bluuebunny/crossref_metadata_2025 huggingface dataset:
Learning of goal-relevant and irrelevant complex visual sequences in human V1
Authors: Rosenthal Clive R. , Mallik Indira , Caballero-Gaudes Cesar , Sereno Martin I. , Soto David
Published: February 2018

Learning and memory are supported by a network involving the medial temporal lobe and linked neocortical regions. Emerging evidence indicates that primary visual cortex (i.e., V1) may contribute to recognition memory, but this has been tested only with a single visuospatial sequence as the target memorandum. The present study used functional magnetic resonance imaging to investigate whether human V1 can support the learning of multiple, concurrent, and complex visual sequences involving discontinous (second-order) associations. Two peripheral, goal-irrelevant but structured sequences of orientated gratings appeared simultaneously in fixed locations of the right and left visual fields alongside a central, goal-relevant sequence that was in the focus of spatial attention. Pseudorandom sequences were introduced at multiple intervals during the presentation of the three structured visual sequences to provide an online measure of sequence-specific knowledge at each retinotopic location. We found that a network involving the precuneus and V1 was involved in learning the structured sequence presented at central fixation, whereas right V1 was modulated by repeated exposure to the concurrent structured sequence presented in the left visual field. The same result was not found in left V1. These results indicate for the first time that human V1 can support the learning of multiple concurrent sequences involving complex discontinuous inter-item associations, even peripheral sequences that are goal-irrelevant.
The relationship between brain atrophy and cognitive-behavioral symptoms in retired Canadian football players with multiple concussions
Authors: Misquitta Karen , Dadar Mahsa , Tarazi Apameh , Hussain MW , Alatwi MK , Ebraheem Ahmed , Multani Namita , Khodadadi Mozhgan , Goswami Ruma , Wennberg Richard , Tator Charles , Green Robin , Colella Brenda , Davis Karen , Mikulis David , Grinberg Mark , Sato Christine , Rogaeva Ekaterina , Collins D. Louis , Tartaglia Maria Carmela
Published: February 2018

Multiple concussions, particularly in contact sports, have been associated with cognitive deficits, psychiatric impairment and neurodegenerative diseases like chronic traumatic encephalopathy. We used volumetric and deformation-based morphometric analyses to test the hypothesis that repeated concussions may be associated with smaller regional brain volumes, poorer cognitive performance and behavioural symptoms among former professional football players compared to healthy controls. This study included fifty-three retired Canadian Football League players, 25 age- and education-matched healthy controls, and controls from the Cambridge Centre for Aging and Neuroscience database for validation. Volumetric analyses revealed greater hippocampal atrophy than expected for age in former athletes with multiple concussions than controls and smaller left hippocampal volume was associated with poorer verbal memory performance. Deformation-based morphometric confirmed smaller bilateral hippocampal volume that were associated with poorer verbal memory performance in athletes. Repeated concussions may lead to greater regional atrophy than expected for age.
Generating genomic platforms to studyCandida albicanspathogenesis
Authors: Legrand Mélanie , Bachellier-Bassi Sophie , Lee Keunsook K. , Chaudhari Yogesh , Tournu Hélène , Arbogast Laurence , Boyer Hélène , Chauvel Murielle , Cabral Vitor , Maufrais Corinne , Nesseir Audrey , Maslanka Irena , Permal Emmanuelle , Rossignol Tristan , Walker Louise A. , Zeidler Ute , Znaidi Sadri , Schoeters Floris , Majgier Charlotte , Julien Renaud A. , Ma Laurence , Tichit Magali , Bouchier Christiane , Dijck Patrick Van , Munro Carol A. , d’Enfert Christophe
Published: February 2018

The advent of the genomic era has made elucidating gene function at large scale a pressing challenge. ORFeome collections, whereby almost all ORFs of a given species are cloned and can be subsequently leveraged in multiple functional genomic approaches, represent valuable resources towards this endeavor. Here we provide novel, genome-scale tools for the study ofCandida albicans, a commensal yeast that is also responsible for frequent superficial and disseminated infections in humans. We have generated an ORFeome collection composed of 5,102 ORFs cloned in a Gateway™donor vector, representing 83% of the currently annotated coding sequences ofC. albicans. Sequencing data of the cloned ORFs are available in the CandidaOrfDB database athttp://candidaorfeome.eu. We also engineered 49 expression vectors with a choice of promoters, tags, and selection markers and demonstrated their applicability to the study of target ORFs transferred from theC. albicansORFeome. In addition, the use of the ORFeome in the detection of protein-protein interaction was demonstrated. Mating-compatible strains as well as Gateway™-compatible two-hybrid vectors were engineered, validated and used in a proof of concept experiment. These unique and valuable resources should greatly facilitate future functional studies inC. albicansand the elucidation of mechanisms that underlie its pathogenicity.
Regulation of Decellularized Tissue Remodeling via Scaffold-Mediated Lentiviral Delivery in Anatomically-Shaped Osteochondral Constructs
Authors: Rowland Christopher R. , Glass Katherine A. , Ettyreddy Adarsh R. , Gloss Catherine C. , Matthews Jared , Huynh Nguyen P.T. , Guilak Farshid
Published: February 2018

Cartilage-derived matrix (CDM) has emerged as a promising scaffold material for tissue engineering of cartilage and bone due to its native chondroinductive capacity and its ability to support endochondral ossification. Because it consists of native tissue, CDM can undergo cellular remodeling, which can promote integration with host tissue and enables it to be degraded and replaced by neotissue over time. However, enzymatic degradation of decellularized tissues can occur unpredictably and may not allow sufficient time for mechanically competent tissue to form, especially in the harsh inflammatory environment of a diseased joint. The goal of the current study was to engineer cartilage and bone constructs with the ability to inhibit aberrant inflammatory processes caused by the cytokine interleukin-1 (IL-1), through scaffold-mediated delivery of lentiviral particles containing a doxycycline-inducible IL-1 receptor antagonist (IL-1Ra) transgene on anatomically-shaped CDM constructs. Additionally, scaffold-mediated lentiviral gene delivery was used to facilitate spatial organization of simultaneous chondrogenic and osteogenic differentiation via site-specific transduction of a single mesenchymal stem cell (MSC) population to overexpress either chondrogenic, transforming growth factor-beta 3 (TGF-β3), or osteogenic, bone morphogenetic protein-2 (BMP-2), transgenes. Controlled induction of IL-1Ra expression protected CDM hemispheres from inflammation-mediated degradation, and supported robust bone and cartilage tissue formation even in the presence of IL-1. In the absence of inflammatory stimuli, controlled cellular remodeling was exploited as a mechanism for fusing concentric CDM hemispheres overexpressing BMP-2 and TGF-β3 into a single bi-layered osteochondral construct. Our findings demonstrate that site-specific delivery of inducible and tunable transgenes confers spatial and temporal control over both CDM scaffold remodeling and neotissue composition. Furthermore, these constructs provide a microphysiological, in vitro, joint, organoid model with site-specific, tunable, and inducible protein delivery systems for examining the spatiotemporal response to pro-anabolic and/or inflammatory signaling across the osteochondral interface.
Mapping diversification metrics in macroecological studies: Prospects and challenges
Authors: Velasco Julián A. , Pinto-Ledezma Jesús N.
Published: February 2018

The intersection of macroecology and macroevolution is one of the most active research areas today. Macroecological studies are increasingly using phylogenetic diversification metrics to explore the role of evolutionary processes in shaping present-day patterns of biodiversity. Evolutionary explanations of species richness gradients are key for our understanding of how diversity accumulated in a region. For instance, the present-day diversity in a region can be a result ofin situdiversification, extinction, or colonization from other regions, or a combination of all of these processes. However, it is unknown whether these metrics capture well these diversification and dispersal processes across geography. Some metrics (e.g., mean root distance -MRD-; lineage diversification-rate -DR-; evolutionary distinctiveness -ED-) seem to provide very similar geographical patterns regardless of how they were calculated (e.g., using branch lengths or not). The lack of appropriate estimates of extinction and dispersal rates in phylogenetic trees can limit our conclusions about how species richness gradients emerged. With a review of the literature and complemented by an empirical comparison, we show that phylogenetic metrics by itself are not capturing well the speciation, extinction and dispersal processes across the geographical gradients. Furthermore, we show how new biogeographic methods can improve our inference of past events and therefore our conclusions about the evolutionary mechanisms driving regional species richness. Finally, we recommend that future studies include several approaches (e.g., spatial diversification modelling, parametric biogeographic methods) to disentangle the relative the role of speciation, extinction and dispersal in the generation and maintenance of species richness gradients.
Systematic Discovery of Conservation States for Single-Nucleotide Annotation of the Human Genome
Authors: Sperlea Adriana , Ernst Jason
Published: February 2018

Comparative genomics sequence data is an important source of information for interpreting genomes. Genome-wide annotations based on this data have largely focused on univariate scores or binary calls of evolutionary constraint. Here we present a complementary whole genome annotation approach, ConsHMM, which applies a multivariate hidden Markov model to learn de novo different ‘conservation states’ based on the combinatorial and spatial patterns of which species align to and match a reference genome in a multiple species DNA sequence alignment. We applied ConsHMM to a 100-way vertebrate sequence alignment to annotate the human genome at single nucleotide resolution into 100 different conservation states. These states have distinct enrichments for other genomic information including gene annotations, chromatin states, and repeat families, which were used to characterize their biological significance. Conservation states have greater or complementary predictive information than standard constraint based measures for a variety of genome annotations. Bases in constrained elements have distinct heritability enrichments depending on the conservation state assignment, demonstrating their relevance to analyzing phenotypic associated variation. The conservation states also highlight differences in the conservation patterns of bases prioritized by a number of scores used for variant prioritization. The ConsHMM method and conservation state annotations provide a valuable resource for interpreting genomes and genetic variation.
AnEscherichia colinitrogen starvation response is important for mutualistic coexistence withRhodopseudomonas palustris
Authors: McCully Alexandra L. , Behringer Megan G. , Gliessman Jennifer R. , Pilipenko Evgeny V. , Mazny Jeffrey L. , Lynch Michael , Drummond D. Allan , McKinlay James B.
Published: February 2018

Microbial mutualistic cross-feeding interactions are ubiquitous and can drive important community functions. Engaging in cross-feeding undoubtedly affects the physiology and metabolism of individual species involved. However, the nature in which an individual’s physiology is influenced by cross-feeding and the importance of those physiological changes for the mutualism have received little attention. We previously developed a genetically tractable coculture to study bacterial mutualisms. The coculture consists of fermentativeEscherichia coliand phototrophicRhodopseudomonas palustris. In this coculture, E. coli anaerobically ferments sugars into excreted organic acids as a carbon source for R. palustris. In return, a genetically-engineered R. palustris constitutively converts N2into NH4+, providingE. coliwith essential nitrogen. Using RNA-seq and proteomics, we identified transcript and protein levels that differ in each partner when grown in coculture versus monoculture. When in coculture withR. palustris, E. coligene-expression changes resembled a nitrogen starvation response under the control of the transcriptional regulator NtrC. By genetically disruptingE. coliNtrC, we determined that a nitrogen starvation response is important for a stable coexistence, especially at lowR. palustrisNH4+excretion levels. Destabilization of the nitrogen starvation regulatory network resulted in variable growth trends and in some cases, extinction. Our results highlight that alternative physiological states can be important for survival within cooperative cross-feeding relationships.

Importance

Mutualistic cross-feeding between microbes within multispecies communities is widespread. Studying how mutualistic interactions influence the physiology of each species involved is important for understanding how mutualisms function and persist in both natural and applied settings. Using a bacterial mutualism consisting ofRhodopseudomonas palustrisandEscherichia coligrowing cooperatively through bidirectional nutrient exchange, we determined that anE. colinitrogen starvation response is important for maintaining a stable coexistence. The lack of anE. colinitrogen starvation response ultimately destabilized the mutualism and, in some cases, led to community collapse after serial transfers. Our findings thus inform on the potential necessity of an alternative physiological state for mutualistic coexistence with another species compared to the physiology of species grown in isolation.
Molecular Clock and Phylogeny ofAnophelesspecies of the subgenusNyssorhynchus(Diptera: Culicidae)
Authors: Hoyos-López Richard
Published: February 2018

The main Phylogenetic hypothesis supporting the Myzorhynchella section as a natural group, but the sections Albimanus and Argyritarsis, do not present clearly resolved relationships, nor is it possible to recover the monophyly of both sections, even within these sections ofNyssorhynchus; it has not been possible identify the relationships between the species that make up these taxonomic subdivisions (Sallum, 2000, Sallum, 2002, Bourke, 2011, Foster, 2013). This lack of resolution has been attributed to the effect of few species for phylogenetic studies, making difficult the determination of monophyly of many groups, subgroups and complexes within sections Albimanus and Argyritarsis

We infer the phylogeny of the subgenusNyssorhynchusthrough the sequences characterized for the molecular markers ND6, COI-Barcode, White and CAD, in addition we calculate the times of divergence for the main lineages corresponding to the sections Albimanus, Argyritarsis and Myzorhynchella using Bayesian approaches.
Absence of the Spindle Assembly Checkpoint restores mitotic fidelity upon loss of sister chromatid cohesion
Authors: Silva Rui D. , Mirkovic Mihailo , Guilgur Leonardo G. , Rathore Om S. , Martinho Rui Gonçalo , Oliveira Raquel A.
Published: February 2018

Sister chromatid cohesion is essential for faithful mitosis, as premature cohesion loss leads to random chromosome segregation and aneuploidy, resulting in abnormal development. To identify specific conditions capable of restoring defects associated with cohesion loss, we screened for genes whose depletion modulatesDrosophilawing development when sister chromatid cohesion is impaired. Cohesion deficiency was induced by knock-down of the acetyltransferase Separation anxiety (San)/Naa50, a cohesin complex stabilizer. Several genes whose function impacts wing development upon cohesion loss were identified. Surprisingly, knockdown of key Spindle Assembly Checkpoint (SAC) proteins, Mad2 and Mps1, suppressed developmental defects associated with San depletion. SAC impairment upon cohesin removal, triggered by San depletion or artificial removal of the cohesin complex, prevented extensive genome shuffling, reduced segregation defects and restored cell survival. This counterintuitive phenotypic suppression was caused by an intrinsic bias for efficient chromosome bi-orientation at mitotic entry, coupled with slow engagement of error-correction reactions. We conclude that mitotic timing determines the severity of defects associated with cohesion deficiency. Therefore, although divisions are still error-prone, SAC inactivation enhances cell survival and tissue homeostasis upon cohesion loss.
DNA methylation oscillation defines classes of enhancers
Authors: Libertini Emanuele , Hamoudi Rifat A. , Heath Simon , Lancashire Lee , Garcia Arcadio Rubio , Grassi Luigi , Downes Kate , Ouwehand Willem H. , Javierre Biola-Maria , Cairns Jonathan , Wingett Steven , Paul Dirk S. , Gut Marta , Gut Ivo G. , Martens Joost H. A. , Ivliev Alexandr , Stunnenberg Hendrik G. , Frontini Mattia , Spivakov Mikhail , Fraser Peter , Cutler Antony , Wallace Chris , Beck Stephan
Published: February 2018

Understanding the regulatory landscape of human cells requires the integration of genomic and epigenomic maps, capturing combinatorial levels of cell type-specific and invariant activity states.

Here, we segmented whole-genome bisulfite sequencing-derived methylomes into consecutive blocks of co-methylation (COMETs) to obtain spatial variation patterns of DNA methylation (DNAm oscillations) integrated with histone modifications and promoter-enhancer interactions derived from promoter capture Hi-C (PCHi-C) sequencing of the same purified blood cells.

Mapping DNAm oscillations onto regulatory genome annotation revealed that enhancers are enriched for DNAm hyper-oscillations (>30-fold), where multiple machine learning models support DNAm as predictive of enhancer location. Based on this analysis, we report overall predictive power of 99% for DNAm oscillations, 77.3% for DNaseI, 41% for CGIs, 20% for UMRs and 0% for LMRs, demonstrating the power of DNAm oscillations over other methods for enhancer prediction. Methylomes of activated and non-activated CD4+ T cells indicate that DNAm oscillations exist in both states irrespective of activation; hence they can be used to determine the location of latent enhancers.

Our approach advances the identification of tissue-specific regulatory elements and outperforms previous approaches defining enhancer classes based on DNA methylation.
Effects of different load on physiological, hematological, biochemical, cytokines indices of Zanskar ponies at high altitude
Authors: Vivek Prince , Bharti Vijay Kumar , Kumar Deepak , Kumar Rohit , Nehra Kapil , Singh Dhananjay , Chaurasia Om Prakash , Kumar Bhuvnesh
Published: February 2018

High altitude people required high endurance pack animals for load carrying and riding at prevalent mountainous terrains and rugged region. So far no studies have been taken to evaluate effect of loads on physiology of ponies in high altitude region. So, in this view we evaluated variation in physiological, hematological, biochemical, and cytokines indices of Zanskar ponies during load carrying at high altitude. Total twelve (12) numbers of Zanskar ponies, mare, age 4–6 years, were divided into three groups; group-A (without load), group-B (60 kg), and group-C (80 kg) of back pack loads. Track was very narrow and slippery with gravel, uneven with rocky surface and has a steep gradient of 4 km uphill at altitude 3291 to 3500 m. When we evaluate these parameters, it is understood that the heart rate, pulse rate and respiration rate was significantly(p<0.05)increased in 80 kg group among the three groups. The hematology parameters viz. hemoglobin, PCV, lymphocytes, monocytes%, ESR and eosinophil% significantly(p<0.05)changed in 80 kg group after load carrying among the three groups which was followed by control and 60 kg group. In biochemical parameters viz. LA, LDH, TP, HK, CORT, T3, CRT, AST, CK-MB, GPx, FRAP and IL-6 significantly(p<0.05)changed in 80 kg group after load carrying among the three groups which was followed by control and 60 kg group. The ALT, ALB, GLB, UR and UA significantly(p<0.05)changed in 80 kg group before and after load carrying among the three groups which was followed by control and 60 kg group. It has been concluded that, this result has revealed strong correlation of change in biomarkers level with performance in ponies during load carry. Hence, these parameters might be use for performance of endurance of Zanskar ponies in high mountain region.
Effects of coil orientation on Motor Evoked Potentials from Orbicularis Oris and First Dorsal Interosseous
Authors: Adank Patti , Kennedy-Higgins Dan , Maegherman Gwijde , Hannah Ricci , Nuttall Helen
Published: February 2018

Objective

This study aimed to characterise effects of coil orientation on the size of Motor Evoked Potentials (MEPs) from both sides of Orbicularis Oris (OO) and compare these effects with those reported for First Dorsal Interosseous (FDI), following stimulation to left lip and left hand Primary Motor Cortex.

Methods

Using a 70 mm figure-of-eight coil, we collected MEPs from eight different orientations while recording from contralateral and ipsilateral OO and FDI using a monophasic pulse.

Results

MEPs from OO were evoked consistently for six out of eight orientations for contralateral and ipsilateral sites. When latency and silent periods were taken into account, contralateral orientations 0°, 45°, 90°, and 315° were found to best elicit OO MEPs with a likely cortical origin. As expected, the largest FDI MEPs were recorded with an orientation of 45°, invoking a posterior-anterior (PA) current flow, from the contralateral location.

Conclusion

Orientations traditionally used for FDI were also found suitable for eliciting OO MEPs. Individuals vary more in their optimal coil orientation for eliciting MEPs from OO than for FDI. It is recommended that researchers iteratively probe several orientations when eliciting MEPs from OO. Care must be taken however because several orientations likely induced direct activation of facial muscles.
Evidence for rapid evolution in a grassland biodiversity experiment
Authors: van Moorsel Sofia J. , Schmid Marc W. , Wagemaker Niels C.A.M. , van Gurp Thomas , Schmid Bernhard , Vergeer Philippine
Published: February 2018

Biodiversity often increases plant productivity. In long-term grassland experiments, positive biodiversity effects on plant productivity commonly increase with time. Also, it has been shown that such positive biodiversity effects persist not only in the local environment but also when plants are transferred into a common environment. Thus, we hypothesized that community diversity had acted as a selective agent, resulting in the emergence of plant monoculture and mixture types with differing genetic composition. To test our hypothesis, we grew offspring from plants that were grown for eleven years in monoculture or mixture environments in a biodiversity experiment (Jena Experiment) under controlled glasshouse conditions in monocultures or two-species mixtures. We used epiGBS, a genotyping-by-sequencing approach combined with bisulfite conversion to provide integrative genetic and epigenetic data. We observed significant genetic and epigenetic divergence according to selection history in three out of five perennial grassland species, namelyGalium mollugo,Prunella vulgarisandVeronica chamaedrys, with epigenetic differences mostly reflecting the genetic differences. In addition, current diversity levels in the glasshouse had weak effects on epigenetic variation. However, given the limited genome coverage of the reference-free bisulfite method epiGBS, it remains unclear how much of this epigenetic divergence was independent of underlying genetic differences. Our results thus suggest that selection of genetic variants, and possibly epigenetic variants, caused the rapid emergence of monoculture and mixture types within plant species in the Jena Experiment.
Active Function Learning
Authors: Jones Angela , Schulz Eric , Meder Björn , Ruggeri Azzurra
Published: February 2018

How do people actively explore to learn about functional relationships, that is, how continuous inputs map onto continuous outputs? We introduce a novel paradigm to investigate information search in continuous, multi-feature function learning scenarios. Participants either actively selected or passively observed information to learn about an underlying linear function. We develop and compare different variants of rule-based (linear regression) and non-parametric (Gaussian process regression) active learning approaches to model participants’ active learning behavior. Our results show that participants’ performance is best described by a rule-based model that attempts to efficiently learn linear functions with a focus on high and uncertain outcomes. These results advance our understanding of how people actively search for information to learn about functional relations in the environment.
Environmentally enriched pigs have transcriptional profiles consistent with neuroprotective effects and reduced microglial activity
Authors: Brown SM , Bush SJ , Summers KM , Hume DA , Lawrence AB
Published: February 2018

Environmental enrichment (EE) is widely used to study the effects of external factors on brain development, function and health in rodent models, but very little is known of the effects of EE on the brain in a large animal model such as the pig. Twenty-four young pigs (aged 5 weeks at start of study, 1:1 male: female ratio) were housed in environmentally enriched (EE) pens and provided with additional enrichment stimulation (a bag filled with straw) once daily. Litter, weight and sex matched controls n= (24) were housed in barren (B) conditions. Behaviour was recorded on alternate days from study day 10. After 21 days, RNA-sequencing of the frontal cortex of male piglets culled one hour after the enrichment stimulation, but not those at 4 hours after stimulation, showed upregulation of genes involved in neuronal activity and synaptic plasticity in the EE compared to the B condition. This result is mirrored in the behavioural response to the stimulation which showed a peak in activity around the 1 hour time-point. By contrast, EE piglets displayed a signature consistent with a relative decrease in microglial activity compared to those in the B condition. These results confirm those from rodents, suggesting that EE may also confer neuronal health benefits in large mammal models, through a potential relative reduction in neuroinflammatory process and increase in neuroprotection driven by an enrichment-induced increase in behavioural activity.
Convergent regulatory evolution and the origin of flightlessness in palaeognathous birds
Authors: Sackton Timothy B. , Grayson Phil , Cloutier Alison , Hu Zhirui , Liu Jun S. , Wheeler Nicole E. , Gardner Paul P. , Clarke Julia A. , Baker Allan J. , Clamp Michele , Edwards Scott V.
Published: February 2018

The relative roles of regulatory and protein evolution in the origin and loss of convergent phenotypic traits is a core question in evolutionary biology. Here we combine phylogenomic, epigenomic and developmental data to show that convergent evolution of regulatory regions, but not protein-coding genes, is associated with flightlessness in palaeognathous birds, a classic example of a convergent phenotype. Eleven new genomes, including a draft genome from an extinct moa, resolve palaeognath phylogeny and show that the incidence of independent, convergent accelerations among 284,000 conserved non-exonic elements is significantly more frequent in ratites than other bird lineages. Ratite-specific acceleration of conserved regions and measures of open chromatin across eight tissues in the developing chick identify candidate regulatory regions that may have modified or lost function in ratites. Enhancer activity assays conducted in the early developing chicken forelimb confirm that volant versions of a conserved element in the first intron of the TEAD1 gene display conserved enhancer activity, whereas an accelerated flightless version fails to drive reporter gene expression. Our results show that convergent molecular changes associated with loss of flight are largely regulatory in nature.
Longitudinal immunosequencing in healthy people reveals persistent T cell receptors rich in public receptors
Authors: Chu Nathaniel D. , Bi Haixin Sarah , Emerson Ryan O. , Sherwood Anna M. , Birnbaum Michael E. , Robins Harlan S. , Alm Eric J.
Published: February 2018

Background

The adaptive immune system maintains a diversity of T cells capable of recognizing a broad array of antigens. Each T cell’s specificity and affinity for antigens is determined by its T cell receptors (TCRs), which together across all T cells form a repertoire of tens of millions of unique receptors in each individual. Although many studies have examined how TCR repertoires change in response to disease or drugs, few have explored the temporal dynamics of the TCR repertoire in healthy individuals.

Results

Here we report immunosequencing of TCR β chains (TCRβ) from the blood of three healthy individuals at eight time points over one year. TCRβ repertoires from samples of all T cells and memory T cells clearly clustered by individual, confirming that TCRβ repertoires are specific to individuals across time. This individuality was absent from TCRβs from naive T cells, suggesting that these differences result from an individual’s antigen exposure history. Many characteristics of the TCRβ repertoire (e.g., alpha diversity, clonality) were stable across time, although we found evidence of T cell expansion dynamics even within healthy individuals. We further identified a subset of “persistent” TCRβs present across all time points, and these receptors were rich in clonal and public receptors.

Conclusions

Our results revealed persistent receptors that may play a key role in immune system maintenance. They further highlight the importance of longitudinal sampling of the immune system and provide a much-needed baseline for TCRβ dynamics in healthy individuals. Such a baseline should help improve interpretation of changes in the TCRβ repertoire during disease or treatment.
Conserved accessory proteins encoded with archaeal and bacterial Type III CRISPR-Cas gene cassettes that may specifically modulate, complement or extend interference activity
Authors: Shah Shiraz A. , Alkhnbashi Omer S. , Behler Juliane , Han Wenyuan , She Qunxin , Hess Wolfgang R. , Garrett Roger A. , Backofen Rolf
Published: February 2018

A study was undertaken to identify conserved proteins that are encoded either within, or directly adjacent to, cas gene cassettes of Type III CRISPR-Cas interference modules. These Type III modules are especially versatile functionally and have been shown to target and degrade dsDNA, ssDNA and ssRNA. In addition, the interference gene cassettes are frequently intertwined with other accessory genes, including genes encoding CARF domains, some of which are likely to be cofunctional. Using a comparative genomics approach, and defining a Type III association score accounting for coevolution and specificity of flanking genes, we identified and classified 39 new Type III associated gene families. Most archaeal and bacterial Type III modules were seen to be flanked by several accessory genes, around half of which did not encode CARF domains and remain of unknown function. Non-CARF accessory genes were found to be more diverse than their CARF counterparts, encoding nuclease, helicase, protease, ATPase, transporter and transmembrane domains and including a considerable fraction that encoded no known domains. The diversity of non-CARF Type III accessory genes found in this study suggests that additional families exist which remain undetected because of the limited number of annotated genomes currently available. The method employed is scalable for potential application on metagenomic data once automated pipelines for annotation of CRISPR-Cas systems have been developed. All accessory genes found in this study are presented online in a readily accessible and searchable format for researchers to audit their model organism of choice: http://accessory.crispr.dk.
A closed-loop hand prosthesis with simultaneous intraneural tactile and position feedback
Authors: D’Anna Edoardo , Valle Giacomo , Mazzoni Alberto , Strauss Ivo , Iberite Francesco , Patton Jérémy , Petrini Francesco , Raspopovic Stanisa , Granata Giuseppe , Di lorio Riccardo , Controzzi Marco , Cipriani Christian , Stieglitz Thomas , Rossini Paolo M. , Micera Silvestro
Published: February 2018

Current myoelectric prostheses allow upper-limb amputees to regain voluntary motor control of their artificial limb by exploiting residual muscle function in the forearm1. However, the over-reliance on visual cues resulting from a lack of sensory feedback is a common complaint2,3. Recently, several groups have provided tactile feedback in upper-limb amputees by using implanted electrodes4,5,6,7,8, surface nerve stimulation9,10 or sensory substitution11,12. These approaches have led to improved function and prosthesis embodiment4,5,6,7,13,14. Nevertheless, the provided information remains limited to a subset of the rich sensory cues available to healthy individuals. More specifically, proprioception, the sense of limb position and movement, is predominantly absent from current systems. Here we show that sensory substitution based on intraneural stimulation can deliver position feedback in real-time and in conjunction with somatotopic tactile feedback. This approach allowed two trans-radial amputees to regain high and close-to-natural remapped proprioceptive acuity, with a median joint angle reproduction accuracy of 9.1° and a median threshold to detection of passive movements of 9.5°, which was compatible with results obtained in healthy subjects15,16,17. The simultaneous delivery of position information and somatotopic tactile feedback allowed both amputees to discriminate object size and compliance with high levels of accuracy (75.5%). These results demonstrate that touch information delivered via somatotopic neural stimulation and position information delivered via sensory substitution can be exploited simultaneously and efficiently by trans-radial amputees. This study paves the way towards more sophisticated bidirectional bionic limbs conveying rich, multimodal sensations.
Sustained release and pharmacologic effects of human glucagon-like peptide-1 and liraglutide from polymeric microparticles
Authors: Icart Luis Peña , Gomes de Souza Fernando , Lima Luís Maurício T. R.
Published: February 2018

The GLP-1 class of peptide agonists has been shown to exert regulatory key roles in both diabetes, obesity and related complications. Given the short half-life of GLP-1 its use has been historically discouraged. We developed polymeric microparticles loaded with either human GLP-1 (7-37) or liraglutide peptides by double emulsion and solvent evaporation approach. The size distribution of all formulations was of about 30-50 μm. The in vitro kinetic release assays showed a sustained release of the peptides extending up to 30 to 40 days with varying profiles. Morphologic analysis demonstrated a more regular particle surface for those comprising polymers PLA, PLA-PEG and PLGA. In vivo evaluation in Swiss male mice demonstrated a similar extension of effect of decreasing in body weight gain for up to 25 days after a single subcutaneous administration of either hGLP-1 or liraglutide peptide-loaded microparticles (200 μg peptide / kg body weight) compared to controls. These demonstrate the effectiveness of hGLP-1 as a therapeutic agent in long-term, continuous release from peptide-load microparticles, and thus its plausibility as an unmodified therapeutic agent.
Integrative analysis of transcription factor occupancy at enhancers and disease risk loci in noncoding genomic regions
Authors: Oki Shinya , Ohta Tazro , Shioi Go , Hatanaka Hideki , Ogasawara Osamu , Okuda Yoshihiro , Kawaji Hideya , Nakaki Ryo , Sese Jun , Meno Chikara
Published: February 2018

Noncoding regions of the human genome possess enhancer activity and harbor risk loci for heritable diseases. Whereas the binding profiles of multiple transcription factors (TFs) have been investigated, integrative analysis with the large body of public data available so as to provide an overview of the function of such noncoding regions has remained a challenge. Here we have fully integrated public ChIP-seq and DNase-seq data (n ~ 70,000), including those for 743 human transcription factors (TFs) with 97 million binding sites, and have devised a data-mining platform —designated ChIP-Atlas—to identify significant TF-genome, TF-gene, and TF-TF interactions. Using this platform, we found that TFs enriched at macrophage or T-cell enhancers also accumulated around risk loci for autoimmune diseases, whereas those enriched at hepatocyte or macrophage enhancers were preferentially detected at loci associated with HDL-cholesterol levels. Of note, we identified “hotspots” around such risk loci that accumulated multiple TFs and are therefore candidates for causal variants. Integrative analysis of public chromatin-profiling data is thus able to identify TFs and tissues associated with heritable disorders.
Chloroplasts of symbiotic microalgae remain active during bleaching induced by thermal stress in Collodaria (Radiolaria)
Authors: Villar Emilie , Dani Vincent , Bigeard Estelle , Linhart Tatiana , Mendez Sandin Miguel , Bachy Charles , Six Christophe , Lombard Fabien , Sabourault Cécile , Not Fabrice
Published: February 2018

Collodaria (Radiolaria) are important contributors to planktonic communities and biogeochemical processes (e.g. the biologic pump) in oligotrophic oceans. Similarly to corals, Collodaria live in symbiosis with dinoflagellate algae, a relationship that is thought to explain partly their ecological success. In the context of global change, the robustness of the symbiotic interaction and potential subsequent bleaching events are worth consideration. In the present study, we compared the ultrastructure morphology, symbiont density, photosynthetic capacities and respiration rates of colonial Collodaria exposed to a range of temperatures corresponding to natural conditions (21°C), moderate (25°C) and high (28°C) thermal stress. We showed that symbiont density immediately decreased when temperature rises to 25°C and the collodaria holobiont metabolic activity increased. When temperature reached 28°C, the collodarian host arrived at a tolerance threshold with a respiration nearly stopped and largely damaged morphological structures. Over the course of the experiment the photosynthetic capacities of remaining symbionts were stable, chloroplasts being the last degraded organelles from the microalgae. These results contribute to a better characterization and understanding of temperature-induced bleaching processes in planktonic photosymbiosis.
Forget Pixels: Adaptive Particle Representation of Fluorescence Microscopy Images
Authors: Cheeseman Bevan L. , Günther Ulrik , Susik Mateusz , Gonciarz Krzysztof , Sbalzarini Ivo F.
Published: February 2018

Modern microscopy modalities create a data deluge with gigabytes of data generated each second, and terabytes per day. Storing and processing these data is a severe bottleneck, not fully alleviated by data compression. We argue that this is because images are processed as regular grids of pixels. To address the root of the problem, we here propose a content-adaptive representation of fluorescence microscopy images called the Adaptive Particle Representation (APR). The APR replaces the regular grid of pixels with particles positioned according to image content. This overcomes storage bottlenecks, as data compression does, but additionally overcomes memory and processing bottlenecks, since the APR can directly be used in processing without going back to pixels. We present the ideas, concepts, and algorithms of the APR and validate them using noisy 3D image data. We show that the APR represents the content of an image while maintaining image quality. We then show that the adaptivity of the APR provides orders of magnitude benefits across a range of image processing tasks. Therefore, the APR provides a simple, extendable, and efficient content-aware representation of images that relaxes current data and processing bottlenecks.
Ultrastructure of salivary glands in Psammotettix alienus Dahlbom (Homoptera: Cicadellidae) infected with Taastrup virus
Authors: Lundsgaard Thorben
Published: February 2018

Taastrup virus (TV) is a novel virus belonging to Mononegavirales and with filovirus-like morphology. In adult Psammotettix alienus infected with TV, the highest concentration of virus particles was found in salivary glands, consisting of a principal gland (type I-VI-cells) and an accessory gland. Examination of thin sections revealed enveloped particles, about 1300 nm long and 62 nm in diameter, located singly or in paracrystalline arrays in canaliculi of type III- and IV-cells. In gland cells with TV particles in canaliculi, granular masses up to 15 micrometer in diameter are present in the cytoplasm. These masses are believed to be viroplasms, the sites for viral replication. TV particles were observed at the connection between a canaliculus and the salivary duct system.
Competitive release in tumors
Authors: Ma Yongqian , West Jeffrey , Newton Paul K.
Published: February 2018

Competitive release is a bedrock principle of coevolutionary ecology and population dynamics. It is also the main mechanism by which heterogeneous tumors develop chemotherapeutic resistance. Understanding, controlling, and exploiting this important mechanism represents one of the key challenges and potential opportunities of current medical oncology. The development of sophisticated mathematical and computational models of coevolution among clonal and sub-clonal cell populations in the tumor ecosystem can guide us in predicting and shaping various responses to perturbations in the fitness landscape which is altered by chemo-toxic agents. This in turn can help us design adaptive chemotherapeutic strategies to combat the release resistant cells.
Shugoshin protects centromere pairing and promotes segregation of non-exchange partner chromosomes in meiosis
Authors: de Almeida Luciana Previato , Evatt Jared M. , Chuong Hoa H. , Kurdzo Emily L. , Eyster Craig A. , Gladstone Mara N. , Gómez-H Laura , Llano Elena , Meyer Régis , Pendas Alberto M. , Pezza Roberto J. , Dawson Dean S.
Published: February 2018

Faithful chromosome segregation during meiosis I depends upon the formation of connections between homologous chromosomes. Crossovers between homologs connect the partners allowing them to attach to the meiotic spindle as a unit, such that they migrate away from one another at anaphase I. Homologous partners also become connected by pairing of their centromeres in meiotic prophase. This centromere pairing can promote proper segregation at anaphase I of partners that have failed to become joined by a crossover. Centromere pairing is mediated by synaptonemal complex (SC) proteins that persist at the centromere when the SC disassembles. Here, using mouse spermatocyte and yeast model systems, we tested the role of shugoshin in promoting meiotic centromere pairing by protecting centromeric synaptonemal components from disassembly. The results show that shugoshin protects centromeric SC in meiotic prophase and, in anaphase, promotes the proper segregation of partner chromosomes that are not linked by a crossover.

SIGNIFICANCE

Meiotic crossovers form a connection between homologous chromosomes that allows them to attach to the spindle as a single unit in meiosis I. In humans, failures in this process are a leading cause of aneuploidy. A recently described process, called centromere pairing, can also help connect meiotic chromosome partners in meiosis. Homologous chromosomes become tightly joined by a structure called the synaptonemal complex (SC) in meiotic prophase. After the SC disassembles, persisting SC proteins at the centromeres mediate their pairing. Here, studies in mouse spermatocytes and yeast are used to show that the shugoshin protein helps SC components persist at centromeres and helps centromere pairing promote the proper segregation of yeast chromosomes that fail to become tethered by crossovers.
Nuclear envelope assembly defects link mitotic errors to chromothripsis
Authors: Liu Shiwei , Kwon Mijung , Mannino Mark , Yang Nachen , Khodjakov Alexey , Pellman David
Published: February 2018

Defects in the architecture or integrity of the nuclear envelope (NE) are associated with a variety of human diseases1. Micronuclei, one common nuclear aberration, are an origin for chromothripsis2,3, a catastrophic mutational process commonly observed in cancer genomes and other contexts4-6. Micronuclei have a defective NE, with the extensive chromosome fragmentation that generates chromothripsis occurring after abrupt, spontaneous loss of NE integrity7. After NE disruption, the exposed cytoplasmic DNA can additionally initiate proinflammatory signaling linked to senescence, metastasis, and the immune clearance of tumor cells8. Despite its broad physiological impact, the basis for the nuclear envelope fragility of micronuclei is unknown. Here we demonstrate that micronuclei undergo markedly defective NE assembly: Only “core” NE proteins9,10 assemble efficiently on lagging chromosomes whereas “non-core” NE proteins9,10, including nuclear pore complexes (NPCs), fail to properly assemble. Consequently, micronuclei have impaired nuclear import, and key nuclear proteins required to maintain the integrity of the NE and the genome fail to accumulate normally. We show that densely bundled spindle microtubules inhibit non-core NE assembly, leading to an irreversible NE assembly defect. Accordingly, experimental manipulations that position missegregated chromosomes away from the spindle correct defective NE assembly, prevent spontaneous NE disruption, and suppress DNA damage in micronuclei. Our findings indicate that chromosome segregation and NE assembly are only loosely coordinated through the timing of mitotic spindle disassembly. The absence of precise regulatory controls can explain why errors during mitotic exit are frequent, and a major trigger for catastrophic genome rearrangements5,6.
GTFtools: a Python package for analyzing various modes of gene models
Authors: Li Hong-Dong
Published: February 2018

Gene-centric bioinformatics studies frequently involve calculation or extraction of various features of genes such as gene ID mapping, GC content calculation and different types of gene lengths, through manipulation of gene models that are often annotated in GTF format and available from ENSEMBL or GENCODE database. Such computation is essential for subsequent analysis such as intron retention detection where independent introns may need to be identified, converting RNA-seq read counts to FPKM where gene length is required, and obtaining flanking regions around transcription start sites. However, to our knowledge, a software package that is dedicated to analyzing various modes of gene models directly from GTF file is not publicly available. In this work, GTFtools (implemented in Python and not dependent on any non-python third-party software), a stand-alone command-line software that provides a set of functions to analyze various modes of gene models, is provided for facilitating routine bioinformatics studies where information about gene models needs to be calculated.

Availability

GTFtools is freely available at www.genemine.org/gtftools.php

Contact

hongdong@csu.edu.cn.