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https://www.readbyqxmd.com/read/28944754/a-double-sided-microscope-to-realize-whole-ganglion-imaging-of-membrane-potential-in-the-medicinal-leech
#1
Yusuke Tomina, Daniel A Wagenaar
Studies of neuronal network emergence during sensory processing and motor control are greatly promoted by technologies that allow us to simultaneously record the membrane potential dynamics of a large population of neurons in single cell resolution. To achieve whole-brain recording with the ability to detect both small synaptic potentials and action potentials, we developed a voltage-sensitive dye (VSD) imaging technique based on a double-sided microscope that can image two sides of a nervous system simultaneously...
September 25, 2017: ELife
https://www.readbyqxmd.com/read/28944753/asymmetry-of-movements-in-cftr-s-two-atp-sites-during-pore-opening-serves-their-distinct-functions
#2
Ben Sorum, Beáta Töröcsik, László Csanády
CFTR, the chloride channel mutated in cystic fibrosis (CF) patients, is opened by ATP binding to two cytosolic nucleotide binding domains (NBDs), but pore-domain mutations may also impair gating. ATP-bound NBDs dimerize occluding two nucleotides at interfacial binding sites; one site hydrolyzes ATP, the other is inactive. The pore opens upon tightening, and closes upon disengagement, of the catalytic site following ATP hydrolysis. Extent, timing, and role of non-catalytic-site movements are unknown. Here we exploit equilibrium gating of a hydrolysis-deficient mutant and apply F value analysis to compare timing of opening-associated movements at multiple locations, from the cytoplasmic ATP sites to the extracellular surface...
September 25, 2017: ELife
https://www.readbyqxmd.com/read/28936969/systematic-integration-of-biomedical-knowledge-prioritizes-drugs-for-repurposing
#3
Daniel Scott Himmelstein, Antoine Lizee, Christine Hessler, Leo Brueggeman, Sabrina L Chen, Dexter Hadley, Ari Green, Pouya Khankhanian, Sergio E Baranzini
The ability to computationally predict whether a compound treats a disease would improve the economy and success rate of drug approval. This study describes Project Rephetio to systematically model drug efficacy based on 755 existing treatments. First, we constructed Hetionet (neo4j.het.io), an integrative network encoding knowledge from millions of biomedical studies. Hetionet v1.0 consists of 47,031 nodes of 11 types and 2,250,197 relationships of 24 types. Data was integrated from 29 public resources to connect compounds, diseases, genes, anatomies, pathways, biological processes, molecular functions, cellular components, pharmacologic classes, side effects, and symptoms...
September 22, 2017: ELife
https://www.readbyqxmd.com/read/28933693/structural-inhibition-of-dynamin-mediated-membrane-fission-by-endophilin
#4
Annika Hohendahl, Nathaniel Talledge, Valentina Galli, Peter S Shen, Frédéric Humbert, Pietro De Camilli, Adam Frost, Aurélien Roux
Dynamin, which mediates membrane fission during endocytosis, binds endophilin and other members of the Bin-Amphiphysin-Rvs (BAR) protein family. How endophilin influences endocytic membrane fission is still unclear. Here we show that dynamin-mediated membrane fission is potently inhibited in vitro when an excess of endophilin co-assembles with dynamin around membrane tubules. We further show by electron microscopy that endophilin intercalates between turns of the dynamin helix and impairs fission by preventing trans interactions between dynamin rungs that are thought to play critical roles in membrane constriction...
September 21, 2017: ELife
https://www.readbyqxmd.com/read/28933692/a-quantitative-hypermorphic-cngc-allele-confers-ectopic-calcium-flux-and-impairs-cellular-development
#5
David M Chiasson, Kristina Haage, Katharina Sollweck, Andreas Brachmann, Petra Dietrich, Martin Parniske
The coordinated control of Ca(2+) signaling is essential for development in eukaryotes. Cyclic nucleotide-gated channel (CNGC) family members mediate Ca(2+) influx from cellular stores in plants(1-4). Here we report the unusual genetic behavior of a quantitative gain-of-function CNGC mutation (brush) in Lotus japonicus resulting in a leaky tetrameric channel. brush resides in a cluster of redundant CNGCs encoding subunits which resemble metazoan voltage-gated potassium (Kv1-Kv4) channels in assembly and gating properties...
September 21, 2017: ELife
https://www.readbyqxmd.com/read/28930071/dynamics-of-the-ift-machinery-at-the-ciliary-tip
#6
Alexander Chien, Sheng Min Shih, Raqual Bower, Douglass Tritschler, Mary E Porter, Ahmet Yildiz
Intraflagellar transport (IFT) is essential for the elongation and maintenance of eukaryotic cilia and flagella. Due to the traffic jam of multiple trains at the ciliary tip, how IFT trains are remodeled in these turnaround zones cannot be determined by conventional imaging. Using Photogate, we visualized the full range of movement of single IFT trains and motors in Chlamydomonas flagella. Anterograde trains split apart and IFT complexes mix with each other at the tip to assemble retrograde trains. Dynein-1b is carried to the tip by kinesin-II as inactive cargo on anterograde trains...
September 20, 2017: ELife
https://www.readbyqxmd.com/read/28930070/rapid-whole-brain-imaging-of-neural-activity-in-freely-behaving-larval-zebrafish-danio-rerio
#7
Lin Cong, Zeguan Wang, Yuming Chai, Wei Hang, Chunfeng Shang, Wenbin Yang, Lu Bai, Jiulin Du, Kai Wang, Quan Wen
The internal brain dynamics that link sensation and action are arguably better studied during natural animal behaviors. Here we report on a novel volume imaging and 3D tracking technique that monitors whole brain neural activity in freely swimming larval zebrafish (Danio rerio). We demonstrated the capability of our system through functional imaging of neural activity during visually evoked and prey capture behaviors in larval zebrafish.
September 20, 2017: ELife
https://www.readbyqxmd.com/read/28930069/initial-elevations-in-glutamate-and-dopamine-neurotransmission-decline-with-age-as-does-exploratory-behavior-in-lrrk2-g2019s-knock-in-mice
#8
Mattia Volta, Dayne A Beccano-Kelly, Sarah A Paschall, Stefano Cataldi, Sarah E MacIsaac, Naila Kuhlmann, Chelsie A Kadgien, Igor Tatarnikov, Jesse Fox, Jaskaran Khinda, Emma Mitchell, Sabrina Bergeron, Heather Melrose, Matthew J Farrer, Austen J Milnerwood
LRRK2 mutations produce end-stage Parkinson's disease (PD) with reduced nigrostriatal dopamine. Conversely, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across ages. Young GKI exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses...
September 20, 2017: ELife
https://www.readbyqxmd.com/read/28925919/computational-design-of-environmental-sensors-for-the-potent-opioid-fentanyl
#9
Matthew J Bick, Per J Greisen, Kevin J Morey, Mauricio S Antunes, David La, Banumathi Sankaran, Luc Reymond, Kai Johnsson, June I Medford, David Baker
We describe the computational design of proteins that bind the potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by design of the surrounding residues to optimize binding affinity. Co-crystal structures of the highest affinity binder reveal a highly preorganized binding site, and an overall architecture and ligand placement in close agreement with the design model. We use the designs to generate plant sensors for fentanyl by coupling ligand binding to design stability...
September 19, 2017: ELife
https://www.readbyqxmd.com/read/28925358/preconditioned-cues-have-no-value
#10
Melissa Sharpe, Hannah Batchelor, Geoffrey Schoenbaum
Sensory preconditioning has been used to implicate midbrain dopamine in model-based learning, contradicting the view that dopamine transients reflect model-free value. However, it has been suggested that model-free value might accrue directly to the preconditioned cue through mediated learning. Here, building on previous work (Sadacca et al., 2016), we address this question by testing whether a preconditioned cue will support conditioned reinforcement in rats. We found that while both directly conditioned and second-order conditioned cues supported robust conditioned reinforcement, a preconditioned cue did not...
September 19, 2017: ELife
https://www.readbyqxmd.com/read/28925356/the-c-elegans-neural-editome-reveals-an-adar-target-mrna-required-for-proper-chemotaxis
#11
Sarah N Deffit, Brian A Yee, Aidan C Manning, Suba Rajendren, Pranathi Vadlamani, Emily C Wheeler, Alain Domissy, Michael C Washburn, Gene W Yeo, Heather A Hundley
ADAR proteins alter gene expression both by catalyzing adenosine (A) to inosine (I) RNA editing and binding to regulatory elements in target RNAs. Loss of ADARs affects neuronal function in all animals studied to date. Caenorhabditis elegans lacking ADARs exhibit reduced chemotaxis, but the targets responsible for this phenotype remain unknown. To identify critical neural ADAR targets in C. elegans, we performed an unbiased assessment of the effects of ADR-2, the only A-to-I editing enzyme in C. elegans, on the neural transcriptome...
September 19, 2017: ELife
https://www.readbyqxmd.com/read/28925355/loss-of%C3%A2-foxo-rescues-stem-cell-aging-in-drosophila-germ-line
#12
Filippo Artoni, Rebecca Kreipke, Ondina Palmeira, Connor Dixon, Zachary Goldberg, Hannele Ruohola-Baker
Aging stem cells lose the capacity to properly respond to injury and regenerate their residing tissues. Here, we utilized the ability of Drosophila melanogaster germline stem cells (GSCs) to survive exposure to low doses of ionizing radiation (IR) as a model of adult stem cell injury and identified a regeneration defect in aging GSCs: while aging GSCs survive exposure to IR, they fail to reenter the cell cycle and regenerate the germline in a timely manner. Mechanistically, we identify foxo and mTOR homologue, Tor as important regulators of GSC quiescence following exposure to ionizing radiation...
September 19, 2017: ELife
https://www.readbyqxmd.com/read/28925353/sec17-%C3%AE-snap-and-an-sm-tethering-complex-regulate%C3%A2-the-outcome-of-snare-zippering-in-vitro-and-in-vivo
#13
Matthew L Schwartz, Daniel P Nickerson, Braden T Lobingier, Rachael L Plemel, Mengtong Duan, Cortney G Angers, Michael Zick, Alexey J Merz
Zippering of SNARE complexes spanning docked membranes is essential for most intracellular fusion events. Here we explore how SNARE regulators operate on discrete zippering states. The formation of a metastable trans-complex, catalyzed by HOPS and its SM subunit Vps33, is followed by subsequent zippering transitions that increase the probability of fusion. Operating independently of Sec18 (NSF) catalysis, Sec17 (α-SNAP) either inhibits or stimulates SNARE-mediated fusion. If HOPS or Vps33 are absent, Sec17 inhibits fusion at an early stage...
September 19, 2017: ELife
https://www.readbyqxmd.com/read/28923166/major-transcriptional-changes-observed-in-the-fulani-an-ethnic-group-less-susceptible-to-malaria
#14
Jaclyn E Quin, Ioana Bujila, Mariama Chérif, Guillaume S Sanou, Ying Qu, Manijeh Vafa Homann, Anna Rolicka, Sodiomon B Sirima, Mary A O'Connell, Andreas Lennartsson, Marita Troye-Blomberg, Issa Nebie, Ann-Kristin Östlund Farrants
The Fulani ethnic group has relatively better protection from Plasmodium falciparum malaria, as reflected by fewer symptomatic cases of malaria, lower infection rates, and lower parasite densities compared to sympatric ethnic groups<strong>.</strong> However, the basis for this lower susceptibility to malaria by the Fulani is unknown. We have performed a pilot study to examine global transcription and DNA methylation patterns in specific immune cell populations in the Fulani to elucidate the mechanisms that confer the lower susceptibility to P...
September 19, 2017: ELife
https://www.readbyqxmd.com/read/28920575/the-p2x7-receptor-forms-a-dye-permeable-pore-independent-of-its-intracellular-domain-but-dependent-on-membrane-lipid-composition
#15
Akira Karasawa, Kevin Michalski, Polina Mikhelzon, Toshimitsu Kawate
The P2X7 receptor mediates extracellular-ATP signaling implicated in the development of devastating diseases such as chronic pain and cancer. Activation of the P2X7 receptor leads to opening of the characteristic dye-permeable membrane pore for molecules up to ~900 Da. However, it remains controversial what constitutes this peculiar pore and how it opens. Here we show that the panda P2X7 receptor, when purified and reconstituted into liposomes, forms an intrinsic dye-permeable pore in the absence of other cellular components...
September 18, 2017: ELife
https://www.readbyqxmd.com/read/28917060/lipids-and-ions-traverse-the-membrane-by-the-same-physical-pathway-in-the-nhtmem16-scramblase
#16
Tao Jiang, Kuai Yu, H Criss Hartzell, Emad Tajkhorshid
From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with experimental assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane...
September 16, 2017: ELife
https://www.readbyqxmd.com/read/28917059/direct-modulation-of-aberrant-brain-network-connectivity-through-real-time-neurofeedback
#17
Michal Ramot, Sara Kimmich, Javier Gonzalez-Castillo, Vinai Roopchansingh, Haroon Popal, Emily White, Stephen J Gotts, Alex Martin
The existence of abnormal connectivity patterns between resting state networks in neuropsychiatric disorders, including Autism Spectrum Disorder (ASD), has been well established. Traditional treatment methods in ASD are limited, and do not address the aberrant network structure. Using real-time fMRI neurofeedback, we directly trained 3 brain nodes in participants with ASD, in which the aberrant connectivity has been shown to correlate with symptom severity. Desired network connectivity patterns were reinforced in real-time, without participants' awareness of the training taking place...
September 16, 2017: ELife
https://www.readbyqxmd.com/read/28917058/lineage-tracing-of-genome-edited-alleles-reveals-high-fidelity-axolotl-limb-regeneration
#18
Grant Parker Flowers, Lucas D Sanor, Craig M Crews
Salamanders are unparalleled among tetrapods in their ability to regenerate many structures, including entire limbs, and the study of this ability may provide insights into human regenerative therapies. The complex structure of the limb poses challenges to the investigation of the cellular and molecular basis of its regeneration. Using CRISPR/Cas, we genetically labelled unique cell lineages within the developing axolotl embryo and tracked the frequency of each lineage within amputated and fully regenerated limbs...
September 16, 2017: ELife
https://www.readbyqxmd.com/read/28914607/cortex-wide-bold-fmri-activity-reflects-locally-recorded-slow-oscillation-associated-calcium-waves
#19
Miriam Schwalm, Florian Schmid, Lydia Wachsmuth, Hendrik Backhaus, Andrea Kronfeld, Felipe Aedo Jury, Pierre-Hugues Prouvot, Consuelo Fois, Franziska Albers, Timo van Alst, Cornelius Faber, Albrecht Stroh
Spontaneous slow oscillation-associated slow wave activity represents an internally generated state which is characterized by alternations of network quiescence and stereotypical episodes of neuronal activity - slow wave events. However, it remains unclear which macroscopic signal is related to these active periods of the slow wave rhythm. We used optic fiber-based calcium recordings of local neural populations in cortex and thalamus to detect neurophysiologically defined slow calcium waves in isoflurane anesthetized rats...
September 15, 2017: ELife
https://www.readbyqxmd.com/read/28914606/nanoscale-architecture-of-the-schizosaccharomyces-pombe-contractile-ring
#20
Nathan A McDonald, Abigail L Lind, Sarah E Smith, Rong Li, Kathleen Gould
The contractile ring is a complex molecular apparatus important for dividing many eukaryotic cells. Despite knowledge of its composition, the molecular architecture of the ring is not known. Here we applied super-resolution microscopy and FRET to determine the nanoscale spatial organization of Schizosaccharomyces pombe contractile ring components relative to the plasma membrane. As in other membrane-tethered actin structures, contractile ring proteins are stratified relative to the membrane. The lowest layer (0-80 nm) contains membrane-binding scaffolds, formin, and the myosin-II tail...
September 15, 2017: ELife
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