Notes

Structural Evolution in BiNbO4.
Epithelial fusion is a key process of morphogenesis by which tissue connectivity is established between adjacent epithelial sheets. A striking and poorly understood feature of this process is "zippering," whereby a fusion point moves directionally along an organ rudiment. Here, we uncover the molecular mechanism underlying zippering during mouse spinal neural tube closure. Fusion is initiated via local activation of integrin β1 and focal anchorage of surface ectoderm cells to a shared point of fibronectin-rich basement membrane, where the neural folds first contact each other. Surface ectoderm cells undergo proximal junction shortening, establishing a transitory semi-rosette-like structure at the zippering point that promotes juxtaposition of cells across the midline enabling fusion propagation. Tissue-specific ablation of integrin β1 abolishes the semi-rosette formation, preventing zippering and causing spina bifida. We propose integrin-mediated anchorage as an evolutionarily conserved mechanism of general relevance for zippering closure of epithelial gaps whose disturbance can produce clinically important birth defects. We summarize recent work illuminating how cerebrospinal fluid (CSF) regulates brain function. More than a protective fluid cushion and sink for waste, the CSF is an integral CNS component with dynamic and diverse roles emerging in parallel with the developing CNS. This review examines the current understanding about early CSF and its maturation and roles during CNS development and discusses open questions in the field. We focus on developmental changes in the ventricular system and CSF sources (including neural progenitors and choroid plexus). We also discuss concepts related to the development of fluid dynamics including flow, perivascular transport, drainage, and barriers. TGF-β is long known to require Ras activation to induce EMT. In a recent issue of Nature, Massagué and colleagues (Su et al., 2020) identify RAS-responsive element binding protein 1 (RREB1) as a critical integrator of TGF-β and Ras signals during both developmental and cancer EMT programs. Chromosomes containing two centromeres (dicentrics) trigger chromosome instability that is avoided by the enigmatic process of centromere inactivation. In this issue of Developmental Cell, Palladino et al. (2020) combine in vivo chromosome engineering and Drosophila genetics to assess consequences of de novo centromere formation and clarify models of centromere inactivation. Boundary formation between nascent tissues prevents cell mixing, powering morphogenesis. In this issue of Developmental Cell, Sidor et al. (2020) describe a novel mechanism whereby the homophilic adhesion protein Crumbs regulates planar-polarized assembly of actomyosin cables at tissue boundaries by affecting dynamics of membrane recruitment of the myosin regulator Rho-kinase. Spatial repositioning of genes in nuclear space has been extensively linked to regulation of gene expression, but the mechanisms behind this directed movement have remained uncertain. In this issue of Developmental Cell, Wang et al. (2020) describe a nuclear actin-myosin-based pathway driving the movement of activated genes to the nuclear periphery. Drosophila neural progenitors require the transcriptional repressor Prospero to promptly establish the neuronal fate of their daughter cells to avoid tumorigenesis. In this issue of Developmental Cell, Liu et al. (2020) find that Prospero is mitotically implanted and forms liquid-like droplets mediating HP1a condensation to permanently repress its targets. Class I phosphoinositide-3-kinases (PI3Ks) phosphorylate PIP2 at its 3' inositol position to generate PIP3, a second messenger that influences signaling cascades regulating cellular growth, survival, and proliferation. Previous studies have suggested that PI3Kα activation involves dislodging the p85α nSH2 domain from the p110α catalytic subunit by binding activated receptor tyrosine kinases. We carried out molecular dynamics simulations to determine, mechanistically and structurally, how PI3Kα conformations are influenced by physiological effectors and the nSH2 domain. We demonstrate that changes in protein dynamics mediated by allosteric regulation significantly increase the population of catalytically competent states without changing the enzyme ground-state structure. Furthermore, we demonstrate that modulation of active-site residue interactions with enzyme substrates can reciprocally influence nSH2 domain dynamics. Together, these results suggest that dynamic allostery plays a role in populating the catalytically competent conformation of PI3Kα, and provide a key platform for the design of novel chemotherapeutic PI3Kα inhibitors. Members of the family Reoviridae package several copies of the viral polymerase complex into their capsid to carry out replication and transcription within viral particles. Classical single-particle reconstruction encounters difficulties resolving structures such as the intraparticle polymerase complex because refinement can converge to an incorrect map and because the map could depict a nonrepresentative subset of particles or an average of heterogeneous particles. Using the nine-segmented Fako virus, we tested hypotheses for the arrangement and number of polymerase complexes within the virion by measuring how well each hypothesis describes the set of cryoelectron microscopy images of individual viral particles. We find that the polymerase complex in Fako virus binds at ten possible sites despite having only nine genome segments. A single asymmetric configuration describes the arrangement of these complexes in both virions and genome-free capsids. Similarities between the arrangements of Reoviridae with 9, 10, and 11 segments indicate the generalizability of this architecture. Alzheimer's disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of β-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progression of tau and amyloid pathology. rTg4510 mice are characterized by widespread transcriptional differences in the entorhinal cortex with changes paralleling neuropathological burden across multiple brain regions. Differentially expressed transcripts overlap with genes identified in genetic studies of familial and sporadic AD. Pimicotinib concentration Systems-level analyses identify discrete co-expression networks associated with the progressive accumulation of tau that are enriched for genes and pathways previously implicated in AD pathology and overlap with co-expression networks identified in human AD cortex. Our data provide further evidence for an immune-response component in the accumulation of tau and reveal molecular pathways associated with the progression of AD neuropathology. The vagus nerve conveys gastrointestinal cues to the brain to control eating behavior. In obesity, vagally mediated gut-brain signaling is disrupted. Here, we show that the cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide synthesized proportional to the food consumed in vagal afferent neurons (VANs) of chow-fed rats. CART injection into the nucleus tractus solitarii (NTS), the site of vagal afferent central termination, reduces food intake. Conversely, blocking endogenous CART action in the NTS increases food intake in chow-fed rats, and this requires intact VANs. Viral-mediated Cartpt knockdown in VANs increases weight gain and daily food intake via larger meals and faster ingestion rate. In obese rats fed a high-fat, high-sugar diet, meal-induced CART synthesis in VANs is blunted and CART antibody fails to increase food intake. However, CART injection into the NTS retains its anorexigenic effect in obese rats. Restoring disrupted VAN CART signaling in obesity could be a promising therapeutic approach. Projections from the nucleus accumbens to the ventral pallidum (VP) regulate relapse in animal models of addiction. The VP contains GABAergic (VPGABA) and glutamatergic (VPGlu) neurons, and a subpopulation of GABAergic neurons co-express enkephalin (VPPenk). Rabies tracing reveals that VPGlu and VPPenk neurons receive preferential innervation from upstream D1- relative to D2-expressing accumbens neurons. Chemogenetic stimulation of VPGlu neurons inhibits, whereas stimulation of VPGABA and VPPenk neurons potentiates cocaine seeking in mice withdrawn from intravenous cocaine self-administration. Calcium imaging reveals cell type-specific activity patterns when animals learn to suppress drug seeking during extinction training versus engaging in cue-induced cocaine seeking. During cued seeking, VPGABA neurons increase their overall activity, and VPPenk neurons are selectively activated around nose pokes for cocaine. In contrast, VPGlu neurons increase their spike rate following extinction training. These data show that VP subpopulations differentially encode and regulate cocaine seeking, with VPPenk and VPGABA neurons facilitating and VPGlu neurons inhibiting cocaine seeking. Vesicle pool properties are known determinants of synaptic efficacy, but their potential role as modifiable substrates in forms of Hebbian plasticity is still unclear. Here, we investigate this using a nanoscale readout of functionally recycled vesicles in natively wired hippocampal CA3→CA1 circuits undergoing long-term potentiation (LTP). We show that the total recycled vesicle pool is larger after plasticity induction, with the smallest terminals exhibiting the greatest relative expansion. Changes in the spatial organization of vesicles accompany potentiation including a specific increase in the number of recycled vesicles at the active zone, consistent with an ultrastructural remodeling component of synaptic strengthening. The cAMP-PKA pathway activator, forskolin, selectively mimics some features of LTP-driven changes, suggesting that distinct and independent modules of regulation accompany plasticity expression. Our findings provide evidence for a presynaptic locus of LTP encoded in the number and arrangement of functionally recycled vesicles, with relevance for models of long-term plasticity storage. Gephyrin interacts with various GABAergic synaptic proteins to organize GABAergic synapse development. Among the multitude of gephyrin-binding proteins is IQSEC3, a recently identified component at GABAergic synapses that acts through its ADP ribosylation factor-guanine nucleotide exchange factor (ARF-GEF) activity to orchestrate GABAergic synapse formation. Here, we show that IQSEC3 knockdown (KD) reduced GABAergic synaptic density in vivo, suggesting that IQSEC3 is required for GABAergic synapse maintenance in vivo. We further show that IQSEC3 KD in the dentate gyrus (DG) increases seizure susceptibility and triggers selective depletion of somatostatin (SST) peptides in the DG hilus in an ARF-GEP activity-dependent manner. Strikingly, selective introduction of SST into SST interneurons in DG-specific IQSEC3-KD mice reverses GABAergic synaptic deficits. Thus, our data suggest that IQSEC3 is required for linking gephyrin-GABAA receptor complexes with ARF-dependent pathways to prevent aberrant, runaway excitation and thereby contributes to the integrity of SST interneurons and proper GABAergic synapse maintenance.
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