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Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes1. This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges2-4. Although this approach forms the basis of undergraduate curriculum in organic chemistry5 and strategic applications of most synthetic methods6, the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography3,4,7. Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed.
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Productos Biológicos , Técnicas de Química Sintética , Descarboxilación , Electroquímica , Electrodos , Preparaciones Farmacéuticas , Ácidos Carboxílicos/química , Nanopartículas del Metal/química , Oxidación-Reducción , Plata/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Níquel/química , Ligandos , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química , Electroquímica/métodos , Técnicas de Química Sintética/métodosRESUMEN
Theories of moral development propose that empathy is transmitted across individuals. However, the mechanisms through which empathy is socially transmitted remain unclear. Here, we combine computational learning models and functional MRI to investigate whether, and if so, how empathic and non-empathic responses observed in others affect the empathy of female observers. The results of three independent studies showed that watching empathic or non-empathic responses generates a learning signal that respectively increases or decreases empathy ratings of the observer. A fourth study revealed that the learning-related transmission of empathy is stronger when observing human rather than computer demonstrators. Finally, we show that the social transmission of empathy alters empathy-related responses in the anterior insula, i.e., the same region that correlated with empathy baseline ratings, as well as its functional connectivity with the temporoparietal junction. Together, our findings provide a computational and neural mechanism for the social transmission of empathy that accounts for changes in individual empathic responses in empathic and non-empathic social environments.
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Encéfalo , Empatía , Humanos , Femenino , Encéfalo/fisiología , Aprendizaje , Refuerzo en Psicología , Medio SocialRESUMEN
Foraging theory prescribes when optimal foragers should leave the current option for more rewarding alternatives. Actual foragers often exploit options longer than prescribed by the theory, but it is unclear how this foraging suboptimality arises. We investigated whether the upregulation of cholinergic, noradrenergic, and dopaminergic systems increases foraging optimality. In a double-blind, between-subject design, participants (N = 160) received placebo, the nicotinic acetylcholine receptor agonist nicotine, a noradrenaline reuptake inhibitor reboxetine, or a preferential dopamine reuptake inhibitor methylphenidate, and played the role of a farmer who collected milk from patches with different yield. Across all groups, participants on average overharvested. While methylphenidate had no effects on this bias, nicotine, and to some extent also reboxetine, significantly reduced deviation from foraging optimality, which resulted in better performance compared to placebo. Concurring with amplified goal-directedness and excluding heuristic explanations, nicotine independently also improved trial initiation and time perception. Our findings elucidate the neurochemical basis of behavioral flexibility and decision optimality and open unique perspectives on psychiatric disorders affecting these functions.
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Acetilcolina , Metilfenidato , Humanos , Nicotina/farmacología , Norepinefrina , Reboxetina , Método Doble CiegoRESUMEN
From deciding which meal to prepare for our guests to trading off the proenvironmental effects of climate protection measures against their economic costs, we often must consider the consequences of our actions for the well-being of others (welfare). Vexingly, the tastes and views of others can vary widely. To maximize welfare according to the utilitarian philosophical tradition, decision-makers facing conflicting preferences of others should choose the option that maximizes the sum of the subjective value (utility) of the entire group. This notion requires comparing the intensities of preferences across individuals. However, it remains unclear whether such comparisons are possible at all and (if they are possible) how they might be implemented in the brain. Here, we show that female and male participants can both learn the preferences of others by observing their choices and represent these preferences on a common scale to make utilitarian welfare decisions. On the neural level, multivariate support vector regressions revealed that a distributed activity pattern in the ventromedial prefrontal cortex (VMPFC), a brain region previously associated with reward processing, represented the preference strength of others. Strikingly, also the utilitarian welfare of others was represented in the VMPFC and relied on the same neural code as the estimated preferences of others. Together, our findings reveal that humans can behave as if they maximized utilitarian welfare using a specific utility representation and that the brain enables such choices by repurposing neural machinery processing the reward others receive.
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Recompensa , Humanos , Masculino , Femenino , Adulto , Adulto Joven , Conducta de Elección/fisiología , Corteza Prefrontal/fisiología , Toma de Decisiones/fisiología , Imagen por Resonancia Magnética , Mapeo EncefálicoRESUMEN
Representing the probability and uncertainty of outcomes facilitates adaptive behavior by allowing organisms to prepare in advance and devote attention to relevant events. Probability and uncertainty are often studied only for valenced (appetitive or aversive) outcomes, raising the question of whether the identified neural machinery also processes the probability and uncertainty of motivationally neutral outcomes. Here, we aimed to dissociate valenced from valence-independent (i.e., generic) probability (p; maximum at pâ =â 1) and uncertainty (maximum at p = 0.5) signals using human neuroimaging. In a Pavlovian task (n = 41; 19 females), different cues predicted appetitive, aversive, or neutral liquids with different probabilities (p = 0, p = 0.5, p = 1). Cue-elicited motor responses accelerated, and pupil sizes increased primarily for cues that predicted valenced liquids with higher probability. For neutral liquids, uncertainty rather than probability tended to accelerate cue-induced responding and decrease pupil size. At the neural level, generic uncertainty signals were limited to the occipital cortex, while generic probability also activated the anterior ventromedial prefrontal cortex. These generic probability and uncertainty signals contrasted with cue-induced responses that only encoded the probability and uncertainty of valenced liquids in medial prefrontal, insular, and occipital cortices. Our findings show a behavioral and neural dissociation of generic and valenced signals. Thus, some parts of the brain keep track of motivational charge while others do not, highlighting the need and usefulness of characterizing the exact nature of learned representations.
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Señales (Psicología) , Humanos , Femenino , Masculino , Incertidumbre , Adulto , Adulto Joven , Probabilidad , Imagen por Resonancia Magnética , Pupila/fisiología , Condicionamiento Clásico/fisiología , Motivación/fisiología , Mapeo Encefálico , Corteza Prefrontal/fisiología , Corteza Prefrontal/diagnóstico por imagenRESUMEN
Adaptive coding of reward is the process by which neurons adapt their response to the context of available compensations. Higher rewards lead to a stronger brain response, but the increase of the response depends on the range of available rewards. A steeper increase is observed in a narrow range and a more gradual slope in a wider range. In schizophrenia, adaptive coding appears to be affected in different domains, especially in the reward domain. Here, we tested adaptive coding of reward in a large group of patients with schizophrenia (n = 86) and control subjects (n = 66). We assessed: (i) the association between adaptive coding deficits and symptoms; (ii) the longitudinal stability of deficits (the same task was performed 3 months apart); and (iii) the stability of results between two experimental sites. We used functional MRI and the monetary incentive delay task to assess adaptation of participants to two different reward ranges: a narrow range and a wide range. We used a region-of-interest analysis to evaluate adaptation within striatal and visual regions. Patients and control subjects underwent a full demographic and clinical assessment. We found reduced adaptive coding in patients, with a decreased slope in the narrow reward range with respect to that of control participants, in striatal but not visual regions. This pattern was observed at both research sites. Upon retesting, patients increased their narrow-range slopes, showing improved adaptive coding, whereas control subjects slightly reduced them. At retesting, patients with overly steep slopes in the narrow range also showed higher levels of negative symptoms. Our data confirm deficits in reward adaptation in schizophrenia and reveal an effect of practice in patients, leading to improvement, with steeper slopes upon retesting. However, in some patients, an excessively steep slope may result in poor discriminability of larger rewards, owing to early saturation of the brain response. Together, the loss of precision of reward representation in new (first exposure, underadaptation) and more familiar (retest, overadaptation) situations might contribute to the multiple motivational symptoms in schizophrenia.
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Apatía , Imagen por Resonancia Magnética , Recompensa , Esquizofrenia , Humanos , Masculino , Femenino , Adulto , Esquizofrenia/fisiopatología , Apatía/fisiología , Persona de Mediana Edad , Psicología del Esquizofrénico , Motivación/fisiología , Adaptación Fisiológica/fisiología , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Adaptación Psicológica/fisiologíaRESUMEN
We and other animals learn because there is some aspect of the world about which we are uncertain. This uncertainty arises from initial ignorance, and from changes in the world that we do not perfectly know; the uncertainty often becomes evident when our predictions about the world are found to be erroneous. The Rescorla-Wagner learning rule, which specifies one way that prediction errors can occasion learning, has been hugely influential as a characterization of Pavlovian conditioning and, through its equivalence to the delta rule in engineering, in a much wider class of learning problems. Here, we review the embedding of the Rescorla-Wagner rule in a Bayesian context that is precise about the link between uncertainty and learning, and thereby discuss extensions to such suggestions as the Kalman filter, structure learning, and beyond, that collectively encompass a wider range of uncertainties and accommodate a wider assortment of phenomena in conditioning.
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Teorema de Bayes , Condicionamiento Clásico , Refuerzo en Psicología , Humanos , Condicionamiento Clásico/fisiología , Aprendizaje/fisiología , Modelos Psicológicos , IncertidumbreRESUMEN
Recent evidence has linked testosterone, a major sex hormone, to selfishness in economic decision-making. Here, we aimed to investigate the neural mechanisms through which testosterone reduces generosity by combining functional MRI with pharmacological manipulation among healthy young males in a double-blind, placebo-controlled, between-subject design. After testosterone or placebo gel administration, participants performed a social discounting task in which they chose between selfish options (benefiting only the participant) and generous options (providing also some benefit to another person at a particular social distance). At the behavioral level, testosterone reduced generosity compared to the placebo. At the neural level (n = 60), the temporoparietal junction (TPJ) encoded the other-regarding value of the generous option during generous choices, and this effect was attenuated by testosterone, suggesting that testosterone reduced the consideration of other's welfare as underpinned by TPJ activity. Moreover, TPJ activity more strongly reflected individual differences in generosity in the placebo than the testosterone group. Furthermore, testosterone weakened the relation between the other-regarding value of generous decisions and connectivity between the TPJ and a region extending from the insula into the striatum. Together, these findings suggest that a network encompassing both cortical and subcortical components underpins the effects of testosterone on social preferences.
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Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiología , Personalidad/efectos de los fármacos , Testosterona/farmacología , Mapeo Encefálico , Estudios de Casos y Controles , Corteza Cerebral/diagnóstico por imagen , Toma de Decisiones , Humanos , Imagen por Resonancia Magnética , Masculino , Conducta SocialRESUMEN
Decisions are based on the subjective values of choice options. However, subjective value is a theoretical construct and not directly observable. Strikingly, distinct theoretical models competing to explain how subjective values are assigned to choice options often make very similar behavioral predictions, which poses a major difficulty for establishing a mechanistic, biologically plausible explanation of decision-making based on behavior alone. Here, we demonstrate that model comparison at the neural level provides insights into model implementation during subjective value computation even though the distinct models parametrically identify common brain regions as computing subjective value. We show that frontal cortical regions implement a model based on the statistical distributions of available rewards, whereas intraparietal cortex and striatum compute subjective value signals according to a model based on distortions in the representations of probabilities. Thus, better mechanistic understanding of how cognitive processes are implemented arises from model comparisons at the neural level, over and above the traditional approach of comparing models at the behavioral level alone.
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Encéfalo/fisiología , Conducta de Elección/fisiología , Adulto , Teorema de Bayes , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Toma de Decisiones/fisiología , Femenino , Humanos , Masculino , Modelos Neurológicos , Modelos Psicológicos , Enmascaramiento Perceptual/fisiología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiología , Adulto JovenRESUMEN
There is a pressing need, particularly in the field of drug discovery, for general methods that will enable direct coupling of tertiary alkyl fragments to (hetero)aryl halides. Herein a uniquely powerful and simple set of conditions for achieving this transformation with unparalleled generality and chemoselectivity is disclosed. This new protocol is placed in context with other recently reported methods, applied to simplify the routes of known bioactive building blocks molecules, and scaled up in both batch and flow. The role of pyridine additive as well as the mechanism of this reaction are interrogated through Cyclic Voltammetry studies, titration experiments, control reactions with Ni(0) and Ni(II)-complexes, and ligand optimization data. Those studies indicate that the formation of a BINAPNi(0) is minimized and the formation of an active pyridine-stabilized Ni(I) species is sustained during the reaction. Our preliminary mechanistic studies ruled out the involvement of Ni(0) species in this electrochemical cross-coupling, which is mediated by Ni(I) species via a Ni(I)-Ni(II)-Ni(III)-Ni(I) catalytic cycle.
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Humans form impressions toward individuals of their own social groups (ingroup members) and of different social groups (outgroup members). Outgroup-focused theories predict that intergroup impressions are mainly shaped by experiences with outgroup individuals, while ingroup-focused theories predict that ingroup experiences play a dominant role. Here we test predictions from these two psychological theories by estimating how intergroup impressions are dynamically shaped when people learn from both ingroup and outgroup experiences. While undergoing fMRI, male participants had identical experiences with different ingroup or outgroup members and rated their social closeness and impressions toward the ingroup and the outgroup. Behavioral results showed an initial ingroup bias in impression ratings which was significantly reduced over the course of learning, with larger effects in individuals with stronger ingroup identification. Computational learning models revealed that these changes in intergroup impressions were predicted by the weight given to ingroup prediction errors. Neurally, the individual weight for ingroup prediction errors was related to the coupling between the left inferior parietal lobule and the left anterior insula, which, in turn, predicted learning-related changes in intergroup impressions. Our findings provide computational and neural evidence for ingroup-focused theories, highlighting the importance of ingroup experiences in shaping social impressions in intergroup settings.Significance Statement:Living in multicultural societies, humans interact with individuals of their own social groups (ingroup members) and of different social groups (outgroup members). However, little is known about how people learn from the mixture of ingroup and outgroup interactions, the most natural experiences in current societies. Here, participants had identical, intermixed experiences with different ingroup and outgroup individuals and rated their closeness and impressions toward the ingroup and the outgroup. Combining computational models and fMRI, we find that the weight given to ingroup experiences (ingroup prediction errors) is the main source of intergroup impression change, captured by changes in connectivity between the parietal lobe and insula. These findings highlight the importance of ingroup experiences in shaping intergroup impressions in complex social environments.
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Deficits in neural processing of reward have been described in both bipolar disorder (BD) and schizophrenia (SZ), but it remains unclear to what extent these deficits are caused by similar mechanisms. Efficient reward processing relies on adaptive coding which allows representing large input spans by limited neuronal encoding ranges. Deficits in adaptive coding of reward have previously been observed across the SZ spectrum and correlated with total symptom severity. In the present work, we sought to establish whether adaptive coding is similarly affected in patients with BD. Twenty-five patients with BD, 27 patients with SZ and 25 healthy controls performed a variant of the Monetary Incentive Delay task during functional magnetic resonance imaging in two reward range conditions. Adaptive coding was impaired in the posterior part of the right caudate in BD and SZ (trend level). In contrast, BD did not show impaired adaptive coding in the anterior caudate and right precentral gyrus/insula, where SZ showed deficits compared to healthy controls. BD patients show adaptive coding deficits that are similar to those observed in SZ in the right posterior caudate. Adaptive coding in BD appeared more preserved as compared to SZ participants especially in the more anterior part of the right caudate and to a lesser extent also in the right precentral gyrus. Thus, dysfunctional adaptive coding could constitute a fundamental deficit in severe mental illnesses that extends beyond the SZ spectrum.
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Trastorno Bipolar , Esquizofrenia , Humanos , Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/patología , Imagen por Resonancia Magnética , Motivación , RecompensaRESUMEN
Studies of neural processes underlying delay of gratification usually focus on prefrontal networks related to curbing affective impulses. Here, we provide evidence for an alternative mechanism that facilitates delaying gratification by mental orientation towards the future. Combining continuous theta-burst stimulation (cTBS) with functional neuroimaging, we tested how the right temporoparietal junction (rTPJ) facilitates processing of future events and thereby promotes delay of gratification. Participants performed an intertemporal decision task and a mental time-travel task in the MRI scanner before and after receiving cTBS over the rTPJ or the vertex (control site). rTPJ cTBS led to both stronger temporal discounting for longer delays and reduced processing of future relative to past events in the mental time-travel task. This finding suggests that the rTPJ contributes to the ability to delay gratification by facilitating mental representation of outcomes in the future. On the neural level, rTPJ cTBS led to a reduction in the extent to which connectivity of rTPJ with striatum reflected the value of delayed rewards, indicating a role of rTPJ-striatum connectivity in constructing neural representations of future rewards. Together, our findings provide evidence that the rTPJ is an integral part of a brain network that promotes delay of gratification by facilitating mental orientation to future rewards.
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Cuerpo Estriado/fisiología , Toma de Decisiones/fisiología , Descuento por Demora/fisiología , Red Nerviosa/fisiología , Lóbulo Parietal/fisiología , Lóbulo Temporal/fisiología , Adulto , Mapeo Encefálico , Cuerpo Estriado/anatomía & histología , Cuerpo Estriado/diagnóstico por imagen , Femenino , Neuroimagen Funcional , Humanos , Conducta Impulsiva/fisiología , Masculino , Red Nerviosa/anatomía & histología , Red Nerviosa/diagnóstico por imagen , Lóbulo Parietal/anatomía & histología , Lóbulo Parietal/diagnóstico por imagen , Recompensa , Lóbulo Temporal/anatomía & histología , Lóbulo Temporal/diagnóstico por imagen , Estimulación Magnética TranscranealRESUMEN
BACKGROUND: Cubital tunnel syndrome is the second most common entrapment neuropathy of the upper extremity. Surgical decompression of the ulnar nerve aims to improve complaints and prevent permanent damage to the nerve. Open and endoscopic release of the cubital tunnel are both used in common practice, but none has proven to be superior. This study assesses patient reported outcome and experience measures (PROMs and PREMs respectively), in addition to objective outcomes of both techniques. METHODS: A prospective single-center open randomized non-inferiority trial will take place at the Plastic Surgery Department in the Jeroen Bosch Hospital, the Netherlands. 160 patients with cubital tunnel syndrome will be included. Patients are allocated to endoscopic or open cubital tunnel release by randomization. The surgeon and patients are not blinded for treatment allocation. The follow-up time will take 18 months. DISCUSSION: Currently, the choice for one of the methods is based on surgeon's preferences and degree of familiarity with a particular technique. It is assumed that the open technique is easier, faster and cheaper. The endoscopic release, however, has better exposure of the nerve and reduces the chance of damaging the nerve and might decrease scar discomfort. PROMs and PREMs have proven potential to improve the quality of care. Better health care experiences are associated with better clinical outcome in self-reported post-surgical questionnaires. Combining subjective measures with objective outcomes, efficacy, patient treatment experience and safety profile could help differentiating between open and endoscopic cubital tunnel release. This could aid clinicians in evidence based choices towards the best surgical approach in patients with cubital tunnel syndrome. TRIAL REGISTRATION: This study is registered prospectively with the Dutch Trial Registration under NL9556. Universal Trial Number (WHO-UTN) U1111-1267-3059. Registration date 26-06-2021. The URL: https://www.trialregister.nl/trial/9556.
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Síndrome del Túnel Cubital , Humanos , Estudios Prospectivos , Endoscopía/métodos , Nervio Cubital , Descompresión Quirúrgica/métodos , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Humans are less likely to learn from individuals belonging to a different group (outgroup) than from individuals of their own group (ingroup), yet the source of this societally relevant deficit has remained unclear. Here we used neuroimaging and computational modeling to investigate how people learn from observing the actions and outcomes of ingroup and outgroup demonstrators. Politically left-wing male and female participants performed worse when observing computer-simulated actions they believed were from a right-wing outgroup member compared with those from a left-wing ingroup member. A control experiment in which participants observed choices from a nonhuman agent confirmed that this performance difference reflected an outgroup deficit, rather than an ingroup gain. Accounting for the outgroup deficit, a computational model showed that participants relied less on information from outgroup actions compared with ingroup actions, while learning from outgroup outcomes was not impaired. At the neural level, the differences in observational ingroup versus outgroup learning were reflected in lateral prefrontal activity. The stronger the activity in this region, the more strongly participants weighed ingroup compared with outgroup learning signals (action prediction errors), which formally captured deficits in outgroup learning. Together, our work provides a computational and neural account of why people learn less from observing outgroups.SIGNIFICANCE STATEMENT Learning from observing others is an efficient way to acquire knowledge. In our globalized world, "the others" often are people from a different social group (outgroup). There is evidence that people learn less from observing outgroup individuals compared with individuals from their own group (ingroup). However, the source of this outgroup deficit in observational learning remained unknown, which limits our chances to improve intergroup learning. Our results showed that participants rely less on observed outgroup actions compared with ingroup actions, while learning from outgroup outcomes is not impaired. On the neural level, this outgroup deficit was reflected in the activation of the inferior frontal gyrus. These findings imply that intergroup learning should rely on observing outcomes, rather than actions.
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Procesos de Grupo , Aprendizaje/fisiología , Observación , Identificación Social , Actitud , Simulación por Computador , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Política , Desempeño Psicomotor/fisiología , Percepción Social , Adulto JovenRESUMEN
A useful protocol for achieving decarboxylative cross-coupling (DCC) of redox-active esters (RAE, isolated or generated in situ) and halo(hetero)arenes is reported. This pragmatically focused study employs a unique Ag-Ni electrocatalytic platform to overcome numerous limitations that have plagued this strategically powerful transformation. In its optimized form, coupling partners can be combined in a surprisingly simple way: open to the air, using technical-grade solvents, an inexpensive ligand and Ni source, and substoichiometric AgNO3, proceeding at room temperature with a simple commercial potentiostat. Most importantly, all of the results are placed into context by benchmarking with state-of-the-art methods. Applications are presented that simplify synthesis and rapidly enable access to challenging chemical space. Finally, adaptation to multiple scale regimes, ranging from parallel milligram-based synthesis to decagram recirculating flow is presented.
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Ésteres , Catálisis , Ligandos , Oxidación-Reducción , SolventesRESUMEN
In today's world, mass-media and online social networks present us with unprecedented exposure to second-hand, vicarious experiences and thereby the chance of forming associations between previously innocuous events (e.g., being in a subway station) and aversive outcomes (e.g., footage or verbal reports from a violent terrorist attack) without direct experience. Such social threat, or fear, learning can have dramatic consequences, as manifested in acute stress symptoms and maladaptive fears. However, most research has so far focused on socially acquired threat responses that are expressed as increased arousal rather than active behavior. In three experiments (n = 120), we examined the effect of indirect experiences on behaviors by establishing a link between social threat learning and instrumental decision making. We contrasted learning from direct experience (i.e., Pavlovian conditioning) (experiment 1) against two common forms of social threat learning-social observation (experiment 2) and verbal instruction (experiment 3)-and how this learning transferred to subsequent instrumental decision making using behavioral experiments and computational modeling. We found that both types of social threat learning transfer to decision making in a strong and surprisingly inflexible manner. Notably, computational modeling indicated that the transfer of observational and instructed threat learning involved different computational mechanisms. Our results demonstrate the strong influence of others' expressions of fear on one's own decisions and have important implications for understanding both healthy and pathological human behaviors resulting from the indirect exposure to threatening events.
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Toma de Decisiones , Aprendizaje Social , Adulto , Nivel de Alerta , Condicionamiento Clásico , Miedo , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
BACKGROUND: Baloxavir marboxil is an antiviral drug that targets the endonuclease activity of the influenza virus polymerase acidic (PA) protein. PA I38T/M/F substitutions reduce its antiviral efficacy. OBJECTIVES: To understand the effects of the 19 possible amino acid (AA) substitutions at PA 38 on influenza A(H1N1)pdm09 polymerase activity and inhibition by baloxavir acid, the active metabolite of baloxavir marboxil. METHODS: Influenza A(H1N1)pdm09 viral polymerase complexes containing all 19 I38X AA substitutions were reconstituted in HEK293T cells in a mini-replicon assay. Polymerase complex activity and baloxavir inhibitory activity were measured in the presence or absence of 50 nM baloxavir acid. RESULTS: Only three substitutions (R, K, P) reduced polymerase activity to <79% of I38-WT. When compared with the prototypical baloxavir marboxil resistance marker T38, 5 substitutions conferred 10%-35% reductions in baloxavir acid inhibitory activity (M, L, F, Y, C) and 11 substitutions conferred >50% reductions (R, K, S, N, G, W, A, Q, E, D, H), while two substitutions (V, P) maintained baloxavir acid inhibitory activity. CONCLUSIONS: Most PA 38 substitutions permit a functional replication complex retaining some drug resistance in the mini-replicon assay. This study provides a targeted approach for virus rescue and analysis of novel baloxavir marboxil reduced-susceptibility markers, supports the consideration of a broader range of these markers during antiviral surveillance and adds to the growing knowledge of baloxavir marboxil resistance profiles.
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Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Antivirales/farmacología , Antivirales/uso terapéutico , Dibenzotiepinas , Farmacorresistencia Viral , Células HEK293 , Humanos , Gripe Humana/tratamiento farmacológico , Morfolinas/farmacología , Morfolinas/uso terapéutico , Oxazinas/farmacología , Piridonas/farmacología , Triazinas/farmacologíaRESUMEN
The value of rewards arises from multiple hedonic and motivational dimensions. Reward-encoding brain regions such as the ventral striatum (VS) are known to process these dimensions. However, the mechanism whereby distinct reward dimensions are selected for neural processing and guiding behavior remains unclear. Here, we used functional imaging to investigate how human individuals make either hedonic (liking) or motivational (wanting) evaluations of everyday items. We found that the two types of evaluations were differently modulated depending on whether participants won or lost these items. Neural activity in the VS encoded both hedonic and motivational dimensions of reward, whereas ventromedial prefrontal activity encoded primarily motivational evaluations and central orbitofrontal activity encoded predominantly hedonic evaluations. These distinct prefrontal representations arose regardless of which judgment was currently relevant for behavior. Critically, the VS preferentially processed the reward dimension currently being evaluated and showed judgment-specific functional connectivity with the dimension-specific prefrontal areas. Thus, our data are in line with a gating mechanism by which prefrontal cortex (PFC)-VS pathways flexibly encode reward dimensions depending on their behavioral relevance. These findings provide a prototype for a generalized information selection mechanism through content-tailored frontostriatal communication.
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Encéfalo/fisiología , Toma de Decisiones/fisiología , Filtrado Sensorial/fisiología , Adulto , Encéfalo/anatomía & histología , Mapeo Encefálico/métodos , Conducta de Elección/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Motivación , Corteza Prefrontal/fisiología , Recompensa , Estriado Ventral/diagnóstico por imagen , Adulto JovenRESUMEN
A novel bacterial strain was isolated from industrially contaminated waste water. In the presence of crude oil, this strain was shown to reduce the rate of total petroleum hydrocarbons (TPH) up to 97.10% in 24 h. This bacterium was subsequently identified by 16S rRNA gene sequence analysis and affiliated to the Serratia genus by the RDP classifier. Its genome was sequenced and annotated, and genes coding for catechol 1,2 dioxygenase and naphthalene 1,2-dioxygenase system involved in aromatic hydrocarbon catabolism, and LadA-type monooxygenases involved in alkane degradation, were identified. Gas Chromatography-Mass Spectrometry (GC-MS) analysis of crude oil after biological treatment showed that Serratia sp. Tan611 strain was able to degrade n-alkanes (from C13 to C25). This bacterium was also shown to produce a biosurfactant, the emulsification index (E24) reaching 43.47% and 65.22%, against vegetable and crude oil, respectively. Finally, the formation of a biofilm was increased in the presence of crude oil. These observations make Serratia sp. Tan611 a good candidate for hydrocarbon bioremediation.