bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure of the Glutamate-Like Receptor GLR3.2 ligand-binding domain
Authors: Gangwar Shanti Pal , Green Marriah , Sobolevsky Alexander I. 
Published: December 2019

AbstractGlutamate-like receptors (GLRs) in plants play an important role in a number of physiological processes, including wound response, stomatal aperture control, seed germination, root development, innate immune responses, pollen tube growth and morphogenesis. GLRs share amino acid sequence similarity with ionotropic glutamate receptors (iGluRs) that mediate neurotransmission in the nervous system of vertebrates. In contrast to iGluRs, however, for which numerous full-length structures are available, the structural information about the plant GLRs has been missing. Here we determine crystal structures ofArabidopsis thalianaGLR3.2 ligand-binding domain (LBD) in complex with glycine and methionine to 1.57 and 1.86 Å resolution, respectively. Our structures show a fold similar to iGluRs, with several secondary structure elements either missing or different. The closed clamshell conformation of GLR3.2 LBD suggests that both glycine and methionine act as agonists. The structures reveal molecular determinants of ligand binding and explain the promiscuity of GLRs’ ligand activation compared to iGluRs. Structural similarities of LBDs confirm an evolutionary relationship between GLRs and iGluRs and predict common molecular principles of their gating mechanisms that are driven by the bilobed clamshell-like LBDs.
Plasma membrane damage removal by F-actin-mediated shedding from repurposed filopodia
Authors: Mageswaran Shrawan Kumar , Yang Wei Y. , Chakrabarty Yogaditya , Oikonomou Catherine M. , Jensen Grant J. 
Published: December 2019

AbstractRepairing plasma membrane damage is vital to eukaryotic cell survival. Membrane shedding is thought to be key to this repair process, but a detailed view of how the process occurs is still missing. Here we used electron cryotomography to image the ultrastructural details of plasma membrane wound healing. We found that filopodia-like protrusions are built at damage sites, accompanied by retraction of neighboring filopodia, and that these repurposed protrusions act as scaffolds for membrane shedding. This suggests a new role for filopodia as reservoirs of membrane and actin for plasma membrane damage repair. Damage-induced shedding was dependent on F-actin dynamics and Myo1a, as well as Vps4B, an important component of the ESCRT machinery. Thus we find that damage shedding is more complex than current models of simple vesiculation from flat membrane domains. Rather, we observe structural similarities between damage-mediated shedding and constitutive shedding from enterocytes that argue for conservation of a general membrane shedding mechanism.
The interaction between non-fusogenic Sec22b-Stx complexes and Extended-Synaptotagmins promotes neurite growth and ramification
Authors: Gallo Alessandra , Danglot Lydia , Giordano Francesca , Binz Thomas , Vannier Christian , Galli Thierry 
Published: December 2019

SummaryAxons and dendrites are long and often ramified neurites that need particularly intense plasma membrane (PM) expansion during the development of the nervous system. Neurite growth depends on non-fusogenic Sec22b–Stx1 SNARE complexes at endoplasmic reticulum (ER)-PM contacts. Here we show that Sec22b interacts with the endoplasmic reticulum lipid transfer proteins Extended-Synaptotagmins (E-Syts) and this interaction depends on the Longin domain of Sec22b. Overexpression of E-Syts stabilizes Sec22b-Stx1 association, whereas silencing of E-Syts has the opposite effect. Overexpression of wild-type E-Syt2, but not mutants unable to transfer lipids or attach to the ER, increase the formation of axonal filopodia and ramification of neurites in developing neurons. This effect is inhibited by a clostridial neurotoxin cleaving Stx1, expression of Sec22b Longin domain and a Sec22b mutant with extended linker between SNARE and transmembrane domains. We conclude that Sec22b-Stx1 ER-PM contact sites contribute to PM expansion by interacting with lipid transfer proteins such as E-Syts.
Unc-4 acts to promote neuronal identity and development of the take-off circuit in the Drosophila CNS
Authors: Lacin Haluk , Williamson W. Ryan , Card Gwyneth M. , Skeath James B. , Truman James W. 
Published: December 2019

ABSTRACTTheDrosophilaventral nerve cord (VNC), the fly equivalent of the spinal cord, is composed of thousands of neurons that are born from a set of individually identifiable stem cells. The VNC harbors neuronal circuits required for the execution of vital behaviors, such as flying and walking. Taking advantage of the lineage-based functional organization of the VNC and genetic tools we developed, we investigated the molecular and developmental basis of behavior by focusing on lineage-specific functions of the homeodomain transcription factor, Unc-4. We found that Unc-4 functions in lineage 11A to promote cholinergic neurotransmitter identity and suppress the GABA fate. In 7B lineage, Unc-4 promotes proper neuronal projections to the leg neuropil, the hub for leg-related neuronal circuits and a specific flight-related take-off behavior. We also uncovered that Unc-4 acts peripherally to promote the development of proprioceptive sense organs and the abilities of flies to execute specific leg-related behaviors such as walking, climbing, and grooming. Our findings, thus, initiates the work on revealing molecular and developmental events that shape the VNC related behaviors.
Donut-like organization of inhibition underlies categorical neural responses in the midbrain
Authors: Mahajan Nagaraj R. , Mysore Shreesh P. 
Published: December 2019

ABSTRACTCategorical neural responses underlie various forms of selection and decision-making. Such binary-like responses promote robust signaling of the winner in the presence of input ambiguity and neural noise. Here, we show that a ‘donut-like’ inhibitory mechanism in which each competing option suppresses all options except itself, is highly effective at generating categorical neural responses. It surpasses motifs of feedback inhibition, recurrent excitation, and divisive normalization invoked frequently in decision-making models. We demonstrate experimentally not only that this mechanism operates in the midbrain spatial selection network in barn owls, but also that it is necessary for categorical signaling by it. The functional pattern of neural inhibition in the midbrain forms an exquisitely structured ‘multi-holed’ donut consistent with this network’s combinatorial inhibitory function for stimulus selection. Additionally, modeling reveals a generalizable neural implementation of the donut-like motif for categorical selection. Self-sparing inhibition may, therefore, be a powerful circuit module central to categorization.
Earliest experience of a relatively rare sound but not a frequent sound causes long term changes in the adult auditory cortex
Authors: Mehra Muneshwar , Mukesh Adarsh , Bandyopadhyay Sharba 
Published: December 2019

AbstractSensory experience during a critical period alters sensory cortical responses and organization. We find that the earliest sound driven activity in the mouse auditory cortex (ACX) starts before ear-canal opening (ECO). Effects of auditory experience before ECO on ACX development are unknown. We find that mouse ACX subplate neurons (SPNs), crucial in thalamocortical maturation, respond to sounds before ECO showing oddball selectivity. Before ECO, SPNs are more selective to oddball sounds in auditory streams than thalamo-recipient layer 4 (L4) neurons and not after ECO. We hypothesize that SPNs’ oddball selectivity can direct development of L4 responses before ECO. Exposing mice before ECO with a rarely occurring tone in a stream of another tone occurring frequently leads to the strengthening of the adult cortical representation of the rare tone, but not that of the frequent tone. Results of control exposure experiments at multiple developmental windows and also with only a single tone corroborate the observations. A computational network model of known thalamic inputs to SPNs and L4 explains the observed developmental plasticity. Information-theoretic analysis with sparse coding assumptions also predicts the observations. Thus, salient low probability sounds in the earliest auditory environment cause long term changes in the ACX.
Cell wallO-acetyl and methyl esterification patterns of leaves reflected in atmospheric emission signatures of acetic acid and methanol
Authors: Dewhirst Rebecca A. , Afseth Cassandra A. , Castanha Cristina , Mortimer Jenny C. , Jardine Kolby J. 
Published: December 2019

AbstractPlants emit high rates of methanol (meOH), generally assumed to derive from pectin demethylation, and this increases during abiotic stress. In contrast, less is known about the emission and source of acetic acid (AA). In this study,Populus trichocarpa(California poplar) leaves in different developmental stages were desiccated and quantified for total meOH and AA emissions together with bulk cell wall acetylation and methylation content. While young leaves showed high emissions of meOH (140 μmol m−2) and AA (42 μmol m−2), emissions were reduced in mature (meOH: 69%, AA: 60%) and old (meOH: 83%, AA: 76%) leaves. In contrast, the ratio of AA/meOH emissions increased with leaf development (young: 35%, mature: 43%, old: 82%), mimicking the pattern ofO-acetyl/methyl ester ratios of leaf bulk cell walls (young: 35%, mature: 38%, old: 51%), which is driven by an increase inO-acetyl and decrease in methyl ester content with age. The results are consistent with meOH and AA emission sources from cell wall de-esterification, with young expanding tissues producing highly methylated pectin that is progressively demethyl-esterified. We highlight the quantification of AA/meOH emission ratios as a potential tool for rapid phenotype screening of structural carbohydrate esterification patterns.
A genome-wide enrichment screen identifies NUMA1-loss as a resistance mechanism against mitotic cell-death induced by BMI1 inhibition
Authors: Gisler Santiago , Maia Ana Rita R. , Chandrasekaran Gayathri , van Lohuizen Maarten 
Published: December 2019

AbstractBMI1 is a core protein of the polycomb repressive complex 1 (PRC1) that is overexpressed in several cancer types, making it a promising target for cancer therapies. However, the underlying mechanisms and interactions associated with BMI1-induced tumorigenesis are often context-dependent and complex. Here, we performed a drug resistance screen on mutagenized human haploid HAP1 cells treated with the BMI1 inhibitor PTC-318 to find new genetic and mechanistic features associated with BMI1-dependent cancer cell proliferation. Our screen identified NUMA1-mutations as the most significant inducer of PTC-318 cell death resistance. Independent validations on NUMA1-proficient HAP1 and non-small cell lung cancer cell lines exposed to BMI1 inhibition by PTC-318 orBMI1knockdown resulted in cell death following mitotic arrest. Interestingly, cells with CRISPR-Cas9 derivedNUMA1knockout also showed a mitotic arrest phenotype following BMI1 inhibition but, contrary to cells with wildtype NUMA1, these cells were resistant to BMI1-dependent cell death. The current study brings new insights to BMI1 inhibition-induced mitotic lethality in cancer cells and presents a previously unknown role for NUMA1 in this process.
The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification
Authors: Cross Sally H. , Mckie Lisa , Hurd Toby W. , Riley Sam , Wills Jimi , Barnard Alun R. , Young Fiona , MacLaren Robert E. , Jackson Ian J. 
Published: December 2019

AbstractThe precise control of eye size is essential for normal vision.TMEM98is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in humanTMEM98are found in patients with nanophthalmos (very small eyes) and variants near the gene are associated in population studies with myopia and increased eye size. As complete loss of function mutations in mouseTmem98result in perinatal lethality, we produced mice deficient forTmem98in the retinal pigment epithelium (RPE), whereTmem98is highly expressed. These mice have greatly enlarged eyes that are very fragile with very thin retinas. To gain insight into the mechanism of action we used a proximity labelling approach to discover interacting proteins and identified MYRF as an interacting partner. Mutations ofMYRFare also associated with nanophthalmos. The protein is an endoplasmic reticulum-tethered transcription factor which undergoes autoproteolytic cleavage to liberate the N-terminal part which then translocates to the nucleus where it acts as a transcription factor. We find that TMEM98 inhibits the self-cleavage of MYRF, in a novel regulatory mechanism. In RPE lacking TMEM98, MYRF is ectopically activated and abnormally localised to the nuclei.Author summaryHaving the correct eye size is important, too large and you will be short-sighted and too small and you will be far-sighted. Nanophthalmos, literally very small eye from the Greek, is a condition where the eye is very small but structurally normal. In addition to being farsighted such eyes are prone to glaucoma which can lead to loss of vision. Here we studied a protein called TMEM98 which is found in the membranes of the cells which form a layer at the back of eye called the retinal pigment epithelium (RPE). Mutations inTMEM98have been found in nanophthalmos patients. Patients have one normal copy of the gene and one carrying a mutation. We removedTmem98from the RPE of mice in order to ascertain its function. We found, surprisingly, that rather than having small eyes this led to the development of very large eyes that were structurally fragile. We went to on to identify protein partners of TMEM98 and found that it interacts with a protein called MYRF, mutations in which also causes nanophthalmos. This work demonstrates the importance ofTMEM98in eye size specification.
A perinuclear microtubule-organizing center controls nuclear positioning and basement membrane secretion
Authors: Zheng Yiming , Buchwalter Rebecca A. , Zheng Chunfeng , Wight Elise M. , Chen Jieyan V. , Megraw Timothy L. 
Published: December 2019

AbstractNon-centrosomal microtubule-organizing centers (ncMTOCs) have a variety of roles presumed to serve the diverse functions of the range of cell types in which they are found. ncMTOCs are diverse in their composition, subcellular localization, and function. Here we report a novel perinuclear MTOC inDrosophilafat body cells that is anchored by Msp300/Nesprin at the cytoplasmic surface of the nucleus. Msp300 recruits the MT minus-end protein Patronin/CAMSAP, which functions redundantly with Ninein to further recruit the MT polymerase Msps/XMAP215 to assemble non-centrosomal MTs and does so independently of the widespread MT nucleation factorγ-tubulin. Functionally, the fat body ncMTOC and the radial MT arrays it organizes is essential for nuclear positioning and for secretion of basement membrane components via retrograde dynein-dependent endosomal trafficking that restricts plasma membrane growth. Together, this study identifies a perinuclear ncMTOC with unique architecture and MT regulation properties that serves vital functions.HighlightsA novel perinuclear MTOC in differentiated fat body cellsThe predominant nucleator,γ-tubulin, is not required at the fat body ncMTOCMsp300/Nesprin organizes the ncMTOC at the nuclear surface by recruiting Patronin/CAMSAP and the spectraplakin ShotPatronin cooperates with Ninein to control MT assembly at the fat body ncMTOC by recruiting MspsMsps, a MT polymerase, is essential for radial MT elongation from the fat body ncMTOCPatronin and Msps associateThe ncMTOC and radial MTs, but not actin, control nuclear positioning in the fat bodyThe fat body MTOC controls retrograde endocytic trafficking to regulate plasma membrane growth and secretion of basement membrane proteins
The spatial structure of feedforward information in mouse primary visual cortex
Authors: Zhuang Jun , Larsen Rylan S. , Takasaki Kevin T. , Ouellette Naveen D. , Daigle Tanya L. , Tasic Bosiljka , Waters Jack , Zeng Hongkui , Reid R. Clay 
Published: December 2019

AbstractLocation-sensitive and motion-sensitive units are the two major functional types of feedforward projections from lateral genicular nucleus (LGN) to primary visual cortex (V1) in mouse. The distribution of these inputs in cortical depth remains under debate. By measuring the calcium activities of LGN axons in V1 of awake mice, we systematically mapped their functional and structural properties. Although both types distributed evenly across cortical depth, we found that they differ significantly across multiple modalities. Compared to the location-sensitive axons, which possessed confined spatial receptive fields, the motion-sensitive axons lacked spatial receptive fields, preferred lower temporal, higher spatial frequencies and had wider horizontal bouton spread. Furthermore, the motion-sensitive axons showed a strong depth-dependent motion direction bias while the location-sensitive axons showed a depth-independent OFF dominance. Overall, our results suggest a new model of receptive biases and laminar structure of thalamic inputs to V1.Abstract Figure
Conservative management of acute perforated diverticulitis: A systematic review
Authors: Chua Terence C. , Jeyakumar Arunan , Ip Julian C.Y. , Yuide Peter J. , Burstow Matthew J. 
Published: December 2019

ObjectiveAcute perforated diverticulitis is frequently observed and spans a spectrum in the severity of its presentation. Emergency surgery is required in patients with generalized peritonitis; however, a large proportion of patients are clinically stable with localized peritonitis. This article aimed to examine this specific group of patients by reviewing the outcomes of their conservative management.MethodsA systematic literature search was performed on the MEDLINE and PubMed databases. The management outcomes of patients undergoing non‐operative treatment for acute perforated diverticulitis were synthesized and tabulated.ResultsOf 479 patients, 407 (85%) were successfully managed non‐operatively. In total 70 (14.6%) patients failed non‐operative treatment and underwent operative surgical management, and two (0.4%) died. Emergency surgery includes a Hartmann's operation (40%) and resection with anastomosis with or without stoma (24%), laparoscopic lavage (16%) and surgical drainage (20%). The success rate of conservative management was 94.0% and 71.4% for patients with pericolic and distant free air, respectively. Treatment failure was associated with a high volume of free air, distant free air and the presence of abscess.ConclusionsConservative management is safe and successful in patients with acute perforated diverticulitis without generalized peritonitis. The early recognition of patients who show clinical signs of persistent perforation is important to ensure the success of this strategy.
Which probiotic has the best effect on preventing Clostridium difficile‐associated diarrhea? A systematic review and network meta‐analysis
Authors: Ma Yan , Yang Jing Yu , Peng Xia , Xiao Ke Yi , Xu Qing , Wang Chen 
Published: December 2019

ObjectiveClostridium difficile‐associated diarrhea (CDAD) accounts for up to 25% of patients with antibiotic‐associated diarrhea (AAD). We aimed to determine which probiotic is most effective in preventing CDAD using a network meta‐analysis.MethodsStudies were identified by searching PubMed, EMBASE and the Cochrane Library databases for randomized controlled trials (RCTs) that evaluated the efficacy of probiotic interventions for CDAD. Primary outcomes were the incidence rates of AAD and CDAD, and secondary outcomes were the duration of diarrhea and the time until onset of diarrhea. The PROSPERO registered number of this study is CRD42018106115.ResultsTen RCTs including 11 analyses and including 4 692 patients were identified. Compared with the control group, probiotic intervention reduced the incidence rates of CDAD (odds ratio [OR] 0.33, 95% confidence interval [CI] 0.17‐0.61) and AAD (OR 0.39, 95% CI 0.23‐0.66). Similar results were observed regarding the duration of diarrhea and the time until onset of diarrhea. Meta‐regression analysis showed a correlation between the type of probiotic used and the incidence of CDAD and AAD. All nine kinds of probiotic interventions were statistically more effective than the placebo, with Lactobacillus casei ranking as the best intervention (OR 0.19, 95% credible interval [CrI] 0.06‐0.63) for decreasing the incidence rate of CDAD. L. casei also ranked the highest in reducing the incidence rate of AAD (OR 0.32, 95% CrI 0.14‐0.74).ConclusionLactobacilli strains, especially L. casei, have a good effect on the prevention of CDAD and AAD.
Oligodendrocyte lineage and myelination are compromised in the gray matter of focal cortical dysplasia type IIa
Authors: Donkels Catharina , Peters Myriam , Fariña Núñez Mateo T. , Nakagawa Julia M. , Kirsch Matthias , Vlachos Andreas , Scheiwe Christian , Schulze‐Bonhage Andreas , Prinz Marco , Beck Jürgen , Haas Carola A. 
Published: December 2019

AbstractObjectivesFocal cortical dysplasias (FCDs) are local malformations of the human neocortex and a leading cause of medically intractable epilepsy. FCDs are characterized by local architectural disturbances of the neocortex and often by a blurred gray‐white matter boundary indicating abnormal white matter myelination. We have recently shown that myelination is also compromised in the gray matter of dysplastic areas, since transcripts encoding factors for oligodendrocyte differentiation and myelination are downregulated and myelin fibers appear fractured and disorganized.MethodsHere, we characterized the gray matter–associated myelination pathology in detail by in situ hybridization, immunohistochemistry, and electron microscopy with markers for myelin, mature oligodendrocytes, and oligodendrocyte precursor cells in tissue sections of FCD IIa and control cortices. In addition, we isolated oligodendrocyte precursor cells from resected dysplastic tissue and performed proliferation assays.ResultsWe show that the proportion of myelinated gray matter is similar in the dysplastic cortex to that in controls and myelinated fibers extend up to layer III. On the ultrastructural level, however, we found that the myelin sheaths of layer V axons are thinner in dysplastic specimens than in controls. In addition, the density of oligodendrocyte precursor cells and of mature oligodendrocytes was reduced. Finally, we show for the first time that oligodendrocyte precursor cells isolated from resected dysplastic cortex have a reduced proliferation capacity in comparison to controls.SignificanceThese results indicate that proliferation and differentiation of oligodendrocyte precursor cells and the formation of myelin sheaths are compromised in FCD and might contribute to the epileptogenicity of this cortical malformation.