Composite structural motifs of binding sites for delineating biological functions of proteins

Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs which represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.Comment: 34 pages, 7 figure

Gender differences in coerced patients with schizophrenia

European Commission (Quality of life and Management of Living Resources Programme, contract number QLG4-CT- 2002-01036), Czech Ministry of Education research grant MSM002160849, and research grants PRVOUK–P26/LF1/4 and PRVOUK–P03/LF1/

Subjective utility moderates bidirectional effects of conflicting motivations on pain perception

Minimizing pain and maximizing pleasure are conflicting motivations when pain and reward co-occur. Decisions to prioritize reward consumption or pain avoidance are assumed to lead to pain inhibition or facilitation, respectively. Such decisions are a function of the subjective utility of the stimuli involved, i.e. the relative value assigned to the stimuli to compare the potential outcomes of a decision. To test perceptual pain modulation by varying degrees of motivational conflicts and the role of subjective utility, we implemented a task in which healthy volunteers had to decide between accepting a reward at the cost of receiving a nociceptive electrocutaneous stimulus or rejecting both. Subjective utility of the stimuli was assessed by a matching task between the stimuli. Accepting reward coupled to a nociceptive stimulus resulted in decreased perceived intensity, while rejecting the reward to avoid pain resulted in increased perceived intensity, but in both cases only if a high motivational conflict was present. Subjective utility of the stimuli involved moderated these bidirectional perceptual effects: the more a person valued money over pain, the more perceived intensity increased or decreased. These findings demonstrate pain modulation when pain and reward are simultaneously present and highlight the importance of subjective utility for such modulation

Dopamine, affordance and active inference.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level

Global Trends and Evidence Gaps in Medical Errors Research: A Mixed-Methods Scientometrics Study

Yessica Angarita-Pacheco,1 Angie Daniela Urbano López,1 David A Hernandez-Paez,2 Ornella Fiorillo-Moreno,3,4 Yelson Alejandro Picón-Jaimes,5 Tulia Beltrán Venegas,1 Alba Marina Rueda Olivella,1 Ivan David Lozada-Martinez,2,6 Valmore Bermúdez7 1Department of Health Sciences, Universidad de la Costa, Barranquilla, Colombia; 2Center for Meta-Research and Scientometrics in Biomedical Sciences, Barranquilla, Colombia; 3Clínica Iberoamérica, Barranquilla, Colombia; 4Clínica El Carmen, Barranquilla, Colombia; 5Facultat de Ciències de la Salut Blanquerna, Universitat Ramon Llull, Barcelona, Spain; 6Biomedical Scientometrics and Evidence-Based Research Unit, Department of Health Sciences, Universidad de la Costa, Barranquilla, Colombia; 7Centro de Investigaciones en Ciencias de la Vida, Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla, ColombiaCorrespondence: Ivan David Lozada-Martinez, Biomedical Scientometrics and Evidence-Based Research Unit, Department of Health Sciences, Universidad de la Costa, Barranquilla, Colombia, Email [email protected] Valmore Bermúdez, Centro de Investigaciones en Ciencias de la Vida, Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla, Colombia, Email [email protected]: Medical errors represent a critical challenge to global healthcare systems, ranking among the leading causes of preventable morbidity and mortality. The aim of this study was to explore the evolution, characteristics, and correlation of research on medical errors and global health and research indicators.Methods: A mixed-methods scientometrics study was conducted to analyse publications from 1865 to 2024 on medical errors from five databases. Correlational analyses were performed, focusing on publication trends, geographic and economic disparities, journal metrics, and thematic evolution. Multiple regression assessed relationships between bibliometric metrics and global indicators.Results: Five thousand seven hundred thirty-two publications related to medical errors were analysed. An annual growth rate of 1.49% was documented, with high-income countries contributing 83.32% of publications. The Americas accounted for the highest regional output, while Africa and Southeast Asia showed marginal contributions. Most studies were published in high-impact journals (46% in Q1), but only 22.98% were open access. Thematic analysis revealed a transition from error reporting to mitigation strategies. Correlations showed strong associations between intellectual property fees and publication volume (r²=0.75; p< 0.001), while official development assistance negatively correlated with publication output (r²=− 0.33; p< 0.01). Disability-adjusted life years showed weak correlations with publication volume (r²=0.32; p< 0.01) and journal impact (r²=0.14; p< 0.001).Conclusion: This study highlights significant inequities in global research on medical errors, with high-income countries dominating production. While thematic shifts suggest advancements in the field, the lack of representation from low- and middle-income countries and limited access to open-access publications pose barriers to global applicability.Keywords: medical errors, health services, health care quality indicators, global health, bibliometrics, meta-researc

The first oviraptorosaur (Dinosauria: Theropoda) bonebed: Evidence of gregarious behaviour in a maniraptoran theropod

A monodominant bonebed of Avimimus from the Nemegt Formation of Mongolia is the first oviraptorosaur bonebed described and the only recorded maniraptoran bonebed from the Late Cretaceous. Cranial elements recovered from the bonebed provide insights on the anatomy of the facial region, which was formerly unknown in Avimimus. Both adult and subadult material was recovered from the bonebed, but small juveniles are underrepresented. The taphonomic and sedimentological evidence suggests that the Avimimus bonebed represents a perimortem gregarious assemblage. The near absence of juveniles in the bonebed may be evidence of a transient age-segregated herd or ‘flock’, but the behaviour responsible for this assemblage is unclear. Regardless, the Avimimus bonebed is the first evidence of gregarious behaviour in oviraptorosaurs, and highlights a potential trend of increasing gregariousness in dinosaurs towards the end of the Mesozoic

Temporal-Difference Reinforcement Learning with Distributed Representations

Temporal-difference (TD) algorithms have been proposed as models of reinforcement learning (RL). We examine two issues of distributed representation in these TD algorithms: distributed representations of belief and distributed discounting factors. Distributed representation of belief allows the believed state of the world to distribute across sets of equivalent states. Distributed exponential discounting factors produce hyperbolic discounting in the behavior of the agent itself. We examine these issues in the context of a TD RL model in which state-belief is distributed over a set of exponentially-discounting “micro-Agents”, each of which has a separate discounting factor (γ). Each µAgent maintains an independent hypothesis about the state of the world, and a separate value-estimate of taking actions within that hypothesized state. The overall agent thus instantiates a flexible representation of an evolving world-state. As with other TD models, the value-error (δ) signal within the model matches dopamine signals recorded from animals in standard conditioning reward-paradigms. The distributed representation of belief provides an explanation for the decrease in dopamine at the conditioned stimulus seen in overtrained animals, for the differences between trace and delay conditioning, and for transient bursts of dopamine seen at movement initiation. Because each µAgent also includes its own exponential discounting factor, the overall agent shows hyperbolic discounting, consistent with behavioral experiments

Measurement of the muon flux at the SND@LHC experiment

The Scattering and Neutrino Detector at the LHC (SND@LHC) started taking data at the beginning of Run 3 of the LHC. The experiment is designed to perform measurements with neutrinos produced in proton-proton collisions at the LHC in an energy range between 100 GeV and 1 TeV. It covers a previously unexplored pseudo-rapidity range of 7.2 < η< 8.4 . The detector is located 480 m downstream of the ATLAS interaction point in the TI18 tunnel. It comprises a veto system, a target consisting of tungsten plates interleaved with nuclear emulsion and scintillating fiber (SciFi) trackers, followed by a muon detector (UpStream, US and DownStream, DS). In this article we report the measurement of the muon flux in three subdetectors: the emulsion, the SciFi trackers and the DownStream Muon detector. The muon flux per integrated luminosity through an 18 × 18 cm 2 area in the emulsion is: 1.5±0.1(stat)×104fb/cm2. The muon flux per integrated luminosity through a 31 × 31 cm 2 area in the centre of the SciFi is: 2.06±0.01(stat)±0.12(sys)×104fb/cm2 The muon flux per integrated luminosity through a 52 × 52 cm 2 area in the centre of the downstream muon system is: 2.35±0.01(stat)±0.10(sys)×104fb/cm2 The total relative uncertainty of the measurements by the electronic detectors is 6 % for the SciFi and 4 % for the DS measurement. The Monte Carlo simulation prediction of these fluxes is 20–25 % lower than the measured values