bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex
Authors: Girn Manesh , Roseman Leor , Bernhardt Boris , Smallwood Jonathan , Carhart-Harris Robin , Spreng R. Nathan 
Published: May 2020

AbstractLSD and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to pharmacological resting-state fMRI data to assess cortical organization in the LSD and psilocybin state. Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes – default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping confirmed that this was underpinned by increased unimodal-transmodal crosstalk. In addition, LSD-dependent principal gradient changes tracked changes in self-reported ego-dissolution. Results involving the second and third gradient, which respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to a pharmacological manipulation, specifically highlighting an important relationship between cortical organization and serotonergic modulation.
Mesenchymal ETV Transcription Factors Regulate Cochlear Length
Authors: Ebeid Michael , Huh Sung-Ho 
Published: May 2020

AbstractMammalian cochlear development encompasses a series of morphological and molecular events that results in the formation of a highly intricate structure responsible for hearing. One remarkable event occurs during development is the cochlear lengthening that starts with cochlear outgrowth around E11 and continues throughout development. Different mechanisms contribute to this process including cochlear progenitor proliferation and convergent extension. We previously identified that FGF9 and FGF20 promote cochlear lengthening by regulating auditory sensory epithelial proliferation through FGFR1 and FGFR2 in the periotic mesenchyme. Here, we provide evidence that ETS-domain transcription factors ETV4 and ETV5 are downstream of mesenchymal FGF signaling to control cochlear lengthening. Next generation RNA sequencing identified thatEtv1, Etv4andEtv5mRNAs are decreased in theFgf9andFgf20double mutant periotic mesenchyme. Deleting bothEtv4andEtv5in periotic mesenchyme resulted in shortening of cochlear length but maintaining normal patterning of organ of Corti and density of hair cells and supporting cells. This recapitulates phenotype of mesenchymal-specificFgfr1andFgfr2deleted inner ear. Furthermore, analysis ofEtv1/4/5triple conditional mutants revealed that ETV1 does not contribute in this process. Our study reveals that ETV4 and ETV5 function downstream of mesenchymal FGF signaling to promote cochlear lengthening.
Global, Highly Specific and Fast Filtering of Alignment Seeds
Authors: Ebel Matthis , Migliorelli Giovanna , Stanke Mario 
Published: May 2020

AbstractAn important initial phase of arguably most homology search and alignment methods such as required for genome alignments isseed finding. The seed finding step is crucial to curb the runtime as potential alignments are restricted to andanchored atthe sequence position pairs that constitute the seed. To identify seeds, it is good practice to use sets of spaced seed patterns, a method thatlocallycompares two sequences and requires exact matches at certain positions only.We introduce a new method for filtering alignment seeds that we callgeometric hashing. Geometric hashing achieves a high specificity by combining non-local information from different seeds using a simple hash function that only requires a constant and small amount of additional time per spaced seed. Geometric hashing was tested on the task of finding homologous positions in the coding regions of human and mouse genome sequences. Thereby, the number of false positives was decreased about million-fold over sets of spaced seeds while maintaining a very high sensitivity.An additional geometric hashing filtering phase could improve the run-time, accuracy or both of programs for various homology-search-and-align tasks.
Sequestration of the exocytic SNARE Psy1 into multiprotein nodes reinforces polarized morphogenesis in fission yeast
Authors: Miller Kristi E. , Magliozzi Joseph O. , Picard Noelle A. , Moseley James B. 
Published: May 2020

ABSTRACTPolarized morphogenesis is achieved by targeting or inhibiting growth at distinct regions. Rod-shaped fission yeast cells grow exclusively at their ends by restricting exocytosis and secretion to these sites. This growth pattern implies the existence of mechanisms that prevent exocytosis and growth along non-growing cell sides. We previously identified a set of 50-100 megadalton-sized node structures along the sides of fission yeast cells that contain the interacting proteins Skb1 and Slf1. Here, we show that Skb1-Slf1 nodes contain the syntaxin-like SNARE Psy1, which mediates exocytosis in fission yeast. Psy1 localizes in a diffuse pattern at cell tips where it likely promotes exocytosis and growth, but Psy1 is sequestered in Skb1-Slf1 nodes at cell sides where growth does not occur. Mutations that prevent node assembly or inhibit Psy1 localization to nodes lead to aberrant exocytosis at cell sides and increased cell width. Genetic results indicate that this Psy1 node mechanism acts in parallel to actin cables and Cdc42 regulation. Our work suggests that sequestration of syntaxin-like Psy1 at non-growing regions of the cell cortex reinforces cell morphology by restricting exocytosis to proper sites of polarized growth.
Virtual Mouse Brain Histology from Multi-contrast MRI via Deep Learning
Authors: Liang Zifei , Lee Choong H. , Arefin Tanzil. M. , Dong Zijun. , Walczak Piotr , Shi Song-Hai , Knoll Florian , Ge Yulin , Ying Leslie , Zhang Jiangyang 
Published: May 2020

Abstract1H MRI maps brain structure and function non-invasively through versatile contrasts that exploit inhomogeneity in tissue micro-environments. Inferring histopathological information from MRI findings, however, remains challenging due to absence of direct links between MRI signals and cellular structures. Here, we show that deep convolutional neural networks, developed using co-registered multi-contrast MRI and histological data of the mouse brain, can estimate histological staining intensity directly from MRI signals at each pixel. The results provide three-dimensional maps of axons and myelin with tissue contrasts that closely mimics target histology and enhanced sensitivity and specificity compared to conventional MRI markers. Furthermore, the relative contribution of each MRI contrast within the networks can be used to optimize multi-contrast MRI acquisition. We anticipate our method to be a starting point for translation of MRI results into easy-to-understand virtual histology for neurobiologists and provide resources for validating novel MRI techniques.
The M1/M4 agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain
Authors: Montani Caterina , Canella Carola , Schwarz Adam J. , Li Jennifer , Gilmour Gary , Galbusera Alberto , Wafford Keith , McCarthy Andrew , Shaw David , Knitowski Karen , McKinzie David , Gozzi Alessandro , Felder Christian 
Published: May 2020

AbstractCholinergic drugs acting at M1/M4 muscarinic receptors hold promise for the treatment of symptoms associated with brain disorders characterized by cognitive impairment, mood disturbances or psychosis, such as Alzheimer’s disease or schizophrenia. However, the brain-wide functional substrates engaged by muscarinic agonists remain poorly understood. Here we used a combination of pharmacological fMRI (phMRI), resting-state fMRI (rsfMRI) and resting-state quantitative EEG (qEEG) to investigate the effects of a behaviorally-active dose of M1/M4 agonist xanomeline on brain functional activity in the rodent brain. We investigated both the effects of xanomelineper seand its modulatory effects on signals elicited by the NMDA-receptor antagonists phencyclidine (PCP) and ketamine. We found that xanomeline induces robust and widespread BOLD signal phMRI amplitude increases and decreased high frequency qEEG spectral activity. rsfMRI mapping in the mouse revealed that xanomeline robustly decreased neocortical and striatal connectivity but induces focal increases in functional connectivity within the nucleus accumbens and basal forebrain. Notably, xanomeline pre-administration robustly attenuated both the cortico-limbic phMRI response and the fronto-hippocampal hyper-connectivity induced by PCP, enhanced PCP-modulated functional connectivity locally within the nucleus accumbens and basal forebrain, and reversed the gamma and high frequency qEEG power increases induced by ketamine. Collectively, these results show that xanomeline robustly induces both cholinergic-like neocortical activation and desynchronization of functional networks in the mammalian brain. These effects could serve as a translatable biomarker for future clinical investigations of muscarinic agents, and bear mechanistic relevance for the putative therapeutic effect of these class of compounds in brain disorders.
Distinct Microcircuit Response to Comparable Input from a Full and Partial Projection Neuron Population
Authors: Colton Gabriel F. , Cook Aaron P. , Nusbaum Michael P. 
Published: May 2020

ABSTRACTNeuronal inputs to microcircuits are often present as multiple copies of apparently equivalent neurons. Thus far, however, little is known regarding the relative influence on microcircuit output of activating all or only some copies of such an input. We are examining this issue in the crab (Cancer borealis) stomatogastric ganglion, where the gastric mill (chewing) microcircuit is activated by MCN1, a paired modulatory projection neuron. Both MCN1s contain the same cotransmitters, influence the same gastric mill circuit neurons, can drive the biphasic gastric mill rhythm, and are co-activated by all identified MCN1-activating pathways. Here, we determine whether the gastric mill circuit response is equivalent when stimulating one or both MCN1s under conditions where the pair are matched to collectively fire at the same overall rate and pattern as single MCN1 stimulation. The dual MCN1 stimulations elicited more consistently coordinated rhythms, and these rhythms exhibited longer phases and cycle periods. These different outcomes from single and dual MCN1 stimulation may have resulted from the relatively modest, and equivalent, firing rate of the gastric mill neuron LG during each matched set of stimulations. The LG neuron-mediated, ionotropic inhibition of the MCN1 axon terminals is the trigger for the transition from the retraction to protraction phase. This LG neuron influence on MCN1 was more effective during the dual stimulations, where each MCN1 firing rate was half that occurring during the matched single stimulations. Thus, equivalent individual- and co-activation of a class of modulatory projection neurons will not necessarily drive equivalent microcircuit output.Summary StatementCo-stimulating both copies of an identified modulatory projection neuron at the same collective firing rate used for single copy stimulation results in distinct microcircuit output.
The importomer is a peroxisomal membrane protein translocase
Authors: Martenson James S , Tam Hanson , McQuown Alexander J , Reif Dvir , Zhou Jing , Denic Vladimir 
Published: May 2020

ABSTRACTThree sites of membrane protein biogenesis (the endoplasmic reticulum, mitochondria and chloroplasts) receive unfolded substrates from organelle-specific protein targeting factors, then integrate them using separate translocation channels. Peroxisomes also receive membrane proteins from known targeting factors, but whether a separate translocase is needed for integration remains unknown. Here, using a novel genetic screening strategy, we reveal that the importomer–known for matrix protein import–integrates the peroxisomal membrane protein Pex14. In importomer mutants, Pex14 is arrested in a pre-integrated state on the peroxisome surface. To undergo integration, a Pex14 translocation signal binds the importomer’s substrate receptor Pex5 at a distinct site from matrix proteins. En bloc translocation of an engineered protein complex with Pex14’s luminal region argues that integration occurs without substrate unfolding. Our work shows that the handling of membrane protein targeting and integration by discrete machineries is a fundamental principle shared by diverse membrane protein biogenesis pathways.
Atomic-scale Characterization of Mature HIV-1 Capsid Stabilization by Inositol Hexakisphosphate (IP6)
Authors: Yu Alvin , Lee Elizabeth M.Y. , Jin Jaehyeok , Voth Gregory A. 
Published: May 2020

AbstractInositol hexakisphosphates (IP6) are cellular cofactors that promote the assembly of mature capsids of the human immunodeficiency virus (HIV). These negatively charged molecules coordinate an electropositive ring of arginines at the center of pores distributed throughout the capsid surface. Kinetic studies indicate that the binding of IP6increases the stable life times of the capsid by several orders of magnitude from minutes to hours. Using all-atom molecular dynamics simulations, we uncover the mechanisms that underlie the unusually high stability of mature capsids in complex with IP6. We find that capsid hexamers and pentamers have differential binding modes for IP6. Ligand density calculations show three sites of interaction with IP6including at a known capsid-inhibitor binding pocket. Free energy calculations demonstrate that IP6preferentially stabilizes pentamers over hexamers to enhance fullerene modes of assembly. These results elucidate the molecular role of IP6in stabilizing and assembling the retroviral capsid.
ATP driven diffusiophoresis: active cargo transport without motor proteins
Authors: Ramm Beatrice , Goychuk Andriy , Khmelinskaia Alena , Blumhardt Philipp , Ganzinger Kristina A. , Frey Erwin , Schwille Petra 
Published: May 2020

AbstractMorphogenesis and homeostasis of biological systems are intricately linked to gradient formation through energy dissipation. Such spatial organization may be achieved via reaction-diffusion or directional cargo transport, as prominently executed by motor proteins. In contrast to these processes that rely on specific protein interactions, active transport based on a non-specific, purely physical mechanism remains poorly explored. Here, by a joint experimental and theoretical approach, we describe a hidden function of the MinDE protein system fromE. coli:Besides forming dynamic patterns, this system accomplishes the active transport of large, functionally unrelated cargo on membranesin vitro. Remarkably, this mechanism allows to sort diffusive objects according to their effective size, as evidenced using modular DNA origami–streptavidin nanostructures. We show that the diffusive fluxes of MinDE and cargo couple via density-dependent friction. This non-specific process constitutes a Maxwell-Stefan diffusiophoresis, so far undescribed in a biologically relevant setting. Such nonlinear coupling between diffusive fluxes could represent a generic physical mechanism for the intracellular organization of biomolecules.
Deep learning enables the atomic structure determination of the Fanconi Anemia core complex from cryoEM
Authors: Farrell Daniel P. , Anishchenko Ivan , Shakeel Shabih , Lauko Anna , Passmore Lori A. , Baker David , DiMaio Frank 
Published: May 2020

AbstractCryo-electron microscopy of protein complexes often leads to moderate resolution maps (4-8 Å), with visible secondary structure elements but poorly resolved loops, making model-building challenging. In the absence of high-resolution structures of homologues, only coarse-grained structural features are typically inferred from these maps, and it is often impossible to assign specific regions of density to individual protein subunits. This paper describes a new method for overcoming these difficulties that integrates predicted residue distance distributions from a deep-learned convolutional neural network, computational protein folding using Rosetta, and automated EM-map-guided complex assembly. We apply this method to a 4.6 Å resolution cryoEM map of Fanconi Anemia core complex (FAcc), an E3 ubiquitin ligase required for DNA interstrand crosslink repair, which was previously challenging to interpret as it is comprised of 6557 residues, only 1897 of which are covered by homology models. In the published structure built from this map, only 387 residues could be assigned to specific subunits. By building and placing into density 42 deep-learning guided models containing 4795 residues not included in the previously published structure, we are able to determine an almost-complete atomic model of FAcc, in which 5182 of the 6557 residues were placed. The resulting model is consistent with previously published biochemical data, and facilitates interpretation of disease related mutational data. We anticipate that our approach will be broadly useful for cryoEM structure determination of large complexes containing many subunits for which there are no homologues of known structure.
Velcro-like mannose and slime-like sialic acid interactions guide self-adhesion and aggregation of virus N-glycan shields
Authors: Ogharandukun Eric , Tewolde Wintana , Damtae Elbethel , Wang Songping , Ivanov Andrey , Kumari Namita , Nekhai Sergei , Chandran Preethi L. 
Published: May 2020

AbstractThe surfaces of cells and pathogens are covered with short polymers of sugars known as glycans. Complex N-glycans have a core of three mannose sugars, with distal repeats of N-acetylglucosamine and galactose sugars terminating with sialic acid (SA). Long-range slime-like and short-range Velcro-like self-adhesions were observed between SA and mannose residues, respectively, in ill-defined monolayers. We investigated if and how these adhesions translate when SA and mannose residues are presented in complex N-glycan shields on two pseudo-typed viruses brought together in force spectroscopy (FS). Slime-like adhesions were observed between the shields at higher ramp rates, whereas Velcro-like adhesions were observed at lower rates. The complex glycan shield appears penetrable at the lower ramp rates allowing the adhesion from the mannose core to be accessed; whereas the whole virus appears compressed at higher rates permitting only surface SA adhesions to be sampled. The slime-like and velcro-like adhesions were lost when SA and mannose, respectively, were cleaved with glycosidases. While virus self-adhesion in FS was modulated by glycan penetrability, virus self-aggregation in solution was only determined by the surface sugar. Mannose-terminal viruses self-aggregated in solution, while SA-terminal ones required Ca2+ions to self-aggregate. Viruses with galactose or N-acetylglucosamine surfaces did not self-aggregate, irrespective of whether or not a mannose core was present below the N-acetylglucosamine surface. Well-defined rules appear to govern the self-adhesion and -aggregation of N-glycosylated surfaces, regardless of whether the sugars are presented in ill-defined monolayer, or N-glycan, or even polymer architecture.
Shared safety abolishes the recovery of learned threat
Authors: Pan Yafeng , Olsson Andreas , Golkar Armita 
Published: May 2020

AbstractSocial learning offers an efficient route to transmit information about threat and safety. To better isolate the processes that contribute to the efficacy of social safety learning, we developed a novel dyadic model of associative threat and extinction learning. In three separate social groups, we manipulated whether safety information during extinction was acquired via direct exposure to the conditioned stimulus (CS) in the presence of another individual (Direct exposure), via observation of other’s safety behavior (Vicarious exposure), or via the combination of both (Shared exposure). These groups were contrasted against a fourth group receiving direct CS exposure alone (Asocial exposure). Based on skin conductance responses, we observed that all social groups outperformed asocial learning ininhibitingthe recovery of threat, but only Shared exposureabolishedthreat recovery. These results suggest that social safety learning is optimized by a combination of direct exposure and vicariously transmitted safety signals.Statement of relevanceHumans, like other social animals, learn about threats and safety in the environment through social cues. Yet, the processes that contribute to the efficacy of social safety learning during threat transmission remain unknown. Here, we used a two-person approach to analyze skin conductance responses as participants engaged in a standard fear conditioning procedure (acquisition, extinction, and reinstatement). We found that during extinction, both (i) direct (conditioned stimulus) exposure in the presence of another individual and (ii) vicarious safety signals alone is sufficient to inhibit subsequent threat recovery, but that abolishing the recovery of conditioned threat responses requires a combination of both. This study has relevance for understanding how social information can optimize standard, asocial safety learning procedures to augment the effects of exposure on previously acquired fears. Thus, our work might help identify psychological and social strategies that can be used to counteract maladaptive fears in humans.