Carbon quaternization of redox active esters and olefins by decarboxylative coupling.

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, we report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (SH2) reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon---containing products from simple chemical feedstocks.

Adaptive coding of reward in schizophrenia, its change over time and relation to apathy.

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 affected in different domains, and in the reward domain in particular. Here we tested adaptive coding of reward in a large group of patients with schizophrenia (N = 86) and controls (N = 66). We assessed 1) the association between adaptive coding deficits and symptoms; 2) the longitudinal stability of deficits (the same task was performed three months apart); 3) the stability of results between two experimental sites. We used fMRI and the Monetary Incentive Delay task to assess participant' adaptation to two different reward ranges: a narrow and a wide range. We used a region of interest analysis, evaluating adaptation within striatal and visual regions. Patients and controls underwent a full demographic and clinical assessment. We found reduced adaptive coding in patients, due to 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 re-test, patients increased their narrow range slopes, showing improved adaptive coding, whereas controls slightly reduced them. At re-test, 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 a practice effect in patients, leading to improvement, with steeper slopes upon retest. However, in some patients, an overly steep slope may result in poor discriminability of larger rewards, due to early saturation of the brain response. Together, the loss of precision of reward representation in new (first exposure, underadaptation) and more familiar (re-test, overadaptation) situations may contribute to the multiple motivational symptoms in schizophrenia.

Neural reward representations enable utilitarian welfare maximization.

From deciding which meal to prepare for our guests to trading-off the pro-environmental 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 subjective value (utility) of the entire group. This notion requires comparing 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 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.Significance statement In many situations politicians and civilians strive to maximize the welfare of social groups. If the preferences of group members are in conflict, identifying the utilitarian welfare-maximizing option requires that decision makers can compare the strengths of conflicting preferences on a common scale. Yet, there is a fundamental lack of understanding which brain mechanisms enable such comparisons of conflicting utilities. Here, we show that brain regions involved in reward processing compute welfare comparisons by representing the preferences of others with a common neural code. This provides a neurobiological mechanism to compute utilitarian welfare maximization as desired by moral philosophy in the Humean tradition.

Bayesian reinforcement learning: A basic overview.

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.

Characterizing Human Habits in the Lab.

Habits pose a fundamental puzzle for those aiming to understand human behavior. They pervade our everyday lives and dominate some forms of psychopathology but are extremely hard to elicit in the lab. In this Registered Report, we developed novel experimental paradigms grounded in computational models, which suggest that habit strength should be proportional to the frequency of behavior and, in contrast to previous research, independent of value. Specifically, we manipulated how often participants performed responses in two tasks varying action repetition without, or separately from, variations in value. Moreover, we asked how this frequency-based habitization related to value-based operationalizations of habit and self-reported propensities for habitual behavior in real life. We find that choice frequency during training increases habit strength at test and that this form of habit shows little relation to value-based operationalizations of habit. Our findings empirically ground a novel perspective on the constituents of habits and suggest that habits may arise in the absence of external reinforcement. We further find no evidence for an overlap between different experimental approaches to measuring habits and no associations with self-reported real-life habits. Thus, our findings call for a rigorous reassessment of our understanding and measurement of human habitual behavior in the lab.

The Discovery of 7-Isopropoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-N-(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,2-a]pyrimidine-6-carboxamide (BIO-7488), a Potent, Selective, and CNS-Penetrant IRAK4 Inhibitor for the Treatment of Ischemic Stroke.

Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of damage-associated molecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation. Lead compounds from the series were evaluated in CNS PK/PD models of inflammation, as well as a mouse model of ischemic stroke. The SAR optimization detailed within culminates in the discovery of BIO-7488, a highly selective and potent IRAK4 inhibitor that is CNS penetrant and has excellent ADME properties.

Synthesis of Unnatural Amino Acids via Ni/Ag Electrocatalytic Cross-Coupling.

A simple protocol is outlined herein for rapid access to enantiopure unnatural amino acids (UAAs) from trivial glutamate and aspartate precursors. The method relies on Ag/Ni-electrocatalytic decarboxylative coupling and can be rapidly conducted in parallel (24 reactions at a time) to ascertain coupling viability followed by scale-up for the generation of useful quantities of UAAs for exploratory studies.

The social transmission of empathy relies on observational reinforcement learning.

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.

State of the art review. Complications after carpal tunnel release.

Carpal tunnel release (CTR) is the most performed surgery of the upper extremity. It is effective but not without complications. This state-of-the-art review covers most common intra- and postoperative complications after CTR. As endoscopic carpal tunnel release (ECTR) has developed over time, severe complications, such as nerve lesions, have diminished. ECTR still has a higher risk on transient nerve lesions. Open CTR on the other hand has a higher incidence of wound-related problems, including scar tenderness, irrespective of incision used. Most complications, such as pillar pain and infection, are ill-defined in the literature, leaving the exact incidence unknown and proposing challenges in treatment. The same is true for failure of treatment. Optimizing the length and location of incisions has played a vital role in reducing intra- and postoperative complications in CTR. It is expected that technical advances, such as ultrasound-guided percutaneous carpal tunnel release, will continue to play a role in the future.Level of evidence: V.

Nickel-Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers.

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.

Complex molecule synthesis by electrocatalytic decarboxylative cross-coupling.

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.

Acetylcholine and noradrenaline enhance foraging optimality in humans.

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.

Testosterone administration modulates inequality aversion in healthy males: evidence from computational modeling.

Fairness concerns play a prominent role in promoting cooperation in human societies. Social preferences involving fairness concern have been associated with individual testosterone levels. However, the causal effects of testosterone administration on fairness-related decision making remain to be elucidated. Here, we used a randomized, double-blind, between-participant design and administered testosterone or placebo gel to 120 healthy young men. Three hours after administration, participants performed a modified Dictator Game from behavioral economics, in which they were asked to choose one of two monetary allocations between themselves and anonymous partners. Participants were either in a position of advantageous inequality (i.e., endowed with more than others) or disadvantageous inequality (i.e., endowed with less than others). Computational modeling showed that inequality-related preferences explained behavior better than competing models. Importantly, compared with the placebo group, the testosterone group showed significantly reduced aversion to advantageous inequality but enhanced aversion to disadvantageous inequality. These findings suggest that testosterone facilitates decisions that prioritize selfish economic motives over fairness concerns, which in turn may boost status-enhancing behaviors.

Toward a Unifying Account of Dopamine's Role in Cost-Benefit Decision Making.

Dopamine is thought to play a crucial role in cost-benefit decision making, but so far there is no consensus on the precise role of dopamine in decision making. Here, we review the literature on dopaminergic manipulations of cost-benefit decision making in humans and evaluate how well different theoretical accounts explain the existing body of evidence. Reduced D2 stimulation tends to increase the willingness to bear delay and risk costs (i.e., wait for later rewards, take riskier options), while increased D1 and D2 receptor stimulation increases willingness to bear effort costs. We argue that the empirical findings can best be explained by combining the strengths of two theoretical accounts: in cost-benefit decision making, dopamine may play a dual role both in promoting the pursuit of psychologically close options (e.g., sooner and safer rewards) and in computing which costs are acceptable for a reward at stake. Moreover, we identify several limiting factors in the study designs of previous investigations that prevented a fuller understanding of dopamine's role in value-based choice. Together, the proposed theoretical framework and the methodological suggestions for future studies may bring us closer to a unifying account of dopamine in healthy and impaired cost-benefit decision making.

Sensory perception relies on fitness-maximizing codes.

Sensory information encoded by humans and other organisms is generally presumed to be as accurate as their biological limitations allow. However, perhaps counterintuitively, accurate sensory representations may not necessarily maximize the organism's chances of survival. To test this hypothesis, we developed a unified normative framework for fitness-maximizing encoding by combining theoretical insights from neuroscience, computer science, and economics. Behavioural experiments in humans revealed that sensory encoding strategies are flexibly adapted to promote fitness maximization, a result confirmed by deep neural networks with information capacity constraints trained to solve the same task as humans. Moreover, human functional MRI data revealed that novel behavioural goals that rely on object perception induce efficient stimulus representations in early sensory structures. These results suggest that fitness-maximizing rules imposed by the environment are applied at early stages of sensory processing in humans and machines.

A process model account of the role of dopamine in intertemporal choice.

Theoretical accounts disagree on the role of dopamine in intertemporal choice and assume that dopamine either promotes delay of gratification by increasing the preference for larger rewards or that dopamine reduces patience by enhancing the sensitivity to waiting costs. Here, we reconcile these conflicting accounts by providing empirical support for a novel process model according to which dopamine contributes to two dissociable components of the decision process, evidence accumulation and starting bias. We re-analyzed a previously published data set where intertemporal decisions were made either under the D2 antagonist amisulpride or under placebo by fitting a hierarchical drift diffusion model that distinguishes between dopaminergic effects on the speed of evidence accumulation and the starting point of the accumulation process. Blocking dopaminergic neurotransmission not only strengthened the sensitivity to whether a reward is perceived as worth the delay costs during evidence accumulation (drift rate) but also attenuated the impact of waiting costs on the starting point of the evidence accumulation process (bias). In contrast, re-analyzing data from a D1 agonist study provided no evidence for a causal involvement of D1R activation in intertemporal choices. Taken together, our findings support a novel, process-based account of the role of dopamine for cost-benefit decision making, highlight the potential benefits of process-informed analyses, and advance our understanding of dopaminergic contributions to decision making.

Protocol for Endoscopic Versus Open Cubital tunnel release (EVOCU): an open randomized controlled trial : EVOCU trial: Endoscopic Versus Open Cubital tunnel release.

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.

Comparing adaptive coding of reward in bipolar I disorder and schizophrenia.

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.

Association of pessimism with cardiovascular events and all-cause mortality.

Poor psychological health is associated with Takotsubo cardiomyopathy, cardiac syndrome X, coronary microcirculatory dysfunction, peripheral artery disease, or spontaneous coronary artery dissection. Data regarding pessimism, cardiovascular disease (CVD) events and mortality and all-cause mortality remained inconclusive. This systematic review and meta-analysis aim to provide an overview of the association between pessimism, CVD outcomes and mortality. A systematic search of electronic databases was conducted from inception through July 2022 for studies evaluating pessimism and adverse outcomes. A total of 17 studies published between 1966 and July 2022 met our inclusion criteria, for a total of 232,533 individuals. Pooled hazard ratios were calculated in random-effects meta-analyses. Based on pooled analysis of adjusted HRs, pessimism was associated with adjusted HR of 1.13 (95% CI 1.07-1.19) for all-cause mortality with minimal heterogeneity (I2 = 28.5%). Based on pooled analysis of adjusted HRs, pessimism was associated with adjusted HR of 1.30 (95% CI 0.43-3.95) for CHD mortality, adjusted HR of 1.41 (95% CI 1.05-1.91) for CVD mortality, and adjusted HR of 1.43 (95% CI 0.64-3.16) for stroke. In conclusion, pessimism seems to be significantly associated with a higher risk for and poorer outcomes from CVD events than optimistic styles. There are genetic and other bases for these life approaches, but behavioral, cognitive and meditative interventions can modify patients' level of pessimism, hopefully leading to better medical outcomes. Testing this theory would yield highly useful and practical data for clinical care.

Masquelet Procedure for the Treatment of Intra-articular Defects of the Wrist.

Background The purpose of this case series is to show our experiences with the Masquelet procedure in a variety of infected defects of the wrist. Case Description All consecutive patients that were treated between 2015 and 2021 were included in this case series. Five patients were included with an infected defect of the wrist, involving the radiocarpal and/or the distal radioulnar joints (DRUJ). All patients underwent thorough debridement of the defect and the created void was filled with a gentamicin/vancomycin cement spacer. Cultures were taken and appropriate antibiotic therapy was initiated. Two patients had a renewal of the cement spacer before definitive surgery. Finally, two patients received a DRUJ prosthesis, two patients had autologous bone grafting and wrist arthrodesis and one patient kept the cement spacer as distal ulna prosthesis due to minor complaints. Literature Review Current literature provides examples of the Masquelet procedure in traumatic defects or non-unions of the long bones. These cases are almost always about metaphyseal or diaphyseal defects but rarely include intra-articular joint defects therefore no comparisons could be made between the cases we reported with any existing literature. Clinical Relevance The Masquelet procedure showed to be effective in eradicating infected defects of the wrist involving the radiocarpal joint and/or DRUJ. All patients had an aseptic environment before performing definitive surgery. This technique showed to be save and no reinfections occurred.