bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crystal structures reveal that Lewis-x and fucose bind to secondary cholera toxin binding site – in contrast to fucosyl-GM1
Authors: Heim Joel B. , Hodnik Vesna , Heggelund Julie E. , Anderluh Gregor , Krengel Ute 
Published: September 2018

AbstractCholera is a life-threatening diarrhoeal disease caused by the human pathogenVibrio cholerae. Infection occurs after ingestion of the bacteria, which colonize the human small intestine and secrete their major virulence factor - the cholera toxin (CT). Recent studies suggest that the GM1 receptor may not be the only target of the CT, and that fucosylated receptors such as Lewisx(Lex) and histo-blood group antigens may also be important for cellular uptake and toxicity. However, where and how Lexbinds to the CT remains unclear. Here we report the high-resolution crystal structure (1.5 Å) of the receptor-binding B-subunit of the CT bound to the Lextrisaccharide, and present matching SPR data for CT holotoxins. Lex, and alsoL-fucose alone (at 500-fold molar excess), bind to the secondary binding site of the toxin, distinct from the GM1 binding site. In contrast, fucosyl-GM1 mainly binds to the primary binding site due to high-affinity interactions of its GM1 core. The two binding sites are likely connected by allosteric cross-talk, potentially affecting toxin uptake. We also discuss why secretors are protected from severe cholera.Author summaryCholera is a severe diarrhoeal disease that is still a major killer in many parts of the world, especially in regions struck by natural disasters and wars. However, some individuals experience milder cholera symptoms. These so-called ‘secretors’, who have blood group antigens also in their bodily fluids like their saliva and the slimy mucus layer covering their stomach and intestines, appear to be somewhat protected. Here we present detailed atomic structures of cholera toxin and quantitative binding data that give clues of the protective mechanisms. Interactions of the protein toxin with sugar molecules are of crucial importance both for toxicity and protection. In addition, we identify a new tool for biochemical studies, and lay the groundwork for the design of cholera drugs and vaccines that may save countless human lives.
Agent-based model of multicellular tumor spheroid evolution including cell metabolism
Authors: Cleri Fabrizio 
Published: September 2018

AbstractComputational models aiming at the spatio-temporal description of cancer evolution are a suitable framework for testing biological hypotheses from experimental data, and generating new ones. Building on our recent work [J Theor Biol 389, 146-158 (2016)] we develop a 3D agent-based model, capable of tracking hundreds of thousands of interacting cells, over time scales ranging from seconds to years. Cell dynamics is driven by a Monte Carlo solver, incorporating partial differential equations to describe chemical pathways and the activation/repression of “genes”, leading to the up- or down-regulation of specific cell markers. Each cell-agent of different kind (stem, cancer, stromal etc.) runs through its cycle, undergoes division, can exit to a dormant, senescent, necrotic state, or apoptosis, according to the inputs from their systemic network. The basic network at this stage describes glucose/oxygen/ATP cycling, and can be readily extended to cancer-cell specific markers. Eventual accumulation of chemical/radiation damage to each cell’s DNA is described by a Markov chain of internal states, and by a damage-repair network, whose evolution is linked to the cell systemic network. Aimed at a direct comparison with experiments of tumorsphere growth from stem cells, the present model will allow to quantitatively study the role of transcription factors involved in the reprogramming and variable radio-resistance of simulated cancer-stem cells, evolving in a realistic computer simulation of a growing multicellular tumorsphere.
A conserved morphogenetic mechanism for epidermal ensheathment of nociceptive sensory neurites
Authors: Jiang Nan , Rasmussen Jeffrey P. , Clanton Joshua A. , Rosenberg Marci F. , Luedke Kory P. , Cronan Mark R. , Parker Ed , Kim Hyeon-Jin , Vaughan Joshua C. , Sagasti Alvaro , Parrish Jay Z. 
Published: September 2018

AbstractInteractions between epithelial cells and neurons influence a range of sensory modalities including taste, touch, and smell. Vertebrate and invertebrate keratinocytes/keratinocyte-like epidermal cells ensheath peripheral arbors of somatosensory neurons, including nociceptors, yet the developmental origins and functional roles of this ensheathment are largely unknown. Here, we describe an evolutionarily conserved morphogenetic mechanism for epidermal ensheathment of somatosensory neurites. We found that somatosensory neurons inDrosophilaand zebrafish induce formation of epidermal sheaths, which wrap neurites of different types of neurons to different extents. Neurites induce formation of plasma membrane phosphatidylinositol 4,5-bisphosphate microdomains at nascent sheaths, followed by a filamentous actin network, and recruitment of junctional proteins that likely form autotypic junctions to seal sheaths. Finally, blocking epidermal sheath formation destabilized dendrite branches and reduced nociceptive sensitivity inDrosophila. Epidermal somatosensory neurite ensheathment is thus a deeply conserved cellular process that contributes to the morphogenesis and function of nociceptive sensory neurons.
Preventing S. aureus biofilm formation on titanium surfaces by the release of antimicrobial β-peptides from polyelectrolyte multilayers
Authors: de L. Rodríguez López Angélica , Lee Myung-Ryul , Whitehead Riley , Lynn David M. , Palecek Sean P. 
Published: September 2018

ABSTRACTStaphylococcus aureus infections represent the major cause of titanium based-orthopaedic implant failure. Current treatments for S. aureus infections involve the systemic delivery of antibiotics and additional surgeries, increasing health-care costs and affecting patient’s quality of life. As a step toward the development of new strategies that can prevent these infections, we build upon previous work demonstrating that the colonization of catheters by the fungal pathogen Candida albicans can be prevented by coating them with thin polymer multilayers composed of chitosan (CH) and hyaluronic acid (HA) designed to release a β-amino acid-based peptidomimetic of antimicrobial peptides (AMPs). We demonstrate here that this β-peptide is also potent against S. aureus (MIC = 4 µg/mL) and characterize its selectivity toward S. aureus biofilms. We demonstrate further that β-peptide-containing CH/HA thin-films can be fabricated on the surfaces of rough planar titanium substrates in ways that allow mammalian cell attachment and permit the long-term release of β-peptide. β-Peptide loading on CH/HA thin-films was then adjusted to achieve release of β-peptide quantities that selectively prevent S. aureus biofilms on titanium substrates in vitro for up to 24 days and remained antimicrobial after being challenged sequentially five times with S. aureus inocula, while causing no significant MC3T3-E1 preosteoblast cytotoxicity compared to uncoated and film-coated controls lacking β-peptide. We conclude that these β-peptide-containing films offer a novel and promising localized delivery approach for preventing orthopaedic implant infections. The facile fabrication and loading of β-peptide-containing films reported here provides opportunities for coating other medical devices prone to biofilm-associated infections.STATEMENT OF SIGNIFICANCETitanium (Ti) and its alloys are used widely in internal fixation devices due to their mechanical strength and long-term biocompatibility. However, these devices are susceptible to bacterial colonization and the subsequent formation of biofilms. Here we report a chitosan and hyaluronic acid polyelectrolyte multilayer-based approach for the localized delivery of helical, cationic, globally amphiphilic β-peptide mimetics of antimicrobial peptides to inhibit S. aureus colonization and biofilm formation. Our results reveal that controlled release of this β-peptide can selectively kill S. aureus cells without exhibiting toxicity toward MC3T3-E1 preosteoblast cells. Further development of this polymer-based coating could result in new strategies for preventing orthopaedic implant-related infections, improving outcomes of these titanium implants.
Single-cell microRNA/mRNA co-sequencing reveals non-genetic heterogeneity and novel regulatory mechanisms
Authors: Wang Nayi , Zheng Ji , Chen Zhuo , Liu Yang , Dura Burak , Kwak Minsuk , Xavier-Ferrucio Juliana , Lu Yi-Chien , Zhang Miaomiao , Roden Christine , Cheng Jijun , Krause Diane , Ding Ye , Fan Rong , Lu Jun 
Published: September 2018

ABSTRACTCo-measurement of multiple omic profiles from the same single cells opens up the opportunity to decode molecular regulation that underlie intercellular heterogeneity in development and disease. Here, we present co-sequencing of microRNAs and mRNAs in the same single cells using a half-cell genomics approach. This method demonstrates good robustness (~95% success rate) and reproducibility (R2=0.93 for both miRNAs and mRNAs), and yields paired half-cell miRNA and mRNA profiles that could be independently validated. Linking the level of miRNAs to the expression of predicted target mRNAs across 19 single cells that are phenotypically identical, we observe that the predicted targets are significantly anti-correlated with the variation of abundantly expressed miRNAs, suggesting that miRNA expression variability alone may lead to non-genetic cell-to-cell heterogeneity. Genome-scale analysis of paired miRNA-mRNA co-profiles further allows us to derive and validate new regulatory relationships of cellular pathways controlling miRNA expression and variability.
The physiological butyrylcholinesterase tetramer is a dimer of dimers stabilized by a superhelical assembly
Authors: Leung Miguel Ricardo , van Bezouwen Laura S. , Schopfer Lawrence M. , Sussman Joel L. , Silman Israel , Lockridge Oksana , Zeev-Ben-Mordehai Tzviya 
Published: September 2018

AbstractThe quaternary structures of the cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are essential for their localisation and function. Of practical importance, BChE is a promising therapeutic candidate for intoxication by organophosphate nerve agents and insecticides, and for detoxification of addictive substances. Efficacy of the recombinant enzyme hinges on its having a long circulatory half-life; this, in turn, depends strongly on its ability to tetramerize. Here, we used cryo-electron microscopy (cryo-EM) to determine the structure of the highly glycosylated native BChE tetramer purified from human plasma at 5.7 Å. Our structure reveals that the BChE tetramer is organised as a staggered dimer of dimers. Tetramerization is mediated by assembly of the C-terminal tryptophan amphiphilic tetramerization (WAT) helices from each subunit as a superhelical assembly around a central anti-parallel polyproline II helix (PRAD). The catalytic domains within a dimer are asymmetrically linked to the WAT/PRAD. In the resulting arrangement, the tetramerization domain is largely shielded by the catalytic domains, which may contribute to the stability of the HuBChE tetramer. Our cryo-EM structure reveals the basis for assembly of the physiological tetramers, and has implications for the therapeutic applications of HuBChE. This mode of tetramerization is seen only in the cholinesterases, and may provide a promising template for designing other proteins with improved circulatory residence times.
LRIT3 is required for nyctalopin expression and normal ON and OFF pathway signaling in the retina
Authors: Hasan Nazarul , Pangeni Gobinda , Ray Thomas A. , Fransen Kathryn M. , Noel Jennifer , Borghuis Bart G. , McCall Maureen A. , Gregg Ronald G. 
Published: September 2018

ABSTRACTAt its first synapse, the retina establishes two parallel channels that encode light increments (ON) or decrements (OFF). At the same synapse, changes in photoreceptor glutamate release are sensed by ON bipolar cells (BCs) via the metabotropic glutamate receptor 6 (mGluR6), and OFF BCs via ionotropic BCs, which differ in their synaptic configuration with the photoreceptor terminal. ON BCs form invaginating synapses that bring them in close proximity to presynaptic ribbons and the presumed sole source of glutamate release. OFF bipolar cells form flat contacts distal to the ribbon synapse. We investigated the role of LRIT3 in normal assembly and function of the mGlur6 signaling cascade present in ON BCs. We demonstrate that LRIT3 is required for nyctalopin expression and thus TRPM1 expression and function. Using glutamate imaging, whole-cell electrophysiology, and multi-electrode array extracellular recordings we demonstrate that the loss of LRIT3 impacts both the ON and OFF pathways at the level of the BCs. The effect on ON pathway signaling, a lack of ON BC response, is shared by mutants lacking mGluR6, TRPM1 GPR179 or nyctalopin. The effects on the OFF pathway are unique to LRIT3, and include a decrease in response amplitude of both OFF BC and GCs. Based on these results, we propose a working model where LRIT3 is required for either efficient glutamate release or reuptake from the first retinal synapse.SIGNIFICANCE STATEMENTAt the first visual synapse, photoreceptor cells signal to two distinct bipolar cell (BC) populations, one characterized by a depolarizing response to light onset (ON or DBCs), the other by a hyperpolarizing response (OFF or HBCs). The DBC light response depends on a G protein-coupled receptor and associated protein complex, known as the signalplex. Mutations in signalplex proteins lead to DBC pathway-specific loss of visual function. Here we show how loss of LRIT3, a previously identified signalplex protein, prevents functional assembly of the DBC signalplex and alters visual function in both ON and OFF signaling pathways. Thus, our results indicate that the function of LRIT3 at this first synapse extends beyond assembly of the DBC signalplex.
VOLARE: Visual analysis of disease-associated microbiome-immune system interplay
Authors: Siebert Janet C. , Neff Charles Preston , Schneider Jennifer M. , Regner EmiLie H. , Ohri Neha , Kuhn Kristine A. , Palmer Brent E. , Lozupone Catherine A. , Görg Carsten 
Published: September 2018

AbstractBackgroundRelationships between specific microbes and proper immune system development, composition, and function have been reported in a number of studies. However, researchers have discovered only a fraction of the likely relationships. High-dimensional “omic” methodologies such as 16S ribosomal RNA (rRNA) sequencing and Time-of-flight mass cytometry (CyTOF) immunophenotyping generate data that support generation of hypotheses, with the potential to identify additional relationships at a level of granularity ripe for further experimentation. Pairwise linear regressions between microbial and host immune features is one approach for quantifying relationships between “omes”, and the differences in these relationships across study cohorts or arms. This approach yields a top table of candidate results. However, the top table alone lacks the detail that domain experts need to vet candidate results for follow-up experiments.ResultsTo support this vetting, we developed VOLARE (Visualization Of LineAr Regression Elements), a web application that integrates a searchable top table, small in-line graphs illustrating the fitted models, a network summarizing the top table, and on-demand detailed regression plots showing full sample-level detail. We applied VOLARE to three case studies—microbiome:cytokine data from fecal samples in HIV, microbiome:cytokine data in inflammatory bowel disease and spondyloarthritis, and microbiome:immune cell data from gut biopsies in HIV. We present both patient-specific phenomena and relationships that differ by disease state. We also analyzed interaction data from system logs to characterize usage scenarios. This log analysis revealed that, in using VOLARE, domain experts frequently generated detailed regression plots, suggesting that this detail aids the vetting of results.ConclusionsSystematically integrating microbe:immune cell readouts through pairwise linear regressions and presenting the top table in an interactive environment supports the vetting of results for scientific relevance. VOLARE allows domain experts to control the analysis of their results, screening dozens of candidate relationships with ease. This interactive environment transcends the limitations of a static top table.
Heading direction with respect to a reference point modulates place-cell activity
Authors: Jercog P.E. , Ahmadian Y. , Woodruff C. , Deb-Sen R. , Abbott L.F. , Kandel E.R. 
Published: October 2018

AbstractUtilizing electrophysiological recordings from CA1 pyramidal cells in freely moving mice, we find that a majority of neural responses are modulated by the heading-direction of the animal relative to a point within or outside their enclosure that we call a reference point. Our findings identify a novel representation in the neuronal responses in the dorsal hippocampus.
New ways to get policy into practice
Authors: Nugus Peter , Ranmuthugala Geetha , Lamothe Josianne , Greenfield David , Travaglia Joanne , Kolne Kendall , Kryluk Julia , Braithwaite Jeffrey 
Published: October 2018

Purpose
Health service effectiveness continues to be limited by misaligned objectives between policy makers and frontline clinicians. While capturing the discretion workers inevitably exercise, the concept of “street-level bureaucracy” has tended to artificially separate policy makers and workers. The purpose of this paper is to understand the role of social-organizational context in aligning policy with practice.

Design/methodology/approach
This mixed-method participatory study focuses on a locally developed tool to implement an Australia-wide strategy to engage and respond to mental health services for parents with mental illness. Researchers: completed 69 client file audits; administered 64 staff surveys; conducted 24 interviews and focus groups (64 participants) with staff and a consumer representative; and observed eight staff meetings, in an acute and sub-acute mental health unit. Data were analyzed using content analysis, thematic analysis and descriptive statistics.

Findings
Based on successes and shortcomings of the implementation (assessment completed for only 30 percent of clients), a model of integration is presented, distinguishing “assimilist” from “externalist” positions. These depend on the degree to which, and how, the work environment affords clinicians the setting to coordinate efforts to take account of clients’ personal and social needs. This was particularly so for allied health clinicians and nurses undertaking sub-acute rehabilitative-transitional work.

Originality/value
A new conceptualization of street-level bureaucracy is offered. Rather than as disconnected, it is a process of mutual influence among interdependent actors. This positioning can serve as a framework to evaluate how and under what circumstances discretion is appropriate, and to be supported by managers and policy makers to optimize client-defined needs.
Estimation of grain elasticity properties from ultrasonic measurements on dry granular pack
Authors: Madadi Mahyar , Ahmed Zubair , Bona Andrej , Lebedev Maxim , Gurevich Boris 
Published: September 2018

ABSTRACTThe elastic properties of crystalline rocks can be estimated from ultrasonic measurements on the powders of crushed rocks produced by the drilling process. To determine the elastic properties of grains from properties of powder packs, we study the dependence of their ultrasonic wave velocities on pressure. From this dependency, using the Hertz–Mindlin theory, we can calculate the effective ratio of the grain shear modulus to one minus the Poisson ratio. The Hertz–Mindlin theory requires the knowledge of grain coordination number as a function of pressure, which can be obtained using an empirical relation based on published numerical simulations. Previous work has shown that this approach gives an accurate prediction of the effective bulk modulus of glass beads but produces a significant discrepancy for sand. This discrepancy may be attributed to the angularity of sand grains. To overcome this problem, we introduce a shape factor into the empirical relation for the coordination number. This new shape factor allows us to reconcile the rock physics model with laboratory measurements. We show that the shape factor varies from 1 to 2.5 for different grain shape angularity and sorting (grain size distributions). The modified theory allows us to estimate a combination of elasticity parameters of the grains from the measured dependence of P‐wave velocity in the pack on the pressure.
Developing the global potential of citizen science: Assessing opportunities that benefit people, society and the environment in East Africa
Authors: Pocock Michael J. O. , Roy Helen E. , August Tom , Kuria Anthony , Barasa Fred , Bett John , Githiru Mwangi , Kairo James , Kimani Julius , Kinuthia Wanja , Kissui Bernard , Madindou Ireene , Mbogo Kamau , Mirembe Judith , Mugo Paul , Muniale Faith Milkah , Njoroge Peter , Njuguna Edwin Gichohi , Olendo Mike Izava , Opige Michael , Otieno Tobias O. , Ng'weno Caroline Chebet , Pallangyo Elisha , Thenya Thuita , Wanjiru Ann , Trevelyan Rosie 
Published: September 2018

Abstract

Citizen science is gaining increasing prominence as a tool for science and engagement. However, despite being a potentially valuable tool for sustainable development, citizen science has little visibility in many developing countries.

We undertook a collaborative prioritisation process with experts in conservation and the environment to assess the potential of environmental citizen science in East Africa, including its opportunities, benefits and barriers. This provided principles that are applicable across developing countries, particularly for large‐scale citizen science.

We found that there was great potential for citizen science to add to our scientific knowledge of natural resources and biodiversity trends. Many of the important benefits of citizen science were for people, as well as the environment directly. Major barriers to citizen science were mostly social and institutional, although projects should also consider access to suitable technology and language barriers.

Policy implications. Citizen science can provide data to support decision‐making and reporting against international targets. Participation can also provide societal benefits, informing and empowering people, thus supporting the United Nations’ Sustainable Development Goals. In developing countries, innovation is needed to further develop culturally relevant citizen science that benefits participants and end users. This should be supported through regional networks of stakeholders for sharing best practice.