Notes

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Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the class IB PI3K catalytic subunit (p110γ) playing key roles in immune signalling. p110γ is a key factor in inflammatory diseases and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall, this work provides unique insights into regulatory mechanisms that control PI3Kγ kinase activity and shows a framework for the design of PI3K isoform and mutant selective inhibitors.Dynamins are targeted to specific cellular membranes that they remodel via membrane fusion or fission. The molecular basis of conferring specificity to dynamins for their target membrane selection is not known. Here, we report a mechanism of nuclear membrane recruitment of Drp6, a dynamin member in Tetrahymena thermophila. Recruitment of Drp6 depends on a domain that binds to cardiolipin (CL)-rich bilayers. Consistent with this, nuclear localization of Drp6 was inhibited either by depleting cellular CL or by substituting a single amino acid residue that abolished Drp6 interactions with CL. Inhibition of CL synthesis, or perturbation in Drp6 recruitment to nuclear membrane, caused defects in the formation of new macronuclei post-conjugation. Taken together, our results elucidate a molecular basis of target membrane selection by a nuclear dynamin and establish the importance of a defined membrane-binding domain and its target lipid in facilitating nuclear expansion.The Adolescent Brain Cognitive Development (ABCD) study is an unprecedented longitudinal neuroimaging sample that tracks the brain development of over 9-10 year olds through adolescence. At the core of this study are the three tasks that are completed repeatedly within the MRI scanner, one of which is the stop-signal task. In analyzing the available stopping experimental code and data, we identified a set of design issues that we believe significantly compromise its value. These issues include but are not limited to variable stimulus durations that violate basic assumptions of dominant stopping models, trials in which stimuli are incorrectly not presented, and faulty stop-signal delays. We present eight issues, show their effect on the existing ABCD data, suggest prospective solutions including task changes for future data collection and preliminary computational models, and suggest retrospective solutions for data users who wish to make the most of the existing data.Aging, obesity, hypertension, and physical inactivity are major risk factors for endothelial dysfunction and cardiovascular disease (CVD). We applied fluorescence-activated cell sorting (FACS), RNA sequencing, and bioinformatic methods to investigate the common effects of CVD risk factors in mouse cardiac endothelial cells (ECs). Aging, obesity, and pressure overload all upregulated pathways related to TGF-β signaling and mesenchymal gene expression, inflammation, vascular permeability, oxidative stress, collagen synthesis, and cellular senescence, whereas exercise training attenuated most of the same pathways. We identified collagen chaperone Serpinh1 (also called as Hsp47) to be significantly increased by aging and obesity and repressed by exercise training. Mechanistic studies demonstrated that increased SERPINH1 in human ECs induced mesenchymal properties, while its silencing inhibited collagen deposition. Our data demonstrate that CVD risk factors significantly remodel the transcriptomic landscape of cardiac ECs inducing inflammatory, senescence, and mesenchymal features. SERPINH1 was identified as a potential therapeutic target in ECs.Callosal projections from primary somatosensory cortex (S1) are key for processing somatosensory inputs and integrating sensory-motor information. How the callosal innervation pattern in S1 is formed during early postnatal development is not clear. We found that the normal termination pattern of these callosal projections is disrupted in cortex specific NMDAR mutants. Rather than projecting selectively to the primary/secondary somatosensory cortex (S1/S2) border, axons were uniformly distributed throughout S1. In addition, the density of this projection increased over postnatal life until the mice died by P30. BAY 1217389 cell line By combining genetic and antibody-mediated loss of function, we demonstrated that it is GluN2B-containing NMDA receptors in target S1 that mediate this guidance phenotype, thus playing a central role in interhemispheric connectivity. Furthermore, we found that this function of NMDA receptors in callosal circuit formation is independent of ion channel function and works with the EPHRIN-B/EPHB system. Thus, NMDAR in target S1 cortex regulates the formation callosal circuits perhaps by modulating EPH-dependent repulsion.Memory helps guide behavior, but which experiences from the past are prioritized? Classic models of learning posit that events associated with unpredictable outcomes as well as, paradoxically, predictable outcomes, deploy more attention and learning for those events. Here, we test reinforcement learning and subsequent memory for those events, and treat signed and unsigned reward prediction errors (RPEs), experienced at the reward-predictive cue or reward outcome, as drivers of these two seemingly contradictory signals. By fitting reinforcement learning models to behavior, we find that both RPEs contribute to learning by modulating a dynamically changing learning rate. We further characterize the effects of these RPE signals on memory and show that both signed and unsigned RPEs enhance memory, in line with midbrain dopamine and locus-coeruleus modulation of hippocampal plasticity, thereby reconciling separate findings in the literature.
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