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Neurons in neocortical layer 1 (L1) are thought to regulate attentional processes through integration of long-range inputs and disinhibitory effects on the underlying cortex. A new study combines genetically targeted voltage imaging and optogenetics to elucidate the input-output transformations of the L1 network in the mouse somatosensory cortex, revealing unique features of sensory-evoked dynamics in L1 neurons. In this issue of Neuron, Morrens et al. (2020) show that stimulus-evoked dopamine responses are enhanced by novelty and increase the rate at which animals acquire conditioned responses. These results provide a candidate neural mechanism for latent inhibition and illustrate a new role of dopamine signals in learning. GSK269962A supplier Experiments identify cortical layer specific effects during induced arousal from general anesthesia. In this issue of Neuron, Redinbaugh et al. (2020) find evidence that central lateral thalamic nucleus electrical stimulation reactivates the cortex by restoring deep-layer firing rates and modulating feedforward and feedback connectivity. Conversion of glial cells into functional neurons represents a potential therapeutic approach for replenishing neuronal loss associated with neurodegenerative diseases and brain injury. Previous attempts in this area using expression of transcription factors were hindered by the low conversion efficiency and failure of generating desired neuronal types in vivo. Here, we report that downregulation of a single RNA-binding protein, polypyrimidine tract-binding protein 1 (Ptbp1), using in vivo viral delivery of a recently developed RNA-targeting CRISPR system CasRx, resulted in the conversion of Müller glia into retinal ganglion cells (RGCs) with a high efficiency, leading to the alleviation of disease symptoms associated with RGC loss. Furthermore, this approach also induced neurons with dopaminergic features in the striatum and alleviated motor defects in a Parkinson's disease mouse model. Thus, glia-to-neuron conversion by CasRx-mediated Ptbp1 knockdown represents a promising in vivo genetic approach for treating a variety of disorders due to neuronal loss. Many cytosolic proteins lacking a signal peptide, called leaderless cargoes, are secreted through unconventional secretion. Vesicle trafficking is a major pathway involved. It is unclear how leaderless cargoes enter into the vesicle. Here, we find a translocation pathway regulating vesicle entry and secretion of leaderless cargoes. We identify TMED10 as a protein channel for the vesicle entry and secretion of many leaderless cargoes. The interaction of TMED10 C-terminal region with a motif in the cargo accounts for the selective release of the cargoes. In an in vitro reconstitution assay, TMED10 directly mediates the membrane translocation of leaderless cargoes into the liposome, which is dependent on protein unfolding and enhanced by HSP90s. In the cell, TMED10 localizes on the endoplasmic reticulum (ER)-Golgi intermediate compartment and directs the entry of cargoes into this compartment. Furthermore, cargo induces the formation of TMED10 homo-oligomers which may act as a protein channel for cargo translocation. The habenula complex is appreciated as a critical regulator of motivated and pathological behavioral states via its output to midbrain nuclei. Despite this, transcriptional definition of cell populations that comprise both the medial habenular (MHb) and lateral habenular (LHb) subregions in mammals remain undefined. To resolve this, we performed single-cell transcriptional profiling and highly multiplexed in situ hybridization experiments of the mouse habenula complex in naive mice and those exposed to an acute aversive stimulus. Transcriptionally distinct neuronal cell types identified within the MHb and LHb, were spatially defined, differentially engaged by aversive stimuli, and had distinct electrophysiological properties. Cell types identified in mice also displayed a high degree of transcriptional similarity to those previously described in zebrafish, highlighting the well-conserved nature of habenular cell types across the phylum. These data identify key molecular targets within habenular cell types and provide a critical resource for future studies. G protein-coupled receptors (GPCRs) are membrane-bound proteins that depend on their lipid environment to carry out their physiological function. Combined efforts from many theoretical and experimental studies on the lipid-protein interaction profile of several GPCRs hint at an intricate relationship of these receptors with their surrounding membrane environment, with several lipids emerging as particularly important. Using coarse-grained molecular dynamics simulations, we explore the lipid-protein interaction profiles of 28 different GPCRs, spanning different levels of classification and conformational states and totaling to 1 ms of simulation time. We find a close relationship with lipids for all GPCRs simulated, in particular, cholesterol and phosphatidylinositol phosphate (PIP) lipids, but the number, location, and estimated strength of these interactions is dependent on the specific GPCR as well as its conformational state. Although both cholesterol and PIP lipids bind specifically to GPCRs, they utilize distinct mechanisms. Interactions with PIP lipids are mediated by charge-charge interactions with intracellular loop residues and stabilized by one or both of the transmembrane helices linked by the loop. Interactions with cholesterol, on the other hand, are mediated by a hydrophobic environment, usually made up of residues from more than one helix, capable of accommodating its ring structure and stabilized by interactions with aromatic and charged/polar residues. Cholesterol binding to GPCRs occurs in a small number of sites, some of which (like the binding site on the extracellular side of transmembrane 6/7) are shared among many class A GPCRs. Combined with a thorough investigation of the local membrane structure, our results provide a detailed picture of GPCR-lipid interactions. Additionally, we provide an accompanying website to interactively explore the lipid-protein interaction profile of all GPCRs simulated to facilitate analysis and comparison of our data. Cytoplasmic dynein is a two-headed molecular motor that moves to the minus end of a microtubule by ATP hydrolysis free energy. By employing its two heads (motor domains), cytoplasmic dynein exhibits various bipedal stepping motions inchworm and hand-over-hand motions, as well as nonalternating steps of one head. However, the molecular basis to achieve such diverse stepping manners remains unclear because of the lack of an experimental method to observe stepping and the ATPase reaction of dynein simultaneously. Here, we propose a kinetic model for bipedal motions of cytoplasmic dynein and perform Gillespie Monte Carlo simulations that qualitatively reproduce most experimental data obtained to date. The model represents the status of each motor domain as five states according to conformation and nucleotide- and microtubule-binding conditions of the domain. In addition, the relative positions of the two domains were approximated by three discrete states. Accompanied by ATP hydrolysis cycles, the model dynein stochastically and processively moved forward in multiple steps via diverse pathways, including inchworm and hand-over-hand motions, similarly to experimental data. The model reproduced key experimental motility-related properties, including velocity and run length, as functions of the ATP concentration and external force, therefore providing a plausible explanation of how dynein achieves various stepping manners with explicit characterization of nucleotide states. Our model highlights the uniqueness of dynein in the coupling of ATPase with its movement during both inchworm and hand-over-hand stepping. OBJECTIVE To assess the effectiveness of weight loss interventions on pain and disability in people with knee and hip osteoarthritis (OA) and spinal pain. DESIGN Intervention systematic review. LITERATURE SEARCH Eight online databases and clinical trial registries. STUDY SELECTION CRITERIA Randomised controlled trials of any weight loss intervention (e.g. diet, physical activity, surgical, pharmaceutical) that reported pain or disability outcomes of people with knee or hip OA, or spinal pain. DATA SYNTHESIS We calculated mean differences (MD) or standardised mean differences (SMD) and 95% confidence intervals (CI). We used the Cochrane risk of bias tool to assess Risk of Bias and GRADE to judge credibility of evidence. RESULTS 22 trials with 3602 participants. There was very low to low credibility evidence for a moderate effect of weight loss interventions on pain intensity (10 trials, n=1806, SMD -0.54, 95%CI -0.86, -0.22, I2= 87%, p less then 0.001) and a small effect on disability (11 trials, n=1821, SMD -0.32, 95%CI -0.49, -0.14, I2=58%, p less then 0.001) compared to minimal care for people with OA. For knee OA there was low to moderate credibility evidence that weight loss interventions were not more effective than exercise only for pain intensity or disability (4 trials n=673, SMD -0.13, 95%CI -0.40, 0.14, I2= 55%; 5 trials, n=737, SMD -0.20 95%CI -0.41, 0.00, I2= 32%). CONCLUSIONS Weight loss interventions may have small to moderate improvements on pain and disability for OA compared to minimal care. There was limited and inconclusive evidence for weight loss interventions targeting spinal pain. J Orthop Sports Phys Ther, Epub 9 Apr 2020. doi10.2519/jospt.2020.9041."Special tests" for rotator cuff-related shoulder pain (RCRSP) have passed their sell-by date. In this Viewpoint, we outline fundamental flaws in the validity of these tests and their proposed ability to accurately identify a pathoanatomical source of pain. The potential harm of these special tests comes in conjunction with imaging findings that are utilized to inform a structural diagnosis or recommend invasive procedures. We offer recommendations for performing a clinical interview and physical examination for people with RCRSP that does not include shoulder orthopaedic tests. J Orthop Sports Phys Ther, Epub 9 Apr 2020. doi10.2519/jospt.2020.0606.OBJECTIVES To determine the added benefit of combining dry needling with a guideline-based physical therapy treatment program consisting of exercise and manual therapy on pain and disability in people with chronic neck pain. DESIGN Randomized controlled trial. METHODS Participants were randomized to receive either guideline-based physical therapy or guideline-based physical therapy plus dry needling. The primary outcomes, measured at 1 month post-randomization, were average pain intensity (in the previous 24 hours and in the previous week) measured with a numerical pain rating scale (0-10), and disability measured with the Neck Disability Index (0-100). The secondary outcomes were pain and disability measured at 3 and 6 months, and global perceived effect, quality of sleep, pain catastrophizing, and self-efficacy measured at 1, 3 and 6 months. RESULTS 116 participants were recruited. At one month post-randomization, people who received dry needling plus guideline-based physical therapy had a small reduction in average pain intensity in the previous 24 hours (mean difference 1.
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