Optical Approaches for Investigating Neuromodulation and G Protein-Coupled Receptor Signaling.

Despite the fact that roughly 40% of all US Food and Drug Administration (FDA)-approved pharmacological therapeutics target G protein-coupled receptors (GPCRs), there remains a gap in our understanding of the physiologic and functional role of these receptors at the systems level. Although heterologous expression systems and in vitro assays have revealed a tremendous amount about GPCR signaling cascades, how these cascades interact across cell types, tissues, and organ systems remains obscure. Classic behavioral pharmacology experiments lack both the temporal and spatial resolution to resolve these long-standing issues. Over the past half century, there has been a concerted effort toward the development of optical tools for understanding GPCR signaling. From initial ligand uncaging approaches to more recent development of optogenetic techniques, these strategies have allowed researchers to probe longstanding questions in GPCR pharmacology both in vivo and in vitro. These tools have been employed across biologic systems and have allowed for interrogation of everything from specific intramolecular events to pharmacology at the systems level in a spatiotemporally specific manner. In this review, we present a historical perspective on the motivation behind and development of a variety of optical toolkits that have been generated to probe GPCR signaling. Here we highlight how these tools have been used in vivo to uncover the functional role of distinct populations of GPCRs and their signaling cascades at a systems level. SIGNIFICANCE STATEMENT: G protein-coupled receptors (GPCRs) remain one of the most targeted classes of proteins for pharmaceutical intervention, yet we still have a limited understanding of how their unique signaling cascades effect physiology and behavior at the systems level. In this review, we discuss a vast array of optical techniques that have been devised to probe GPCR signaling both in vitro and in vivo.

MELLODDY: Cross-pharma Federated Learning at Unprecedented Scale Unlocks Benefits in QSAR without Compromising Proprietary Information.

Federated multipartner machine learning has been touted as an appealing and efficient method to increase the effective training data volume and thereby the predictivity of models, particularly when the generation of training data is resource-intensive. In the landmark MELLODDY project, indeed, each of ten pharmaceutical companies realized aggregated improvements on its own classification or regression models through federated learning. To this end, they leveraged a novel implementation extending multitask learning across partners, on a platform audited for privacy and security. The experiments involved an unprecedented cross-pharma data set of 2.6+ billion confidential experimental activity data points, documenting 21+ million physical small molecules and 40+ thousand assays in on-target and secondary pharmacodynamics and pharmacokinetics. Appropriate complementary metrics were developed to evaluate the predictive performance in the federated setting. In addition to predictive performance increases in labeled space, the results point toward an extended applicability domain in federated learning. Increases in collective training data volume, including by means of auxiliary data resulting from single concentration high-throughput and imaging assays, continued to boost predictive performance, albeit with a saturating return. Markedly higher improvements were observed for the pharmacokinetics and safety panel assay-based task subsets.

Does Researcher Allegiance Bias Outcomes in Psychotherapy Research? A Quasi-Experimental Secondary Analysis.

Researchers who conduct studies comparing the efficacy of two treatments often find that their preferred treatment outperforms the comparison treatment. This finding has been labelled the allegiance association. Although this association is robust, it is unclear whether it reflects an allegiance bias on the part of the researchers or whether it is noncausal, with researchers being allied to the more effective treatments. This study applied a quasi-experimental method proposed by a previous study to 19 pairs of treatment comparison studies. Each member of a pair had used the same two psychotherapies to treat clients with the same disorder, but the researchers in each of the two studies had opposing allegiances. If the authors of one study in the pair concluded that their preferred treatment was superior and the authors of the other study concluded that their preferred treatment was superior or that the two treatments were equivalent, these patterns would suggest allegiance bias. In 10 of the 19 pairs, the patterns were consistent with the operation of an allegiance bias, indicating that although allegiance biases are not inevitable, they are ubiquitous. Practitioners and other psychotherapy research consumers should use caution when interpreting the findings from treatment comparison studies.

Bipolar disorders and narcissism: Diagnostic concerns, conceptual commonalities and potential antecedents.

Narcissistic personality disorder (NPD) and the manic and hypomanic episodes found in the bipolar disorders are characterized by grandiosity. It is possible that this shared grandiosity is a 'homologous structure' or reflects a superficial similarity between two disparate conditions. It is, however, possible that NPD and the bipolar disorders are more closely related than implied by their segregation into the separate superordinate categories of personality disorders and mood disorders. Whereas narcissism is considered to be a life-course, stable trait and the bipolar disorders are characterized by episodes of mania and depression, there is considerable research indicating that narcissism may be linked to mood instability (including depression) and bipolar disorder may have a pervasive personality component (i.e., hypomanic personality). Utilizing dimensional models of psychopathology, the current review examined the evidence linking narcissism and the bipolar disorders and suggests that considerable overlap may exist in the domains associated with reward-seeking, harm avoidance and social functioning.

Arrestin-3 scaffolding of the JNK3 cascade suggests a mechanism for signal amplification.

Scaffold proteins tether and orient components of a signaling cascade to facilitate signaling. Although much is known about how scaffolds colocalize signaling proteins, it is unclear whether scaffolds promote signal amplification. Here, we used arrestin-3, a scaffold of the ASK1-MKK4/7-JNK3 cascade, as a model to understand signal amplification by a scaffold protein. We found that arrestin-3 exhibited >15-fold higher affinity for inactive JNK3 than for active JNK3, and this change involved a shift in the binding site following JNK3 activation. We used systems biochemistry modeling and Bayesian inference to evaluate how the activation of upstream kinases contributed to JNK3 phosphorylation. Our combined experimental and computational approach suggested that the catalytic phosphorylation rate of JNK3 at Thr-221 by MKK7 is two orders of magnitude faster than the corresponding phosphorylation of Tyr-223 by MKK4 with or without arrestin-3. Finally, we showed that the release of activated JNK3 was critical for signal amplification. Collectively, our data suggest a "conveyor belt" mechanism for signal amplification by scaffold proteins. This mechanism informs on a long-standing mystery for how few upstream kinase molecules activate numerous downstream kinases to amplify signaling.

Evidence for the taxonic latent structure for DSM-5 intermittent explosive disorder in adults.

BACKGROUND: Identification of individuals with clinically significant aggressive behavior is critical for the prevention and management of human aggressive behavior. A previous population-based taxometric study reported that the Diagnostic and Statistical Manual of Mental Disorders-4th Edition (DSM-IV) intermittent explosive disorder (IED) belongs to its own discrete class (taxon) rather than existing along a continuum. METHODS: This study sought to extend previous population-based findings in a clinical research sample of adults with DSM-5 IED (n = 346), adults with non-aggressive DSM-5 disorders (n = 293), and adults without any DSM-5 disorder (n = 174), using standardized assessments of DSM-5 diagnoses, aggression, and other related measures not available in past studies. RESULTS: Analyses revealed a taxonic latent structure that overlapped with the DSM-5 diagnosis of IED. Within the sample, taxon group members had higher scores on a variety of measures of psychopathology than did the complement members of the sample. Comorbidity of other diagnoses with IED did not affect these results. CONCLUSION: These findings support the proposition that DSM-5 IED represents a distinct behavioral disorder rather than the severe end of an aggressive behavior continuum.

Neuropsychological Phenotypes of Pediatric Anti-Myelin Oligodendrocyte Glycoprotein Associated Disorders: A Case Series.

Emerging research has demonstrated that anti-myelin oligodendrocyte associated disorders (MOG-AD) are associated with a less severe clinical course than demyelinating conditions associated with the presence of aquaporin-4 antibodies. While a heterogeneity of neuropsychological outcomes in pediatric demyelinating conditions have been described in the literature, no studies to date have investigated the neuropsychological sequelae of pediatric MOG-AD specifically. The objective of the present case series was to describe the clinical and neuropsychological phenotypes of seven pediatric patients (ages 3-15 years) with MOG-AD of different diagnoses (e.g., acute disseminated encephalomyelitis, optic neuritis, multiple sclerosis, and neuromyelitis spectrum disorders). Neuropsychological outcomes were evaluated by retrospective chart review. Results indicated largely intact neuropsychological profiles in five of the seven patients, with mild weaknesses in attention, executive functioning, processing speed, visual-motor/fine-motor skills, and mood concerns being observed. Two patients with a Kurtzke Extended Disability Status Scale of 0 still demonstrated findings on neuropsychological testing. Of the other two patients, one demonstrated higher levels of impairment in the context of a complex medical history and premorbid learning difficulties, while the other demonstrated declines in functioning likely associated with an earlier age of onset. Findings suggest that neuropsychological outcomes may be correspondingly less severe in this population compared with what has previously been described in the pediatric demyelinating disease literature. This differential impact may contribute to the heterogeneity of neuropsychological outcomes found in previous studies, and future research should separate participants with myelin oligodendrocyte antibodies given the difference in clinical course, treatment outcomes, and neuropsychological sequelae.

BRADSHAW: a system for automated molecular design.

This paper introduces BRADSHAW (Biological Response Analysis and Design System using an Heterogenous, Automated Workflow), a system for automated molecular design which integrates methods for chemical structure generation, experimental design, active learning and cheminformatics tools. The simple user interface is designed to facilitate access to large scale automated design whilst minimising software development required to introduce new algorithms, a critical requirement in what is a very fast moving field. The system embodies a philosophy of automation, best practice, experimental design and the use of both traditional cheminformatics and modern machine learning algorithms.

Correction to: BRADSHAW: a system for automated molecular design.

The original version of this article unfortunately contained some mistakes in the references.

Design thinking in medical ethics education.

BACKGROUND: Design thinking (DT) is a tool for generating and exploring ideas from multiple stakeholders. We used DT principles to introduce students to the ethical implications of organ transplantation. Students applied DT principles to propose solutions to maximise social justice in liver transplant allocation. METHODS: A 150 min interactive workshop was integrated into the longitudinal ethics curriculum. Following a group didactic on challenges of organ donation in the USA supplemented by patient stories, teams of students considered alternative solutions to optimise fairness of organ distribution and ethical implications of changing the current model. Facilitators led students through DT steps of empathy, defining the team's point of view, ideating on potential solutions, prototyping a specific idea and testing the idea through oral presentation, with questions and answers by peers and faculty. The curriculum was evaluated with presurveys and postsurveys including quantitative and open-ended items. RESULTS: 100 first year medical students participated. Before the session, 75.3% of students had no practical experience with DT. Following participation, students reported an increased understanding of the current liver transplant allocation system (p<0.01) and an increased appreciation of shortcomings of the current organ allocation system (p<0.01). After the session, 73.8% of students felt that DT could be used to approach complex health system problems. DISCUSSION: Students participating in a DT workshop displayed improved knowledge and attitudes toward organ transplantation and DT. In this pilot study, DT showed promise as a student-led approach emphasising collaboration and creativity in ethics curricula in medical education.