bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure to unpredictable trips and slips while walking can improve balance recovery responses with minimum predictive gait alterations
Authors: Okubo Yoshiro , Brodie Matthew A , Sturnieks Daina L , Hicks Cameron , Carter Hilary , Toson Barbara , Lord Stephen R 
Published: June 2018

AbstractINTRODUCTIONThis study aimed to determine if repeated exposure to unpredictable trips and slips while walking can improve balance recovery responses when predictive gait alterations (e.g. slowing down) are minimised.METHODSTen young adults walked on a 10-m walkway that induced slips and trips in fixed and random locations. Participants were exposed to a total of 12 slips, 12 trips and 6 non-perturbed walks in three conditions: 1) right leg fixed location, 2) left leg fixed location and 3) random leg and location. Kinematics during non-perturbed walks and previous and recovery steps were analysed.RESULTSThroughout the three conditions, participants walked with similar gait speed, step length and cadence(p>0.05). Participants’ extrapolated centre of mass (XCoM) was anteriorly shifted immediately before slips at the fixed location (p<0.01), but this predictive gait alteration did not transfer to random perturbation locations. Improved balance recovery from trips in the random location was indicated by increased margin of stability and step length during recovery steps (p<0.05). Changes in balance recovery from slips in the random location was shown by reduced backward XCoM displacement and reduced slip speed during recovery steps (p<0.05).CONCLUSIONSEven in the absence of most predictive gait alterations, balance recovery responses to trips and slips were improved through exposure to repeated unpredictable perturbations. A common predictive gait alteration to lean forward immediately before a slip was not useful when the perturbation location was unpredictable. Training balance recovery with unpredictable perturbations may be beneficial to fall avoidance in everyday life.
No support for the sexy-sperm hypothesis in the seed beetle: sons of monandrous females fare better in post-copulatory competition
Authors: Hook Kristin A. 
Published: June 2018

ABSTRACTThe sexy-sperm hypothesis posits that polyandrous females derive an indirect fitness benefit from multi-male mating because they increase the probability their eggs are fertilized by males whose sperm have high fertilizing efficiency, which is assumed to be heritable and conferred on their sons. However, whether this process occurs is contentious because father-to-son heritability may be constrained by the genetic architecture underlying traits important in sperm competition within certain species. Previous empirical work has revealed such genetic constraints in the seed beetle,Callosobruchus maculatus, a model system in sperm competition studies in which female multi-male mating is ubiquitous. Using the seed beetle, I tested a critical prediction of the sexy-sperm hypothesis that polyandrous females produce sons that are on average more successful under sperm competition than sons from monandrous females. Contrary to the prediction of the sexy-sperm hypothesis, I found that sons from monandrous females had significantly higher relative paternity in competitive double matings. Moreover, post-hoc analyses revealed that these sons produced significantly larger ejaculates when second to mate, despite being smaller. This study is the first to provide empirical evidence for post-copulatory processes favoring monandrous sons and discusses potential explanations for the unexpected bias in paternity.
Functional and Anatomical Specificity in a Higher Olfactory Centre
Authors: Frechter Shahar , Bates Alexander S. , Tootoonian Sina , Dolan Michael-John , Manton James D. , Jamasb Arian , Kohl Johannes , Bock Davi , Jefferis Gregory S. X. E. 
Published: June 2018

AbstractMost sensory systems are organized into parallel neuronal pathways that process distinct aspects of incoming stimuli. For example, in insects, second order olfactory projection neurons target both the mushroom body, which is required for learning, and the lateral horn (LH), which has been proposed to mediate innate olfactory behavior. Mushroom body neurons encode odors in a sparse population code, which does not appear stereotyped across animals. In contrast the functional principles of odor coding in the LH remain poorly understood. We have carried out a comprehensive anatomical analysis of the Drosophila LH, counting ~1400 neurons; combining genetic driver lines, anatomical and functional criteria, we identify 165 LHN cell types. We then show that genetically labeled LHNs have stereotyped odor responses across animals for 33 of these cell types. LHN tuning can be ultra-sparse (1/40 odors tested), but on average single LHNs respond to three times more odors than single projection neurons. This difference can be rationalized by our observation that LHNs are better odor categorizers, likely due to pooling of input projection neurons responding to different odors of the same category. Our results reveal some of the principles by which a higher sensory processing area can extract innate behavioral significance from sensory stimuli.
Novel tumor suppressor roles forGZMAandRASGRP1in dissemination of bothTheileria annulata-transformed macrophages and human B-lymphoma cells
Authors: Rchiad Zineb , Haidar Malak , Ansari Hifzur Rahman , Tajeri Shahin , Mfarrej Sara , Rached Fathia Ben , Kaushik Abhinav , Langsley Gordon , Pain Arnab 
Published: June 2018

AbstractTheileria annulatais a tick-transmitted apicomplexan parasite that infects and transforms bovine leukocytes into disseminating tumors that cause a disease called tropical theileriosis. Using comparative transcriptomics we identified genes transcriptionally perturbed duringTheileria-induced transformation. Dataset comparisons highlighted a small set of genes associated withTheileria-transformed leukocyte dissemination. The roles of Granzyme A (GZMA) and RAS guanyl-releasing protein 1 (RASGRP1) were verified by CRISPR/Cas9-mediated knock-down. Knocking down ofGZMAandRASGRP1in attenuated macrophages led to a regain in their dissemination in Rag2/γC mice confirming their role as dissemination suppressorsin vivo. We further evaluated the roles ofGZMAandRASGRP1in human B-lymphoma cells by comparing the transcriptome of 934 human cancer cell lines to that ofTheileria-transformed bovine host cells. We confirmed dampened dissemination potential of human B-lymphoma cells that overexpressGZMAandRASGRP1. Our results provide evidence thatGZMAandRASGRP1have a novel tumor suppressor function in bothT. annulata-infected bovine host cells and in human B-lymphomas.SummaryWe compared the transcriptomes ofTheileria annulatatransformed B-lymphocytes to 934 human cancer cell lines and provide functional evidence for shared tumor suppressor roles for GZMA and RASGRP1 in controlling the dissemination phenotype of both human B lymphomas and Theileria-transformed leukocytes.
Predicting onset, progression, and clinical subtypes of Parkinson disease using machine learning
Authors: Faghri Faraz , Hashemi Sayed Hadi , Leonard Hampton , Scholz Sonja W. , Campbell Roy H. , Nalls Mike A. , Singleton Andrew B. 
Published: June 2018

AbstractBackgroundThe clinical manifestations of Parkinson disease are characterized by heterogeneity in age at onset, disease duration, rate of progression, and constellation of motor versus nonmotor features. Due to these variable presentations, counseling of patients about their individual risks and prognosis is limited. There is an unmet need for predictive tests that facilitate early detection and characterization of distinct disease subtypes as well as improved, individualized predictions of the disease course. The emergence of machine learning to detect hidden patterns in complex, multi-dimensional datasets provides unparalleled opportunities to address this critical need.Methods and FindingsWe used unsupervised and supervised machine learning approaches for subtype identification and prediction. We used machine learning methods on comprehensive, longitudinal clinical data from the Parkinson Disease Progression Marker Initiative (PPMI) (n=328 cases) to identify patient subtypes and to predict disease progression. The resulting models were validated in an independent, clinically well-characterized cohort from the Parkinson Disease Biomarker Program (PDBP) (n=112 cases). Our analysis distinguished three distinct disease subtypes with highly predictable progression rates, corresponding to slow, moderate and fast disease progressors. We achieved highly accurate projections of disease progression four years after initial diagnosis with an average Area Under the Curve of 0.93 (95% CI: 0.96 ± 0.01 for PDvec1, 0.87 ± 0.03 for PDvec2, and 0.96 ± 0.02 for PDvec3). We have demonstrated robust replication of these findings in the independent validation cohort.ConclusionsThese data-driven results enable clinicians to deconstruct the heterogeneity within their patient cohorts. This knowledge could have immediate implications for clinical trials by improving the detection of significant clinical outcomes that might have been masked by cohort heterogeneity. We anticipate that machine learning models will improve patient counseling, clinical trial design, allocation of healthcare resources and ultimately individualized clinical care.
A long-non-coding RNA, LINC00473, confers the human adipose tissue thermogenic phenotype through enhanced cAMP responsiveness
Authors: Tran Khanh-Van , Nandrup-Bus Cecilie , DeSouza Tiffany , Soares Ricardo , Jespersen Naja Zenius , Min So Yun , Rojas-Rodriguez Raziel , Willenbrock Hanni , Juhlin Therese , Severinsen Mai Charlotte Krogh , Malka Kimberly , Pedersen Bente Klarlund , Fitzgibbons Timothy , Scheele Camilla , Corvera Silvia , Nielsen Søren 
Published: June 2018

SummarySpecialized adipocytes localized in distinct depots mediate the many physiological functions of adipose tissue. In humans, paucity of thermogenic adipocytes correlates with high metabolic disease risk, raising much interest in the mechanisms by which these cells arise. Here we report molecular signatures associated with adipocyte development in different human depots and identify a long non-coding RNA, LINC00473, as the transcript most closely associated with enrichment of thermogenic adipocytes. LINC00473 expression is low in subjects with obesity or type-2 diabetes and is highly correlated with cAMP signaling and mitochondrial oxidative phosphorylation pathways. LINC00473 is localized in the nucleus and the cytoplasm, and its knockdown impairs induction of UCP1 and mitochondrial respiration. These results reveal that depot-enriched genes that modulate responsiveness to external stimuli, specifically LINC00473, are important determinants of the adipose tissue thermogenic phenotype, and potential targets for metabolic disease therapy.
Targeted Molecular Dynamics Simulations Suggest Direct Ligand Competition as a Plausible Efflux Inhibition Mechanism in the Multidrug Resistance Pump AcrB
Authors: Silva Lande , da Silva Pedro Eduardo Almeida , Machado Karina S. , Dutra Nelson , Lybrand Terry P. 
Published: June 2018

AbstractWe report computer simulation results using the Targeted Molecular Dynamics technique to explore possible transport mechanisms in the multidrug efflux pump AcrB for two substrates, ethidium bromide and a tetrahydropyridine derivative. These studies revealed structural elements, including specific α-helices, β-strands and flexible loops that define a physically plausible pathway for substrates to the extracellular environment. These calculation results can be used to plan future biophysical experiments and may suggest interesting drug design possibilities to address drug resistance due to AcrB function.ImportanceAddressing the issue of antimicrobial resistance mediated by efflux, this study presents possible binding sites and structures in the AcrB MDR pump that could be molecular targets for drugs. Targeted molecular dynamics simulations suggested that these sites and structures seem vital for a successful efflux. The AcrB is proposed to be divided into three distinct zones, with loops, sheets and helices mediating the passage of molecules from one zone to another. We also described possible capture sites on the outer part of the protein and access ways to its interior. Finally, we proposed that ligand competition for same pathways could be thought as an efflux inhibitory mechanism, thus assisting to conceive new ways of designing efflux pump inhibitors.
Connecting the dots between mechanosensitive channel abundance, osmotic shock, and survival at single-cell resolution
Authors: Chure Griffin , Lee Heun Jin , Phillips Rob 
Published: June 2018

AbstractRapid changes in extracellular osmolarity are one of many insults microbial cells face on a daily basis. To protect against such shocks,Escherichia coliand other microbes express several types of transmembrane channels which open and close in response to changes in membrane tension. InE. coli, one of the most abundant channels is the mechanosensitive channel of large conductance (MscL). While this channel has been heavily characterized through structural methods, electrophysiology, and theoretical modeling, our understanding of its physiological role in preventing cell death by alleviating high membrane tension remains tenuous. In this work, we examine the contribution of MscL alone to cell survival after osmotic shock at single cell resolution using quantitative fluorescence microscopy. We conduct these experiments in anE. colistrain which is lacking all mechanosensitive channel genes save for MscL whose expression is tuned across three orders of magnitude through modifications of the Shine-Dalgarno sequence. While theoretical models suggest that only a few MscL channels would be needed to alleviate even large changes in osmotic pressure, we find that between 500 and 700 channels per cell are needed to convey upwards of 80% survival. This number agrees with the average MscL copy number measured in wild-typeE. colicells through proteomic studies and quantitative Western blotting. Furthermore, we observe zero survival events in cells with less than 100 channels per cell. This work opens new questions concerning the contribution of other mechanosensitive channels to survival as well as regulation of their activity.
Heterologous Expression ofPseudomonas putidaMethyl-Accepting Chemotaxis Proteins YieldsEscherichia coliChemotactic to Aromatic Compounds
Authors: Roggo Clémence , Clerc Estelle Emilie , Hadadi Noushin , Carraro Nicolas , Stocker Roman , van der Meer Jan Roelof 
Published: June 2018

ABSTRACTEscherichia coli, commonly used in chemotaxis studies, is attracted mostly by amino acids, sugars and peptides. We envisioned modifying chemotaxis specificity ofE. coliby expressing heterologous chemoreceptors fromPseudomonas putidaenabling attraction either to toluene or benzoate. ThemcpTgene encoding the type 40H methyl-accepting chemoreceptor for toluene fromPseudomonas putidaMT53 and thepcaYgene for the type 40H receptor for benzoate and related molecules fromP. putidaF1 were expressed from thetrgpromoter on a plasmid in motile wild-typeE. coliMG1655.E. colicells expressing McpT accumulated in chemoattraction assays to sources with 60–200 μM toluene; less strongly than the response to 100 μM serine, but statistically significantly stronger than to sources without any added attractant. An McpT-mCherry fusion protein was detectably expressed inE. coliand yielding weak but distinguishable membrane and polar foci in 1% of cells.E. coliexpressing PcaY showed weak attraction to 0.1–1 mM benzoate but 50–70% of cells localized the PcaY-mCherry fusion to their membrane. We conclude that implementing heterologous receptors in theE. colichemotaxis network is possible and, upon improvement of the compatibility of the type 40H chemoreceptors, may bear interest for biosensing.IMPORTANCEBacterial chemotaxis might be harnessed for the development of rapid biosensors, in which chemical availability is deduced from cell accumulation to chemoattractants over time. Chemotaxis ofEscherichia colihas been well-studied, but the bacterium is not attracted to chemicals of environmental concern, such as aromatic solvents. We show here that heterologous chemoreceptors for aromatic compounds fromPseudomonas putidaat least partly functionally complement theE. colichemotaxis network, yielding cells attracted to toluene or benzoate. Complementation was still inferior to native chemoattractants like serine, but our study demonstrates the potential for obtaining selective sensing for aromatic compounds inE. coli.
TGFβ1-induced cell motility is mediated through Cten in colorectal cancer
Authors: Asiri Abdulaziz , Raposo Teresa Pereira , Alfahed Abdulaziz , Ilyas Mohammad 
Published: June 2018

ABSTRACTCten is a tensin which promotes epithelial-mesenchymal transition (EMT) and cell motility. The precise mechanisms regulating Cten are unknown, although Cten could be regulated by several cytokines and growth factors. Since Transforming growth factor beta 1 (TGF-β1) regulates integrin function and promotes EMT / cell motility, we investigated whether this happens through Cten signalling in colorectal cancer (CRC).TGF-β1 signalling was modulated by either stimulation or knockdown in the CRC cell lines SW620 and HCT116. The effect of this modulation on expression of Cten, EMT markers and cellular function was tested. Cten role as a direct mediator of TGF-β1 signalling was investigated in a CRC cell line with a deleted Cten gene (SW620ΔCten).When TGF-β1 was stimulated or inhibited, this resulted in, respectively, upregulation and downregulation of Cten expression and EMT markers. Cell migration and invasion were significantly increased following TGF-β1 stimulation and lost by TGF-β1 knockdown. TGF-β1 stimulation in SW620ΔCten resulted in selective loss of the effect of TGF-β1 signalling on EMT and cell motility whilst the stimulatory effect on cell proliferation was retained.These data suggested Cten may play an essential role in mediating TGF-β1-induced EMT and cell motility and may play a role in metastasis in CRC.
Unified Analysis of Global and Focal Aspects of Absence Epilepsy via Neural Field Theory of the Corticothalamic System
Authors: Yang Dong-Ping , Robinson P. A. 
Published: June 2018

AbstractA physiology-based corticothalamic model is investigated with focal spatial heterogeneity, to unify global and focal aspects of absence epilepsy. Numerical and analytical calculations are employed to investigate the emergent spatiotemporal dynamics induced by focal activity as well as their underlying dynamical mechanisms. The spatiotemporal dynamics can be categorized into three scenarios: suppression, localization, and generalization of the focal activity, as summarized from a phase diagram vs. focal width and characteristic axon range. The corresponding temporal frequencies and spatial extents of wave activity during seizure generalization and localization agree well with experimental observations of global and focal aspects of absence epilepsy, respectively. The emergent seizure localization provide a biophysical explanation of the temporally higher frequency but spatially more localized cortical waves observed in genetic rat models that display characteristics of human absence epilepsy. Predictions are also presented for further experimental test.Author SummaryAbsence epilepsy is characterized by a sudden paroxysmal loss of consciousness accompanied by oscillatory activity propagating over many brain areas. Although primary generalized absence seizures are supported by the global corticothalamic system, converging experimental evidence supports a focal theory of absence epilepsy. Here we propose a dynamical mechanism to unify the global and focal aspects of absence epilepsy, with focal absence seizures associated with seizure localization, and the global ones associated with seizure generalization. Our corticothalamic model is used to investigate how seizure rhythms and spatial extents are related in these two different aspects of absence epilepsy. The results account for the difference of the experimentally observed seizure rhythms and spatial extents between humans and genetic rat models, which has previously been used to argue against the validity of such rats as animal models of absence epilepsy in humans.
Physical and transcriptional organisation of the bread wheat intracellular immune receptor repertoire
Authors: Steuernagel Burkhard , Witek Kamil , Krattinger Simon G. , Ramirez-Gonzalez Ricardo H. , Schoonbeek Henk-jan , Yu Guotai , Baggs Erin , Witek Agnieszka I. , Yadav Inderjit , Krasileva Ksenia V. , Jones Jonathan D. G. , Uauy Cristobal , Keller Beat , Ridout Christopher J. ,   The International Wheat Genome Sequencing Consortium, Wulff Brande B. H. 
Published: June 2018

AbstractDisease resistance genes encoding intracellular immune receptors of the nucleotide-binding and leucine-rich repeat (NLR) class of proteins detect pathogens by the presence of pathogen effectors. Plant genomes typically contain hundreds of NLR encoding genes. The availability of the hexaploid wheat cultivar Chinese Spring reference genome now allows a detailed study of its NLR complement. However, low NLR expression as well as high intra-family sequence homology hinders their accurate gene annotation. Here we developed NLR-Annotator forin silicoNLR identification independent of transcript support. Although developed for wheat, we demonstrate the universal applicability of NLR-Annotator across diverse plant taxa. Applying our tool to wheat and combining it with a transcript-validated subset of genes from the reference gene annotation, we characterized the structure, phylogeny and expression profile of the NLR gene family. We detected 3,400 full-length NLR loci of which 1,540 were confirmed as complete genes. NLRs with integrated domains mostly group in specific sub-clades. Members of another subclade predominantly locate in close physical proximity to NLRs carrying integrated domains suggesting a paired helper-function. Most NLRs (88%) display low basal expression (in the lower 10 percentile of transcripts), which may be tissue-specific and/or induced by biotic stress. As a case study for applying our tool to the positional cloning of resistance genes, we estimated the number of NLR genes within the intervals of mapped rust resistance genes. Our study will support the identification of functional resistance genes in wheat to accelerate the breeding and engineering of disease resistant varieties.
Amylasecopy number analysis in several mammalian lineages reveals convergent adaptive bursts shaped by diet
Authors: Pajic Petar , Pavlidis Pavlos , Dean Kirsten , Neznanova Lubov , Daugherity Erin , Romano Rose-Anne , Garneau Danielle , Globig Anja , Ruhl Stefan , Gokcumen Omer 
Published: June 2018

AbstractThe amylase gene (AMY), which codes for a starch-digesting enzyme in animals, underwent several gene copy number gains in humans1, dogs2, and mice3, presumably along with increased starch consumption during the evolution of these species. Here we present evidence for additionalAMYcopy number expansions in several mammalian species, most of which also consume starch-rich diets. We also show that these independentAMYcopy number gains are often accompanied by a gain in enzymatic activity of amylase in saliva. We used multi-species coalescent modeling to provide further evidence that these recurrentAMYgene copy number expansions were adaptive. Our findings underscore the overall importance of gene copy number amplification as a flexible and fast adaptive mechanism in evolution that can independently occur in different branches of the phylogeny.