Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating rewardrelated phenotypes, including ethanol consumption, across phyla.

Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and the vacuolar protein sorting-associated protein 4A (VPS4A) gene in humans, and the causal role of Vps4 for hyperactivity was validated in Drosophila. Our data provide a neurobehavioral model explaining the heterogeneity of rewardrelated behaviors and generate a hypothesis accounting for their enduring nature.uccessful behavioral adaptation requires effective reward processing that determines whether a desired goal is approached and maintained. Reward processing can be separated into behavioral anticipation or reward expectancy as a consequence of learning and behavioral and subjective responses to rewarding outcomes (1). In humans, dysfunctional reward processing (in particular, dysfunctional reward anticipation) has been implicated in various externalizing disorders, including attention-deficit hyperactivity disorder (ADHD) (2) and addiction (3). Brain regions involved in reward anticipation include the ventral tegmental area, the medial forebrain bundle, and the nucleus accumbens/ventral striatum (VS; including the ventral caudate-putamen) as well as the ventromedial and insular cortices (4). More recently, observations have been reported to link reward processing in humans with cortical activation (5), including the primary somatosensory (6), primary visual (V1) (7), and auditory (8) cortices. Dopamine is the principal neurotransmitter regulating reward processing, particularly through the mesocorticolimbic pathway (9), the neuronal projection from the ventral tegmental area to the VS and prefrontal cortex. A general feature of striatal information processing is the control by rewardrelated dopamine signals of direct and indirect cortical inputs from different neurotransmitter systems, including noradrenaline, glutamate, and GABA as well as acetylcholine, endogenous opioids, and cannabinoids (10). As a consequence, striatal dopaminergic activity integrates cortical and subcortical inputs with reward response. In addition to direct and indirect regulation by heteroceptors, dopamine release is regulated by presynaptic autoreceptors of the D2 family, in particular D2 dopamine receptors (DRD2) that Author contributions: T.J., S.D., C.P.M., J.F., A.R., H.F., and G.S. designed research; T.J., C.M., S.D., D.A.G., C.T., B.R., F.N., T.B., G.J.B., A.L.W.B., U.B...

. (2014) Oxytocin receptor genotype modulates ventral striatal activity to social cues and response to stressful life events. Biological Psychiatry, 76 (5). pp. 367-376. Permanent WRAP url:http://wrap.warwick.ac.uk/77505 Copyright and reuse:The Warwick Research Archive Portal (WRAP) makes this work by researchers of the University of Warwick available open access under the following conditions. Copyright © and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable the material made available in WRAP has been checked for eligibility before being made available. Copies of full items can be used for personal research or study, educational, or not-forprofit purposes without prior permission or charge. Provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way.

Hepatocellular carcinoma (HCC) is an immunotherapy-resistant malignancy characterized by high cellular heterogeneity. The diversity of cell types and the interplay between tumor and non-tumor cells remain to be clarified. Single cell RNA sequencing of human and mouse HCC tumors revealed heterogeneity of cancer-associated fibroblast (CAF). Cross-species analysis determined the prominent CD36+ CAFs exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). Lineage-tracing assays showed CD36+CAFs were derived from hepatic stellate cells. Furthermore, CD36 mediated oxidized LDL uptake-dependent MIF expression via lipid peroxidation/p38/CEBPs axis in CD36+ CAFs, which recruited CD33+myeloid-derived suppressor cells (MDSCs) in MIF- and CD74-dependent manner. Co-implantation of CD36+ CAFs with HCC cells promotes HCC progression in vivo. Finally, CD36 inhibitor synergizes with anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC. Our work underscores the importance of elucidating the function of specific CAF subset in understanding the interplay between the tumor microenvironment and immune system.