed by experimental results obtained from a classical memristor emulator. Both simulation and experimental findings confirm the effectiveness of the circuit designs. Full article

Climate denialism represents a significant challenge to public awareness and the implementation of effective environmental policies. In Portugal, as in other countries, social networks have been the place where denialist ideas are disseminated, influencing the public perception of the climate crisis. This research aims to understand how denialist discourse manifests and spreads on digital platforms. The research question of this work is: how does climate denialist discourse manifest itself on social media in Portugal? This work has two objectives: (1) to analyze the arguments and discursive strategies used by climate deniers in comments on Facebook, specifically on the pages of the three largest Portuguese newspapers, and (2) to understand the social and discursive dynamics that underpin their beliefs. This work adopted a qualitative methodology that involved manual data collection during the month of September 2024. Posts about climate that were informative were selected. The comments were examined manually and categorized by type of discourse. This approach enabled capturing specific nuances and contexts of denial discourses, providing a deeper understanding of the phenomenon. The study concluded that (I) comments that use fallacies or rhetoric that deny the climate crisis tended to receive more “likes” and approval from users; (II) fallacies that do not offer scientific evidence to refute the existence of climate change were identified in all these comments. Full article

Background/Objectives: Pain is a complex and subjective experience influenced by psychological, cultural, and social factors. This study aims to investigate how social perceptions of pain affect the lived experiences and coping mechanisms of individuals suffering from pain. By comparing public discourse with the experiences of sufferers, we explore whether the social legitimacy of pain influences how it is managed. Methods: A multi-phase qualitative study was conducted, comprising eight focus groups with members of the Spanish general population and 19 in-depth interviews with individuals suffering from various types of pain. The focus groups explored social perceptions of pain’s legitimacy, while the interviews delved into the sufferers’ personal experiences. The data were analyzed using thematic analysis to identify patterns and disparities between public discourse and individual narratives. Results: The focus groups revealed widespread social empathy towards all types of pain. However, interviewees reported significant social pressure to normalize their behavior and downplay their pain. Many felt misunderstood, unsupported, and stigmatized, especially in environments where they held subordinate roles, such as the workplace or healthcare settings. Sufferers often resorted to silence or isolation to avoid judgment. Conclusions: While Spanish society outwardly legitimizes all forms of pain, sufferers experience significant discrepancies between public empathy and actual social support. The findings suggest that raising awareness alone is insufficient, and that structural changes are needed to address the daily burdens that individuals face when coping with pain, particularly in workplace and healthcare environments. Full article

The situation wherein a hydrological series does satisfy the assumption of “independent and identically distributed” is called runoff inconsistency. “Flow Inversion Phenomenon” is also a kind of runoff inconsistency in space that reflects errors in the hydrological modeling process and can provide a basis for curve correction. In this paper, the causes of the flow inversion phenomenon are analyzed, and a characteristic curve correction method for hydropower stations based on runoff inconsistency is proposed. “Interval Fallacy Rate” is proposed to quantify the flow inversion phenomenon, and with the goal of minimizing the interval fallacy rate, several characteristic curve correction methods, such as single-point discrete optimization, multi-point discrete optimization, overall translation optimization and partial translation optimization, are constructed to correct the turbine characteristic curve, discharge curve, and capacity curve of a hydropower station. In the case study, we take a six-reservoir cascade reservoir system in China as an example. After curve correction, the interval fallacy rate of each interval is reduced to varying degrees. This study provides a new idea for the correction of hydropower stations’ characteristic curves in basins lacking measured flow data. Full article