bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbial community shifts associated with the ongoing stony coral tissue loss disease outbreak on the Florida Reef Tract
Authors: Meyer Julie L. , Castellanos-Gell Jessy , Aeby Greta S. , Häse Claudia , Ushijima Blake , Paul Valerie J. 
Published: May 2019

ABSTRACTAs many as 22 of the 45 coral species on the Florida Reef Tract are currently affected by stony coral tissue loss disease (SCTLD). The ongoing disease outbreak was first observed in 2014 in Southeast Florida near Miami and as of early 2019 has been documented from the northernmost reaches of the reef tract in Martin County down to Key West. We examined the microbiota associated with disease lesions and apparently healthy tissue on diseased colonies of Montastraea cavernosa, Orbicella faveolata, Diploria labyrinthiformis, and Dichocoenia stokesii. Analysis of differentially abundant taxa between disease lesions and apparently healthy tissue identified five unique amplicon sequence variants enriched in the diseased tissue in three of the coral species, namely an unclassified genus of Flavobacteriales and sequences identified as Fusibacter (Clostridiales), Planktotalea (Rhodobacterales), Algicola (Alteromonadales), and Vibrio (Vibrionales). In addition, several groups of likely opportunistic or saprophytic colonizers such as Epsilonbacteraeota, Patescibacteria, Clostridiales, Bacteroidetes, and Rhodobacterales were also enriched in SCTLD disease lesions. This work represents the first microbiological characterization of SCTLD, as an initial step toward identifying the potential pathogen(s) responsible for SCTLD.
A heme-binding protein produced byHaemophilus haemolyticusinhibits non-typeableHaemophilus influenzae
Authors: Latham Roger D. , Torrado Mario , Atto Brianna , Walshe James L. , Wilson Richard , Guss J. Mitchell , Mackay Joel P. , Tristram Stephen , Gell David A. 
Published: May 2019

AbstractMany commensal bacteria and opportunistic pathogens scavenge heme from their environment. Pathogens and host are engaged in an arms race to control access to heme, but similar conflicts between bacterial species that might regulate pathogen colonisation are largely unknown. We show here that a commensal bacterium,Haemophilus haemolyticus, makes hemophilin, a heme-binding protein that not only allows the bacterium to effectively scavenge heme for its own growth, but also inhibits co-culture of the opportunistic pathogen, non-typeableHaemophilus influenzae(NTHi), by heme starvation. Knockout of the hemophilin gene abrogates the ability ofH. haemolyticusto inhibit NTHi and an x-ray crystal structure shows that hemophilin has a previously unreported heme-binding structure. The bound heme molecule is deeply buried and the heme iron atom is coordinated through a single histidine side chain. Biochemical characterization shows that this arrangement allows heme to be captured in the ferrous or ferric state, and with small ferrous or ferric heme-ligands bound, suggesting hemophilin could function over in a wide range of physiological conditions. Our data raise the possibility that competition for heme between commensal and pathogenic bacteria can influence bacterial colonisation, and therefore disease likelihood, and suggest that strains ofH. haemolyticusthat overproduce hemophilin might have therapeutic uses in reducing colonisation and subsequent opportunistic infection by NTHi.
Two separation-of-function isoforms of human TPP1 and a novel intragenic noncoding RNA dictate telomerase regulation in somatic and germ cells
Authors: Grill Sherilyn , Bisht Kamlesh , Tesmer Valerie M. , Sifuentes Christopher J. , Nandakumar Jayakrishnan 
Published: May 2019

SummaryTelomerase replicates chromosome ends in germ and somatic stem cells to facilitate continued proliferation. Telomerase action depends on the telomeric protein TPP1, which recruits telomerase to telomeres and facilitates processive DNA synthesis. Here we identify separation-of-function long (TPP1-L) and short (TPP1-S) isoforms of TPP1 differing only in 86 amino acids at their N-terminus. While both isoforms retain the ability to recruit telomerase, only TPP1-S facilitates telomere synthesis. We identify a novel intragenic noncoding RNA in the 3’-UTR of the TPP1-encoding gene that specifically shuts down telomerase activation-incompatible TPP1-L to establish TPP1-S as the predominant isoform in somatic cells. Strikingly, TPP1-L is the major isoform in testes, where it can function to restrain telomerase in mature germ cells. Our studies uncover how differential expression of two isoforms allows TPP1 to perform separate functions in different cells, and demonstrate how isoform choice can be determined by an intragenic noncoding RNA.
Defined cell types in superior colliculus make distinct contributions to prey capture behavior in the mouse
Authors: Hoy Jennifer L. , Bishop Hannah I. , Niell Cristopher M. 
Published: May 2019

SummaryThe superior colliculus (SC) mediates rapid orienting to visual stimuli across species. To determine the specific circuits within the SC that drive orienting and approach behavior toward appetitive stimuli, we explored the role of three genetically defined cell types in mediating prey capture in mice. Chemogenetic inactivation of two classically defined cell types, the wide-field (WF) and narrow-field (NF) vertical neurons, revealed that they are involved in distinct aspects of prey capture. WF neurons were required for rapid prey detection and distant approach initiation, whereas NF neurons were required for continuous and accurate orienting during pursuit. In contrast, prey capture did not require parvalbumin-expressing (PV) neurons that have previously been implicated in fear responses. The visual coding of WF and NF cells in the awake mouse and their projection targets were consistent with their roles in prey detection versus pursuit. Thus, our studies link specific neural circuit connectivity and function with stimulus detection and orienting behavior, providing insight into visuomotor and attentional mechanisms mediated by superior colliculus.HighlightsThis study provides the first demonstration of the role of specific cell populations in the superior colliculus in orienting and approach behavior.A genetically targeted population of wide-field vertical neurons in the superior colliculus is required for rapid prey detection and initiation of long-distance approaches.A genetically targeted population of narrow-field vertical neurons is required for approach initiation, accurate targeting, and approach continuity.Visual response properties and projection targets of these cells are consistent with their role in prey capture, linking neural circuit connectivity and function with behavior.
Human immune cells infiltrate the lesioned spinal cord and impair recovery after spinal cord injury in humanized mice
Authors: Carpenter Randall S. , Jiang Roselyn R. , Brennan Faith H. , Hall Jodie C.E. , Gottipati Manoj K. , Niewiesk Stefan , Popovich Phillip G. 
Published: May 2019

Summary PointsImmune compromised mice require ~4 months of engraftment with human umbilical cord blood CD34+ stem cells to develop a full and functional human immune systemThe human neuroinflammatory response elicited after spinal cord injury in humanized mice is limited at 2 months post-engraftment but matures by 4 monthsIntraspinal neuroinflammation consists of a florid human T cell and macrophage response, and human T cells co-localize with human macrophagesA human intraspinal neuroinflammatory response exacerbates lesion pathology and impairs functional recoveryAbstractHumanized mice are a useful tool to help better understand how the human immune system responds to central nervous system (CNS) injury. However, the optimal parameters for using humanized mice in preclinical CNS injury models have not been established. Here, we show that it takes 3-4 months after engraftment of neonatal immune compromised mice with human umbilical cord stem cells to generate a robust human immune system. Indeed, sub-optimal human immune cell responses occurred when humanized mice received spinal contusion injuries at 2 months vs. 4 months post-engraftment. Human T cells directly contact human macrophages within the spinal cord lesion of these mice and the development of a mature human immune system was associated with worse lesion pathology and neurological recovery. Together, data in this report establish an optimal experimental framework for using humanized mice to help translate promising preclinical therapies for CNS injury.
A hydrophobic network: Intersubunit and intercapsomer interactions stabilizing the bacteriophage P22 capsid
Authors: Asija Kunica , Teschke Carolyn M. 
Published: May 2019

AbstractdsDNA tailed phages and herpesviruses assemble their capsids using coat proteins that have the ubiquitous HK97 fold. Though this fold is common, we do not have a thorough understanding of the different ways viruses adapt it to maintain stability in various environments. The HK97-fold E-loop, which connects adjacent subunits at the outer periphery of capsomers, has been implicated in capsid stability. Here we show that in bacteriophage P22, residue W61 at the tip of the E-loop plays a role in stabilizing procapsids and in maturation. We hypothesize that a hydrophobic pocket is formed by residues I366 and W410 in the P-domain of a neighboring subunit within a capsomer, into which W61 fits like a peg. In addition, W61 likely bridges to residues A91 and L401 in P-domain loops of an adjacent capsomer, thereby linking the entire capsid together with a network of hydrophobic interactions. There is conservation of this hydrophobic network in the distantly related P22-like phages, indicating that this structural feature is likely important for stabilizing this family of phages. Thus, our data shed light on one of the varied elegant mechanisms used in nature to consistently build stable viral genome containers through subtle adaptation of the HK97 fold.IMPORTANCESimilarities in assembly reactions and coat protein structures of the dsDNA tailed phages and herpesviruses make phages ideal models to understand capsid assembly and identify potential targets for antiviral drug discovery. The coat protein E-loops of these viruses are involved in both intra-and intercapsomer interactions. In phage P22, hydrophobic interactions peg the coat protein subunits together within a capsomer, where the E-loop hydrophobic residue W61 of one subunit packs into a pocket of hydrophobic residues I366 and W410 of the adjacent subunit. W61 also makes hydrophobic interactions with A91 and L401 of a subunit in an adjacent capsomer. We show these intra-and intercapsomer hydrophobic interactions form a network crucial to capsid stability and proper assembly.
The CXCL12/CXCR4 signalling axis retains neutrophils at inflammatory sites in zebrafish
Authors: Isles Hannah M. , Herman Kimberly , Robertson Anne L. , Loynes Catherine A. , Prince Lynne R. , Elks Philip M. , Renshaw Stephen A. 
Published: May 2019

AbstractThe inappropriate retention of neutrophils in the lung is a major driver of the excessive tissue damage characteristic of respiratory inflammatory diseases including COPD, ARDS and cystic fibrosis. The molecular programmes which orchestrate neutrophil recruitment to inflammatory sites through chemotactic guidance have been well studied. However, how neutrophil sensitivity to these cues is modulated during inflammation resolution is not understood. The identification of neutrophil reverse migration as a mechanism of inflammation resolution and the ability to modulate this therapeutically has identified a new target to treat inflammatory disease. Here we investigate the role of the CXCL12/CXCR4 signalling axis in modulating neutrophil retention at inflammatory sites. We used anin vivotissue injury model to study inflammation using transgenic zebrafish larvae. Expression ofcxcl12aandcxcr4bduring the tissue damage response was assessed usingin situhybridisation and analysis of RNA sequencing data. CRISPR/Cas9 was used to knockdowncxcl12aandcxcr4bin zebrafish larvae. The CXCR4 antagonist AMD3100 was used to block the Cxcl12/Cxcr4 signalling axis pharmacologically. We identified thatcxcr4bandcxcl12aare expressed at the wound site in zebrafish larvae during the inflammatory response. Following tail-fin transection, removal of neutrophils from inflammatory sites is significantly increased incxcr4bandcxcl12aCRISPR knockdown larvae. Pharmacological inhibition of the Cxcl12/Cxcr4 signalling axis accelerates inflammation resolution, an effect caused by an increase in neutrophil reverse migration. The findings of this study suggest that CXCR4/CXCL12 signalling may play an important role in neutrophil retention at inflammatory sites, identifying a potential new target for the therapeutic removal of neutrophils from the lung in chronic inflammatory disease.
Characterization of bulk phosphatidylcholine compositions in human plasma using side-chain resolving lipidomics
Authors: Quell Jan D. , Römisch-Margl Werner , Haid Mark , Krumsiek Jan , Skurk Thomas , Halama Anna , Stephan Nisha , Adamski Jerzy , Hauner Hans , Mook-Kanamori Dennis , Mohney Robert P. , Daniel Hannelore , Suhre Karsten , Kastenmüller Gabi 
Published: May 2019

AbstractKit-based assays, such as AbsoluteIDQ™ p150, are widely used in large cohort studies and provide a standardized method to quantify blood concentrations of phosphatidylcholines (PCs). Many disease-relevant associations of PCs were reported using this method. However, their interpretation is hampered by lack of functionally relevant information on the detailed fatty acid side chain compositions as only the total number of carbon atoms and double bonds is identified by the kit. To enable more substantiated interpretations, we characterized these PC sums using the side chain resolving Lipidyzer™ platform, analyzing 223 samples in parallel to the AbsoluteIDQ™. Combining these datasets, we estimated the quantitative composition of PC sums and subsequently tested their replication in an independent cohort. We identified major constituents of 28 PC sums, revealing also various unexpected compositions. As an example, PC 16:0_22:5 accounted for more than 50% of the PC sum with in total 38 carbon atoms and 5 double bonds (PC aa 38:5). For 13 PC sums, we found relatively high abundances of odd-chain fatty acids. In conclusion, our study provides insights in PC compositions in human plasma, facilitating interpretation of existing epidemiological datasets and potentially enabling imputation of PC compositions for future meta-analyses of lipidomics data.
Microtubule Binding Kinetics of Membrane-bound Kinesin Predicts High Motor Copy Numbers on Intracellular Cargo
Authors: Jiang Rui , Vandal Steven , Park SooHyun , Majd Sheereen , Tüzel Erkan , Hancock William O. 
Published: May 2019

AbstractBidirectional vesicle transport along microtubules is necessary for cell viability and function, particularly in neurons. When multiple motors are attached to a vesicle, the distance a vesicle travels before dissociating is determined by the race between detachment of the bound motors and attachment of the unbound motors. Motor detachment rate constants (koff) can be measured via single-molecule experiments, but motor reattachment rate constants (kon) are generally unknown, as they involve diffusion through the bilayer, geometrical considerations of the motor tether length, and the intrinsic microtubule binding rate of the motor. To understand motor attachment dynamics during vesicle transport, we quantified the microtubule accumulation rate of fluorescently-labeled kinesin-1 motors in a 2D system where motors were linked to a supported lipid bilayer. From the first-order accumulation rate at varying motor densities, we extrapolated a koff that matched single-molecule measurements, and measured a two-dimensional kon for membrane-bound kinesin-1 motors binding to the microtubule. This kon is consistent with kinesin-1 being able to reach roughly 20 tubulin subunits when attaching to a microtubule. By incorporating cholesterol to reduce membrane diffusivity, we demonstrate that this kon is not limited by the motor diffusion rate, but instead is determined by the intrinsic motor binding rate. For intracellular vesicle trafficking, this two-dimensional kon predicts that long-range transport of 100 nm diameter vesicles requires 35 kinesin-1 motors, suggesting that teamwork between different motor classes and motor clustering may play significant roles in long-range vesicle transport.Significance StatementLong-distance transport of membrane-coated vesicles involves coordination of multiple motors such that at least one motor is bound to the microtubule at all times. Microtubule attachment of a membrane-bound motor comprises two steps – diffusing through the lipid bilayer to a binding zone near the microtubule, followed by binding. Using a 2D supported lipid bilayer system, we show that membrane diffusion is not the limiting factor for motor attachment. This result suggests that in cells kinesin-1 binding kinetics are not altered by the membrane composition of vesicle cargos. The intrinsically slow binding properties of kinesin-1 suggest that divergent motor binding kinetics and motor clustering regulate long-range vesicle transport.
Multiple non-auditory cortical regions innervate the auditory midbrain
Authors: Olthof Bas MJ , Rees Adrian , Gartside Sarah E 
Published: May 2019

ABSTRACTOur perceptual experience of sound depends on the integration of multiple sensory and cognitive domains, but the networks sub-serving this integration are unclear. There are connections linking different cortical domains, however we do not know if there are also connections between multiple cortical domains and subcortical structures. Retrograde tracing in rats revealed that the inferior colliculus – the auditory midbrain - receives dense descending projections from not only the auditory cortex, but also the visual, somatosensory, motor, and prefrontal cortices. While all these descending connections are bilateral, those from sensory areas show a more pronounced ipsilateral dominance than those from motor and prefrontal cortices. Anterograde tracing from cortical areas identified by retrograde tracing, showed cortical fibres terminating in all three subdivisions of the inferior colliculus, targeting both inhibitory and excitatory neurons. These findings demonstrate that auditory perception is served by a network that includes extensive descending connections from sensory, behavioural, and executive cortices.
The rich get richer: synaptic remodeling between climbing fibers and Purkinje cells in the developing cerebellum begins with positive feedback addition of synapses
Authors: Wilson Alyssa Michelle , Schalek Richard , Suissa-Peleg Adi , Jones Thouis Ray , Knowles-Barley Seymour , Pfister Hanspeter , Lichtman Jeff William 
Published: May 2019

SUMMARYDuring postnatal development, cerebellar climbing fibers strongly innervate a subset of their original Purkinje cell targets and eliminate their connections from the rest. In the adult, each climbing fiber innervates a small number of Purkinje cells and each Purkinje cell is innervated by a single climbing fiber. To get insight about the processes responsible for this remapping, we reconstructed serial electron microscopy datasets from mice during the first postnatal week. In contrast to adult connectivity, individual neonatal climbing fibers innervate many nearby Purkinje cells, and multiple climbing fibers innervate each Purkinje cell. Between postnatal days 3 and 7, Purkinje cells retract long dendrites and grow many proximal dendritic processes. On this changing landscape, individual climbing fibers selectively add many synapses to a subset of Purkinje cell targets in a positive-feedback manner, without pruning synapses from other Purkinje cells. The active zone sizes of synapses associated with powerful versus weak inputs are indistinguishable. These results show that changes in synapse number rather than synapse size are the predominant form of early developmental plasticity. Finally, although multiple climbing fibers innervate each Purkinje cell in early postnatal development, the number of climbing fibers and Purkinje cells in a local cerebellar region nearly match. Thus, initial over-innervation of Purkinje cells by climbing fibers is economical, in that the number of axons entering a region is enough to assure that each axon ends up with a postsynaptic target, and that none branched there in vain.HIGHLIGHTSDeveloping climbing fibers establish synapses on many neighboring Purkinje cells unlike the sparse pattern of innervation in later lifeClimbing fibers add many synapses onto a few of their Purkinje targets before the pruning stage in a rich-get-richer type processThe synapse sizes of strengthened and weakened climbing fiber inputs are indistinguishable.Exuberant branching of climbing fiber axons in early postnatal life appears to be economical because the numbers of axons and Purkinje cells in a local region match, ensuring that each axon can establish a long-lasting connection thereBLURBHigh-resolution serial electron microscopy reconstructions reveal that climbing fiber-Purkinje cell synaptic refinement in the developing cerebellum begins with significant synapse addition. Climbing fibers focus their synapses onto a smaller number of Purkinje cells by selectively adding synapses onto some target cells. All axons that project to a region in development play a role in the final connectivity.
FOP plays a negative role in ciliogenesis and promotes cell cycle re-entry by facilitating primary cilia disassembly
Authors: Jiang Huadong , Cheung Man-Hei , Amin Aftab , Liang Chun 
Published: May 2019

AbstractPrimary cilia are microtubule-based, antenna-like organelles, which are formed in G0phase and resorbed as cells re-enter the cell cycle. It has been reported that the length of primary cilia can influence the timing of cell cycle progression. However, the molecular links between ciliogenesis and cell cycle progression are not clear. FOP (Fibroblast growth factor receptor 1 Oncogene Partner, also known as FGFR1OP) has been implicated in ciliogenesis. Here, we show that the expression of FOP during cell cycle exit and re-entry is negatively correlated with ciliogenesis. Knockdown of FOP promotes cilia elongation and suppresses timely cilia disassembly. In contrast, ectopic expression of FOP inhibits cilia growth. Moreover, pharmacological inhibition of actin polymerization with Cytochalasin D abrogates FOP-induced cilia disassembly, suggesting that FOP facilitates cilia disassembly by promoting actin cytoskeleton formation. Lastly, knockdown of FOP delays cell cycle re-entry of quiescent cells following serum re-stimulation, and this can be reversed by silencing IFT20 (intraflagellar transport 20), an intraflagellar transport protein essential for ciliogenesis. Collectively, these results suggest that FOP plays a negative role in ciliogenesis and can promote cell cycle re-entry by facilitating cilia disassembly.