Charge Characteristics of Agouti-Related Protein Implicate Potent Involvement of Heparan Sulfate Proteoglycans in Metabolic Function.

The endogenous melanocortin peptide agouti-related protein (AgRP) plays a well-known role in foraging, but its contribution to metabolic regulation is less understood. Mature AgRP(83-132) has distinct residues for melanocortin receptor binding and heparan sulfate interactions. Here, we show that AgRP increases ad libitum feeding and operant responding for food in mice, decreases oxygen consumption, and lowers body temperature and activity, indicating lower energy expenditure. AgRP increased the respiratory exchange ratio, indicating a reduction of fat oxidation and a shift toward carbohydrates as the primary fuel source. The duration and intensity of AgRP's effects depended on the density of its positively charged amino acids, suggesting that its orexigenic and metabolic effects depend on its affinity for heparan sulfate. These findings may have major clinical implications by unveiling the critical involvement of interactions between AgRP and heparan sulfate to the central regulation of energy expenditure, fat utilization, and possibly their contribution to metabolic disease

Rho-kinase regulates tissue morphogenesis via non-muscle myosin and LIM-kinase during Drosophila development

BACKGROUND: The Rho-kinases (ROCKs) are major effector targets of the activated Rho GTPase that have been implicated in many of the Rho-mediated effects on cell shape and movement via their ability to affect acto-myosin contractility. The role of ROCKs in cell shape change and motility suggests a potentially important role for Rho-ROCK signaling in tissue morphogenesis during development. Indeed, in Drosophila, a single ROCK ortholog, DRok, has been identified and has been found to be required for establishing planar cell polarity. RESULTS: We have examined a potential role for DRok in additional aspects of tissue morphogenesis using an activated form of the protein in transgenic flies. Our findings demonstrate that DRok activity can influence multiple morphogenetic processes, including eye and wing development. Furthermore, genetic studies reveal that Drok interacts with multiple downstream effectors of the Rho GTPase signaling pathway, including non-muscle myosin heavy chain, adducin, and Diaphanous in those developmental processes. Finally, in overexpression studies, we determined that Drok and Drosophila Lim-kinase interact in the developing nervous system. CONCLUSION: These findings indicate widespread diverse roles for DRok in tissue morphogenesis during Drosophila development, in which multiple DRok substrates appear to be required

A Case Study on Designing Evaluations of ML Explanations with Simulated User Studies

When conducting user studies to ascertain the usefulness of model explanations in aiding human decision-making, it is important to use real-world use cases, data, and users. However, this process can be resource-intensive, allowing only a limited number of explanation methods to be evaluated. Simulated user evaluations (SimEvals), which use machine learning models as a proxy for human users, have been proposed as an intermediate step to select promising explanation methods. In this work, we conduct the first SimEvals on a real-world use case to evaluate whether explanations can better support ML-assisted decision-making in e-commerce fraud detection. We study whether SimEvals can corroborate findings from a user study conducted in this fraud detection context. In particular, we find that SimEvals suggest that all considered explainers are equally performant, and none beat a baseline without explanations -- this matches the conclusions of the original user study. Such correspondences between our results and the original user study provide initial evidence in favor of using SimEvals before running user studies. We also explore the use of SimEvals as a cheap proxy to explore an alternative user study set-up. We hope that this work motivates further study of when and how SimEvals should be used to aid in the design of real-world evaluations.Comment: 9 pages, 2 figure

UBP12 and UBP13 negatively regulate the activity of the ubiquitin-dependent peptidases DA1, DAR1 and DAR2

Protein ubiquitination is a very diverse post-translational modification leading to protein degradation or delocalization, or altering protein activity. In Arabidopsis thaliana, two E3 ligases, BIG BROTHER (BB) and DA2, activate the latent peptidases DA1, DAR1 and DAR2 by mono-ubiquitination at multiple sites. Subsequently, these activated peptidases destabilize various positive regulators of growth. Here, we show that two ubiquitin-specific proteases, UBP12 and UBP13, deubiquitinate DA1, DAR1 and DAR2, hence reducing their peptidase activity. Overexpression of UBP12 or UBP13 strongly decreased leaf size and cell area, and resulted in lower ploidy levels. Mutants in which UBP12 and UBP13 were downregulated produced smaller leaves that contained fewer and smaller cells. Remarkably, neither UBP12 nor UBP13 were found to be cleavage substrates of the activated DA1. Our results therefore suggest that UBP12 and UBP13 work upstream of DA1, DAR1 and DAR2 to restrict their protease activity and hence fine-tune plant growth and development

Perspectives on Incorporating Expert Feedback into Model Updates

Machine learning (ML) practitioners are increasingly tasked with developing models that are aligned with non-technical experts' values and goals. However, there has been insufficient consideration on how practitioners should translate domain expertise into ML updates. In this paper, we consider how to capture interactions between practitioners and experts systematically. We devise a taxonomy to match expert feedback types with practitioner updates. A practitioner may receive feedback from an expert at the observation- or domain-level, and convert this feedback into updates to the dataset, loss function, or parameter space. We review existing work from ML and human-computer interaction to describe this feedback-update taxonomy, and highlight the insufficient consideration given to incorporating feedback from non-technical experts. We end with a set of open questions that naturally arise from our proposed taxonomy and subsequent survey

Meaningful Gameplay Design and the Effect on Eudaimonic and Hedonic Gaming Experience

Past research has looked into meaningfulness in video game narratives, as well as meaningful play. However, more empirical studies are needed to understand the mechanisms of meaningful play. This paper first investigates how the design of game dialogues may enable meaningfulness in video games (eudaimonic gaming experience) and how it relates to game enjoyment (hedonic gaming experience). Second, it also examines how meaningful play influences prosocial attitudes toward culturally different outgroups. A pre-posttest experiment of a management game was conducted with 174 adult participants. Participants were randomly assigned to either a game with moral scenarios or one without. Results showed that participants who played the game with moral decision-making perceived a higher level of meaningfulness and game enjoyment. No significant relationship was found between perceived meaningfulness and intergroup perceptions

The Effect of Intermittent Theta Burst Stimulation (iTBS) in Patients With Alcohol Use Disorder: Study Protocol for a Randomized Controlled Trial.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation technique which has a treatment potential for alcohol use disorder. Intermittent theta burst stimulation (iTBS) is a new rTMS technique which is shorter in duration and thus with better tolerability and shows similar efficacy as rTMS for the treatment of depression. The effect of iTBS on reducing craving in alcohol use disorder patients requires further investigation. METHODS: A randomized, controlled, single-blind, multicenter study with 60 alcohol use disorder patients randomized (2:1) to the iTBS group or the control group (sham iTBS). The stimulation target will be identical in the left dorsolateral prefrontal cortex (DLPFC). Baseline evaluations will be occurred before the intervention, after the intervention immediately, and 1 and 3 months after the intervention. The primary outcome of the study will be decrease of visual analogue scale (VAS) scores from baseline to the end of treatment. DISCUSSION: This study is a randomized controlled trial to investigate the efficacy of left DLPFC iTBS in a population of alcohol use disorder patients, compared with sham iTBS. If it is effective for alcohol use disorder, it may provide a potential treatment which is tolerable, accessible, and clinical useful. CINICAL TRIAL REGISTRATION: This study is registered in the ClinicalTrials with trial number NCT03932149. Registered 17 April 2019