bluuebunny/crossref_metadata_2025 huggingface dataset:
Hierarchical Heterogeneity Across Human Cortex Shapes Large-Scale Neural Dynamics
Authors: Demirtaş Murat , Burt Joshua B. , Helmer Markus , Ji Jie Lisa , Adkinson Brendan D. , Glasser Matthew F. , Van Essen David C. , Sotiropoulos Stamatios N. , Anticevic Alan , Murray John D.
Published: June 2018

The large-scale organization of dynamical neural activity across cortex emerges through long-range interactions among local circuits. We hypothesized that large-scale dynamics are also shaped by heterogeneity of intrinsic local properties across cortical areas. One key axis along which microcircuit properties are specialized relates to hierarchical levels of cortical organization. We developed a large-scale dynamical circuit model of human cortex that incorporates heterogeneity of local synaptic strengths, following a hierarchical axis inferred from MRI-derived T1w/T2w mapping, and fit the model using multimodal neuroimaging data. We found that incorporating hierarchical heterogeneity substantially improves the model fit to fMRI-measured resting-state functional connectivity and captures sensory-association organization of multiple fMRI features. The model predicts hierarchically organized high-frequency spectral power, which we tested with resting-state magnetoencephalography. These findings suggest circuit-level mechanisms linking spatiotemporal levels of analysis and highlight the importance of local properties and their hierarchical specialization on the large-scale organization of human cortical dynamics.
Neuroligin dependence of pharyngeal pumping reveals an extrapharyngeal modulation ofCaenorhabditis elegansfeeding
Authors: Calahorro Fernando , Keefe Francesca , Dillon James , Holden-Dye Lindy , O’Connor Vincent
Published: June 2018

The integration of distinct sensory modalities is essential for behavioural decision making. InC. elegansthis process is coordinated by neural circuits that integrate sensory cues from the environment to generate an appropriate behaviour at the appropriate output muscles. Food is a multimodal cue that impacts on the microcircuits to modulating feeding and foraging drivers at the level of the pharyngeal and body wall muscle respectively. When food triggers an upregulation in pharyngeal pumping it allows the effective ingestion of food. Here we show that aC.elegansmutant in the single orthologous gene of human neuroligins,nlg-1are defective in food induced pumping. This is not explained by an inability to sense food, asnlg-1mutants are not defective in chemotaxis towards bacteria. In addition, we show that neuroligin is widely expressed in the nervous system including AIY, ADE, ALA, URX and HSN neurones. Interestingly, despite the deficit in pharyngeal pumping neuroligin is not expressed within the pharyngeal neuromuscular network, which suggests an extrapharyngeal regulation of this circuit. We resolve electrophysiologically the neuroligin contribution to the pharyngeal circuit by mimicking a food-dependent pumping, and show that thenlg-1phenotype is similar to mutants impaired in GABAergic and/or glutamatergic signalling. We suggest that neuroligin organizes extrapharyngeal circuits that regulate the pharynx. These observations based on the molecular and cellular determinants of feeding are consistent with the emerging role of neuroligin in discretely impacting functional circuits underpinning complex behaviours.
Boundary Strength Analysis: Combining colour pattern geometry and coloured patch visual properties for use in predicting behaviour and fitness
Authors: Endler John A. , Cole Gemma L. , Kranz Alexandrea
Published: June 2018

Colour patterns are used by many species to make decisions that ultimately affect their Darwinian fitness. Colour patterns consist of a mosaic of patches that differ in geometry and visual properties. Although traditionally pattern geometry and colour patch visual properties are analysed separately, these components are likely to work together as a functional unit. Despite this, the combined effect of patch visual properties, patch geometry, and the effects of the patch boundaries on animal visual systems, behaviour and fitness are relatively unexplored. Here we describe Boundary Strength Analysis (BSA), a novel way to combine the geometry of the edges (boundaries among the patch classes) with the receptor noise estimate (ΔS) of the intensity of the edges. The method is based upon known properties of vertebrate and invertebrate retinas. The mean and SD of ΔS (mΔS, sΔS) of a colour pattern can be obtained by weighting each edge class ΔS by its length, separately for chromatic and achromatic ΔS. This assumes those colour patterns, or parts of the patterns used in signalling, with larger mΔS and sΔS are more stimulating and hence more salient to the viewers. BSA can be used to examine both colour patterns and visual backgrounds. BSA was successful in assessing the estimated conspicuousness of colour pattern variants in two species, guppies (Poecilia reticulata) and Gouldian finches (Erythrura gouldiae), both polymorphic for patch colour, luminance and geometry. The pattern difference between chromatic and achromatic edges in both species reveals the possibility that chromatic and achromatic edges could function differently. BSA can be applied to any colour pattern used in intraspecific and interspecific behaviour. Seven predictions and four questions about colour patterns are presented.
Dauer diapause has transgenerational effects on starvation survival and gene expression plasticity
Authors: Webster Amy K. , Jordan James M. , Hibshman Jonathan D. , Chitrakar Rojin , Ryan Baugh L.
Published: June 2018

Phenotypic plasticity is facilitated by epigenetic regulation, and remnants of such regulation may persist after plasticity-inducing cues are gone. However, the relationship between plasticity and transgenerational epigenetic memory is not understood. Dauer diapause in Caenorhabditis elegans provides an opportunity to determine how a plastic response to the early-life environment affects traits later in life and in subsequent generations. We report that after extended diapause, post-dauer worms initially exhibit reduced reproductive success and greater inter-individual variation. In contrast, F3 progeny of post-dauers display increased starvation resistance and lifespan, revealing potentially adaptive transgenerational effects. Transgenerational effects are dependent on the duration of diapause, indicating an effect of extended starvation. In agreement, RNA-seq demonstrates a transgenerational effect on nutrient-responsive genes. Further, post-dauer F3 progeny exhibit reduced gene expression plasticity, suggesting a trade-off between plasticity and epigenetic memory. This work reveals complex effects of nutrient stress over different time scales in an animal that evolved to thrive in feast and famine.
Sublethal β-lactam antibiotics induce PhpP phosphatase expression and StkP kinase phosphorylation in PBP-independent β-lactam antibiotic resistance ofStreptococcus pneumoniae
Authors: Huang Yan-Ying , Sun Yan-Hong , Du Peng , Liu Xiao-Xiang , Yan Jie , Sun Ai-Hua
Published: June 2018

StkP and PhpP ofStreptococcus pneumoniaehave been confirmed to compose a signaling couple, in which the former is a serine/threonine (Ser/Thr) kinase while the latter was annotated as a phosphotase. StkP has been reported to be involved in penicillin-binding protein (PBP)-independent penicillin resistance ofS. pneumoniae. However, the enzymatic characterization of PhpP and the role of PhpP in StkP-PhpP couple remain poorly understood. Here we showed that 1/4 minimal inhibitory concentration (MIC) of penicillin (PCN) or cefotaxime (CTX), the representatives of β-lactam antibiotics, could induce the expression ofstkPandphpPgenes and phosphorylation of StkP in PCN/CTX-sensitive strain ATCC6306 and three isolates ofS. pneumoniae(MICs: 0.02-0.5 μg/ml). The product ofphpPgene hydrolyzed PP2C type Ser/Thr phosphotase-specific RRA(pT)VA phosphopeptide substrate with the Km and Kcat values of 277.35 μmol/L and 0.71 S−1, and the hydrolytic activity was blocked by sodium fluoride, a PP2C type Ser/Thr phosphatase inhibitor. The phosphorylation levels of StkP in the fourphpPgene-knockout (ΔphpP) mutants were significantly higher than that in the wild-type strains. In particular, the MICs of PCN and CTX against the ΔphpPmutants were significantly elevated as 4-16 μg/ml. Therefore, our findings confirmed that sublethal PCN and CTX act as environmental inducers to cause the increase ofphpPandstkPgene expression and StkP phosphorylation. PhpP is a PP2C type Ser/Thr protein phosphatase responsible for dephosphorylation of StkP. Knockout of thephpPgene results in a high level of StkP phosphorylation and PBP-independent PCN/CTX resistance ofS. pneumoniae.

Importance

Streptococcus pneumoniaeis a common pathogen in human populations in many countries and areas due to the prevalence of β-lactam antibiotic-resistant pneumococcal strains. Production of β-lactamases and mutation of penicillin-binding proteins (PBP) have been considered as the major β-lactam antibiotic-resistant mechanisms in bacteria, butS. pneumoniaehas not been confirmed to produce any β-lactamases and many pneumococcal strains present PBP mutation-independent β-lactam antibiotic resistance. StkP is a Ser/Thr kinase ofS. pneumoniaeto compose a signal-couple with PhpP protein. The present study demonstrated that the PhpP is a PP2C-type phosphotase for dephosphorylation of StkP and the sublethal penicillin (PCN) or cefotaxime (CTX) acted as environmental signal molecules to induce the expression of PhpP. The knockout of PhpP-encoding gene caused the PCN/CTX resistance generation of PCN/CTX-sensitive pneumococcal strains. All the data indicate that StkP-PhpP couple ofS. pneumoniaeis involved in PBP mutation-independent β-lactam antibiotic resistance by phosphorylation of StkP.
In vivogene expression analyses provide unique insights onP. vivaxgametocytogenesis and chloroquine response
Authors: Kim Adam , Popovici Jean , Menard Didier , Serre David
Published: June 2018

Studies of gene expression have provided insights on the regulation ofPlasmodiumparasites. However, few studies have targetedP. vivax, the cause of one third of all human malaria cases outside Africa, due to the lack ofin vitroculture system and the difficulties associated with studying clinical samples. Here, we describe robust RNA-seq profiles ofP. vivaxparasites generated directly from infected patient blood. Gene expression deconvolution analysis reveals that most parasite mRNAs derive from trophozoites and that the asynchronicity ofP. vivaxinfections is unlikely to confound gene expression studies. We also show that gametocyte genes form two clusters of co-regulated genes, possibly indicating the independent regulation of male and female gametocytogeneses. Finally, despite a large effect on parasitemia, we find that chloroquine does not alter trophozoite gene expression. Overall, our study highlights the biological knowledge that can be gathered by directly studyingP. vivaxpatient infections.

Importance

Plasmodium vivaxis the second most common cause of human malaria worldwide but, since it cannot be cultured in the laboratory, its biology remains poorly understood. In this study, we describe the analysis of the parasite gene expression profiles generated from 26 patient infections. We show that the proportion of male and female parasites varies greatly among infections, suggesting that they are independently regulated. We also compare the gene expression profiles of the same infections before and after treatment with chloroquine, a common antimalarial, and show that the drug efficiently kills mostP. vivaxparasites but appears to have little effect on one specific parasite stage, the trophozoites, in contrast with the effect of the drug onP. falciparum. Overall, our study exemplifies the biological insights that can be gained from applying modern genomic tools to study this difficult human pathogen.
The effects of psychiatric history and age on self-regulation of the default mode network
Authors: Skouras Stavros , Scharnowski Frank
Published: June 2018

Real-time neurofeedback enables human subjects to learn to regulate their brain activity, effecting behavioral changes and improvements of psychiatric symptomatology. Neurofeedback up-regulation and down-regulation have been assumed to share common neural correlates. Neuropsychiatric pathology and aging incur suboptimal functioning of the default mode network. Despite the exponential increase in real-time neuroimaging studies, the effects of aging, pathology and the direction of regulation on neurofeedback performance remain largely unknown. Using open-access analyses and real-time fMRI data shared through the Rockland Sample Real-Time Neurofeedback project (N=136), we first modeled neurofeedback performance and learning in a group of subjects with psychiatric history (na=74) and a healthy control group (nb=62). Subsequently, we examined the relationship between up-regulation and down-regulation learning, the relationship between age and neurofeedback performance in each group and differences in neurofeedback performance between the two groups. Results show that in an initial session of default mode network neurofeedback with real-time fMRI, up-regulation and down-regulation learning scores are negatively correlated. Moreover, age correlates negatively with default mode network neurofeedback performance, only in absence of psychiatric history. Finally, adults with psychiatric history outperform healthy controls in default mode network up-regulation. Interestingly, the performance difference is related to no up-regulation learning in controls.
SHANK3 downregulation in the VTA accelerates the extinction of contextual associations induced by non-familiar conspecific interaction
Authors: Bariselli Sebastiano , Contestabile Alessandro , Tzanoulinou Stamatina , Bellone Camilla
Published: June 2018

Conditioned place preference (CPP) paradigms, traditionally adopted to study the reinforcing properties of drugs of abuse, have been developed to investigate the neurobiological mechanisms underlying the reinforcing properties of social stimuli. These protocols are largely based on single-housing before and/or during the social stimulus-contextual cues acquisition phase. Here, based on previously established social interaction-induced CPP paradigms, we characterize a place preference task relying on the reinforcing properties of free interaction with a non-familiar (novel) conspecific. The formation of contextual associations induced by the interaction with a novel social stimulus does not require single-housing, necessitates dopamine (DA) receptor 2/3 (D2/3R) activation and undergoes extinction. Interestingly, while extinction of CPP responses is reduced by single-housing, it is accelerated by the downregulation of the autism spectrum disorder (ASD)-related protein SHANK3 in the ventral tegmental area (VTA). Thus, inspired by the literature on drug of abuse-induced contextual learning, we propose that acquisition and extinction of CPP might be used as behavioral assays to assess social-induced contextual association and “social-seeking” dysfunctions in animal models of psychiatric disorders.
Manipulation of subcortical and deep cortical activity in the primate brain using transcranial focused ultrasound stimulation
Authors: Folloni Davide , Verhagen Lennart , Mars Rogier B. , Fouragnan Elsa , Constans Charlotte , Aubry Jean-François , Rushworth Matthew F.S. , Sallet Jérôme
Published: June 2018

The causal role of an area within a neural network can be determined by interfering with its activity and measuring the impact. Many current reversible manipulation techniques have limitations preventing their focal application particularly in deep areas of the primate brain. Here we demonstrate a transcranial focused ultrasound stimulation (TUS) protocol that manipulates activity even in deep brain areas: a subcortical brain structure, the amygdala (experiment 1), and a deep cortical region, anterior cingulate cortex (ACC, experiment 2), in macaques. TUS neuromodulatory effects were measured by examining relationships between activity in each area and the rest of the brain using functional magnetic resonance imaging (fMRI). In control conditions without sonication, activity in a given area is related to activity in interconnected regions but such relationships are reduced after sonication. Dissociable and focal effects on neural activity could not be explained by auditory artefacts.
“Ancestralization” of human pluripotent stem cells by multiplexed precise genome editing
Authors: Riesenberg Stephan , Maricic Tomislav , Pääbo Svante
Published: June 2018

We show that inactivation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) results in a drastic increase in efficiency of precise genome editing with CRISPR enzymes in human stem cells, allowing up to 79% of chromosomes to carry an intended nucleotide substitution when a single genomic site is targeted. When three different genes are simultaneously targeted, 12% of the isolated cells carry the targeted amino acid-changing substitutions in homozygous forms. These substitutions represent the first step towards resurrecting the proteome ancestral to Neandertals and modern humans. DNA-PKcs inactivation will greatly facilitate multiplexed precise genome editing in animal cells.
Offline impact of transcranial focused ultrasound on cortical activation in primates
Authors: Verhagen Lennart , Gallea Cécile , Folloni Davide , Constans Charlotte , Jensen Daria EA , Ahnine Harry , Roumazeilles Léa , Santin Mathieu D , Ahmed Bashir , Lehericy Stéphane , Klein-Flügge Miriam , Krug Kristine , Mars Rogier B , Rushworth Matthew FS , Pouget Pierre , Aubry Jean-François , Sallet Jérôme
Published: June 2018

To understand brain circuits it is necessary both to record and manipulate their activity. Transcranial ultrasound (TUS) is a promising non-invasive brain stimulation technique. To date, investigations have focused on short-lived neuromodulatory effects, but to deliver on its full potential for research and therapy, ultrasound protocols are required that induce longer-lasting ‘offline’ changes. Here, we present a TUS protocol that modulates brain activation in macaques for more than one hour after 40 seconds of stimulation, while circumventing auditory confounds. Normally activity in brain areas reflects activity in interconnected regions but TUS’ impact can be demonstrated by showing such patterns change for stimulated areas. We report regionally specific TUS effects for two medial frontal brain regions – supplementary motor area and frontal polar cortex. Independently of these site-specific effects, TUS also induced signal changes in the meningeal compartment. TUS effects were temporary and not associated with microstructural changes.
TOL proteins mediate vacuolar sorting of the borate transporter BOR1 in Arabidopsis thaliana
Authors: Yoshinari Akira , Korbei Barbara , Takano Junpei
Published: June 2018

Boron (B) is an essential micronutrient for plants, however, it shows cytotoxicity at high concentrations. A borate transporter BOR1 is required for efficient transport of boron (B) toward the root stele in Arabidopsis thaliana. BOR1 shows polar localization in the plasma membrane of various root cells toward the stele-side under B limitation. To avoid over-accumulation of B, BOR1 in the plasma membrane is rapidly internalized and transported into the vacuole for proteolysis after high-B supply in an ubiquitination-dependent manner. Although BOR1 has been predicted to be transported into multi-vesicular bodies/late endosomes (MVB/LEs) via the endosomal sorting complex required for transport (ESCRT) machinery, experimental evidence was absent so far. In this study, we investigated the intracellular localization of BOR1 by visualizing endomembrane compartments, and tested the involvement of ESCRT-0-like proteins TOM1-LIKEs (TOLs) in the vacuolar sorting of BOR1. Under low-B conditions, a large portion of cytoplasmic BOR1 was localized in the trans-Golgi networks/early endosomes (TGN/EEs) labeled with VHA-a1 subunit. Pharmacological interference of endosomal recycling using brefeldin A induced colocalization of BOR1 with RabA5D, which labels recycling vesicles associated with the TGN. These data suggest that BOR1 cycles between plasma membrane and TGN/EE via RabA5D-positive endomembrane compartments under low-B conditions. On the other hand, under high-B conditions, BOR1 was localized in the inside of TOL5-positive MVB/LEs. To examine the roles of TOL proteins in intracellular trafficking of BOR1, we analyzed BOR1-GFP localization in the TOL quintuple mutant (tolQ; tol2-1tol3-1tol5-1tol6-1tol9-1) after high-B supply. In the tolQ mutant, vacuolar sorting of BOR1 was delayed, while the polar localization of BOR1 was not disturbed. Taken together, BOR1 is constantly transported to the TGN/EE by endocytosis and recycled to the plasma membrane likely via RabA5D-positive endomembrane compartments under low-B conditions. On the other hand, BOR1 is transported to the vacuole via TOL5-positive MVB/LEs under high-B conditions. TOL proteins are required for sorting of ubiquitinated BOR1 into MVB/LE for vacuolar degradation but not for the polar trafficking of BOR1.
SVCollector: Optimized sample selection for validating and long-read resequencing of structural variants
Authors: Sedlazeck Fritz J. , Lemmon Zachary , Soyk Sebastian , Salerno William J. , Lippman Zachary , Schatz Michael C.
Published: June 2018

Structural Variations (SVs) are increasingly recognized for their importance in genomics. Short-read sequencing is the most widely-used approach for genotyping large numbers of samples for SVs but suffers from relatively poor accuracy. Here we present SVCollector, an open-source method that optimally selects samples to maximize variant discovery and validation using long read resequencing or PCR-based validation. SVCollector has two modes: selecting those samples that are individually the most diverse or those that collectively capture the largest number of variations.

Availability

https://github.com/fritzsedlazeck/SVCollector

Contact

fritz.sedlazeck@bcm.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
Genome-Wide Association Study of Brain Connectivity Changes for Alzheimer’s Disease
Authors: Elsheikh Samar S. M. , Chimusa Emile R. , Mulder Nicola J. , Crimi Alessandro
Published: June 2018

Variations in the human genome have been found to be an essential factor that affects susceptibility to Alzheimer’s disease. Genome-wide association studies (GWAS) have identified genetic loci that significantly contribute to the risk of Alzheimers. The availability of genetic data, coupled with brain imaging technologies have opened the door for further discoveries, by using data integration methodologies and new study designs. Although methods have been proposed for integrating image characteristics and genetic information for studying Alzheimers, the measurement of disease is often taken at a single time point, therefore, not allowing the disease progression to be taken into consideration. In longitudinal settings, we analyzed neuroimaging and single nucleotide polymorphism datasets obtained from the Alzheimer’s Disease Neuroimaging Initiative for three clinical stages of the disease, including healthy control, early mild cognitive impairment and Alzheimer’s disease subjects. We conducted a GWAS regressing the absolute change of global connectivity metrics on the genetic variants, and used the GWAS summary statistics to compute the gene and pathway scores. We observed significant associations between the change in structural brain connectivity defined by tractography and genes, which have previously been reported to biologically manipulate the risk and progression of certain neurodegenerative disorders, including Alzheimer’s disease.
Single-cell transcriptional analysis reveals naïve helper ILC-like cells in zebrafish
Authors: Hernández Pedro P. , Strzelecka Paulina M. , Athanasiadis Emmanouil I. , Robalo Ana F. , Collins Catherine M. , Boudinot Pierre , Levraud Jean-Pierre , Cvejic Ana
Published: June 2018

Innate lymphoid cells (ILCs) are important mediators of the immune response and homeostasis in barrier tissues of mammals. However, the existence and function of ILCs in other vertebrates is poorly understood. Here, we use single-cell RNA sequencing to generate a comprehensive atlas of zebrafish lymphocytes during tissue homeostasis and following immune challenge. We profiled 14,080 individual cells from the gut of wild-type zebrafish, as well as of rag1-deficient fish which lack T and B cells, and discovered diverse populations of helper ILC-like cells. Unexpectedly, fish displayed a rorc-positive, naïve subset that established a Type 3 or Type 2 response only upon immune challenge. Specifically, naïve ILC-like cells expressed il22 and tnfa following exposure to inactivated bacteria, or il13 following exposure to helminth extract. Cytokine-producing ILC-like cells express a specific repertoire of novel immune-type receptors, likely involved in recognition of environmental cues. We identified additional novel markers of zebrafish ILCs and generated a cloud repository for their in-depth exploration.
Recording and reproducing the diurnal oviposition rhythms of wild populations of the soft- and stone- fruit pest Drosophila suzukii
Authors: Shaw Bethan , Fountain Michelle T. , Wijnen Herman
Published: June 2018

Drosophila suzukii is a horticultural pest on a global scale which causes both yield and economic losses on a range of soft- and stone-fruit. Tackling this pest is problematic but exploiting behavioral rhythms could increase the impact of control. To do this, a better understanding of behavioral patterns is needed. Within this study we aimed to investigate rhythms in reproductive behavior of wild D. suzukii under natural conditions in the field. Environmental parameters were also recorded to decipher how they influence these rhythms. Assays were then performed on laboratory cultures, housed under artificial conditions mimicking the temperature and light cycles, to see if these patterns were reproducible and rhythmic. We were able to promote field like oviposition patterns within the laboratory using realistic temperature and light cycles regardless of variations in other factors including substrate, humidity, and lighting type. Locomotion activity was also recorded under these mimicked conditions to identify how this behavior interacts with oviposition rhythms. Both our field and laboratory assays show that oviposition behavior is likely under the control of the circadian clock and primarily occurs during the day, but these patterns will be disrupted by unfavorable temperature conditions. This was also found within locomotion rhythms. With an increased understanding of how these behaviors are influenced by environmental conditions, we highlight the importance of using realistic temperature and light cycles when investigating behavioral patterns. From an increased understanding of D. suzukii behavior we increase our ability to target the pest in the field.
Contrasted hybridization patterns between two local populations of European wildcats in France
Authors: Marie-Pauline Beugin , Olivier Salvador , Guillaume Leblanc , Guillaume Queney , Eugenia Natoli , Dominique Pontier
Published: June 2018

The European wildcat (Felis silvestris silvestris) is threatened across the totality of its area of distribution by hybridization with the domestic catF.s. catus. The underlying ecological processes promoting hybridization, remain largely unknown. In France, wildcats are mainly present in the North-East but signs of their presence in the Pyrenees have been recently provided. However, no studies have been carried out in the French Pyrenees to assess the genetic status of wildcats. We have compared a local population of wildcats living in a continuous habitat in the French Pyrenees and a local population of wildcats living in a fragmented habitat in Northeastern France to evaluate how habitat fragmentation influence the population structure of European wildcats. Close kin were not found in the same geographic location contrary to what was observed for females in the Northeastern wildcat population. Furthermore, there was no evidence of hybridization in the Pyrenean wildcats and only one domestic cat raised suspicions while hybridization was categorically detected in northeastern France. The two wildcat populations were significantly differentiated (Fst= 0.08) and the genetic diversity of the Pyrenean wildcats was lower than that of other wildcat populations in France and in Europe. Taken together, these results suggest that habitat fragmentation, and in particular the absence of agricultural fields, may play an important role in lowering the probability of hybridization by reducing the likelihood of contact with domestic cats. Moreover, our results suggest that the French Pyrenean wildcat populations is isolated and may be threatened by a lack of genetic diversity.
A Narrative Systematic Review of Coaching Interventions to Improve Dyslexia at Work
Authors: Doyle Nancy , McDowall Almuth
Published: June 2018

Although dyslexia affects 5-8% of the workforce this developmental disorder is insufficiently researched within adult psychological research. Dyslexia confers legal protections wherein employers must provide ‘accommodations’ to support work performance, including coaching activities. Implementation of accommodations has moved forward without an evidence-base to date. The present systematic review investigates to what extent face-to-face learning interventions improve the working memory capacity and self-efficacy of adults with dyslexia guided by a realist, narrative framework. We extracted 25 studies from eleven countries, prioritizing relevant learning intervention protocols above population context, synthesizing the delivery context and impact on mechanisms of working memory (N=501) and self-efficacy (N=1211) also contextual, work-related outcomes such as comprehension. Though limited by inadequate intervention descriptions in primary papers, a narrative synthesis determined that learning interventions compliant with Social Cognitive Learning Theory elicited reliable outcomes for not only self-efficacy, as would be expected, but also improved working memory and workplace contextualized variables. Development of metacognition, stress management and fidelity to Goal Setting Theory were also inferred as valuable intervention features. Implications include the need for population-specific evaluation of the emergent conceptual framework to further our understanding of disability accommodations, and questioning the ecological validity of working memory as an intervening mechanism.
14-3-3 proteins activatePseudomonasexotoxins-S and –T by chaperoning a hydrophobic surface
Authors: Karlberg Tobias , Hornyak Peter , Filipa Pinto Ana , Milanova Stefina , Ebrahimi Mahsa , Lindberg Mikael , Püllen Nikolai , Nordström Axel , Löverli Elinor , Caraballo Rémi , Wong Emily V. , Näreoja Katja , Thorsell Ann-Gerd , Elofsson Mikael , De La Cruz Enrique M. , Björkegren Camilla , Schüler Herwig
Published: June 2018

Pseudomonasare a common cause of hospital acquired infections that may be lethal. ADP-ribosyltransferase activities ofPseudomonasexotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in the 14-3-3 phosphopeptide binding groove, a hydrophobic C-terminal helix of ExoS and ExoT has been thought to be crucial for their activation. However, crystal structures of the 14-3-3β:ExoS and -ExoT complexes presented here reveal an extensive novel binding interface that is sufficient for complex formation and toxin activation. We show that C-terminally truncated ExoS ADP-ribosyltransferase domain lacking the hydrophobic binding motif is active when co-expressed with 14-3-3. Moreover, swapping the hydrophobic C-terminus with a fragment fromVibrioVis toxin creates a 14-3-3 independent toxin that ADP-ribosylates known ExoS targets. Finally, we show that 14-3-3 stabilizes ExoS against thermal aggregation. Together, this indicates that 14-3-3 proteins activate exotoxin ADP-ribosyltransferase domains by chaperoning their hydrophobic surfaces independently of the hydrophobic C-terminal segment.

Short summary

Crystal structures of Pseudomonas exotoxins-S and –T identify a novel hydrophobic interface with 14-3-3 proteins, and we show that 14-3-3 activates these toxins independent of their phosphopeptide groove binding C-termini, by preventing their aggregation.
Dietary Advanced Glycation End-Product Consumption Leads to Mechanical Stiffening of Murine Intervertebral Discs
Authors: Krishnamoorthy Divya , Hoy Robert C. , Natelson Devorah M , Torre Olivia M. , Laudier Damien M , Iatridis James C. , Illien-Jünger Svenja
Published: June 2018

Back pain is a leading cause of disability strongly associated with intervertebral disc (IVD) degeneration. Reducing structural disruption and catabolism in IVD degeneration remains an important clinical challenge. Pro-oxidant and structure-modifying advanced glycation end-products (AGEs) contribute to obesity and diabetes, which are associated with increased back pain, and accumulate in tissues due to hyperglycemia or ingestion of foods processed at high heat. Collagen-rich IVDs are particularly susceptible to AGE accumulation due to their slow metabolic rates yet it is unclear if dietary AGEs can cross the endplates to accumulate in IVDs. We apply a dietary mouse model to test the hypothesis that chronic consumption of high AGE diets results in sex-specific IVD structural disruption and functional changes. High AGE diet resulted in AGE accumulation in IVDs and increased IVD compressive stiffness, torque range, and failure torque, particularly for females. These biomechanical changes were likely caused by significantly increased AGE crosslinking in the annulus fibrosus, measured by multiphoton imaging. Increased collagen damage measured with collagen hybridizing peptide may be a risk factor for IVD degeneration as these animals age. The greater influence of high AGE diet on females is an important area of future investigation that may involve AGE receptors, known to interact with estrogen. We conclude high AGE diets can be a source for IVD crosslinking and collagen damage known to be important in IVD degeneration. This suggests dietary and other interventions that modify AGEs warrant further investigation and may be particularly important for diabetics where AGEs accumulate more rapidly.

Summary Statement

Dietary advanced glycation end-products (AGE) lead to sex-specific intervertebral disc structural and functional changes and may be targeted for promoting spinal health especially in diabetes where AGEs form rapidly.
Association between Parkinson’s Disease subtypes and tests of physical function: the 360-degree turn test is most predictive
Authors: Prime Morgane , McKay J. Lucas , Bay Allison , Hart Ariel , Kim Chaejin , Abraham Amit , Hackney Madeleine E.
Published: June 2018

BACKGROUND AND PURPOSE

People with Parkinson’s disease (PD) present phenotypes that can be characterized as tremor-dominant (TD) or postural instability / gait difficulty (PIGD) subtypes. Differentiation of subtypes allows clinicians to predict the disease course and adjust treatment accordingly. We examined whether brief mobility and balance measures can discriminate PIGD from TD phenotypes.

METHODS

We performed a cross-sectional study with individuals with PD (N=104). Blinded raters assessed participants with the UPDRS or MDS-UPDRS, and potential predictor variables: 360-degree turn test, one-leg stance, backward perturbation test and tandem walk. Participant were classified as PIGD or TD based on the Unified Parkinson’s Disease Rating Scale or the Movement Disorder Society revision (UPDRS or MDS-UPDRS) assessment results. Differences in study variables between subtype groups were assessed with univariate analyses. Receiver operating characteristic (ROC) curve analyses were performed to investigate the ability of candidate predictor variables to differentiate PD subtypes.

RESULTS

Mean age and disease duration were 68±9 and 7±5 years, respectively, and Hoehn & Yahr Stages I-IV median (1st,3rd quartile) = II (II, III). No differences between subtypes were observed for tandem walk or reactive postural control. PIGD participants performed worse on number of steps (p<0.001) and time to complete (p=0.003) the 360-degree turn test and one-leg stance (p=0.006). ROC curves showed only the 360-degree turn test could discriminate PIGD from TD with high sensitivity.

CONCLUSIONS

The 360-degree turn test requires minimal time to administer and may be useful in mild-moderate PD for distinguishing PIGD from TD subtypes.
A behavior-manipulating virus relative as a source of adaptive genes for parasitoid wasps
Authors: Di Giovanni Deborah , Lepetit David , Boulesteix Matthieu , Coute Yohann , Ravallec Marc , Varaldi Julien
Published: June 2018

To circumvent host immune response, some hymenopteran endo-parasitoids produce virus-like structures in their reproductive apparatus that are injected into the host together with the eggs. These viral-like structures are absolutely necessary for the reproduction of these wasps. The viral evolutionary origin of these viral-like particles has been demonstrated in only a few cases of wasp species all belonging to the Ichneumonoidea superfamily. In addition, the nature of the initial virus-wasp association remains unknown for all. This is either because no closely related descendant infects the wasps, because it has not been sampled yet, or because the virus lineage went extinct. In this paper, we show that the virus-like particles (VLPs) produced by endoparasitoids of Drosophila belonging to the Leptopilina genus (superfamily Cynipoidea) do have a viral origin, solving the debate on their origin. Furthermore, the ancestral donor virus still has close relatives infecting one of the wasp species, thus giving us insights on the ecological interaction that possibly allowed the domestication process. Intriguingly, this contemporary virus is both vertically and horizontally transmitted and has the particularity to manipulate the superparasitism behavior of the wasp. This raises the possibility that behavior manipulation has been instrumental in the birth of such association between wasps and viruses.
Altered Stool Microbiota of Infants with Cystic Fibrosis Shows Reduction in Genera Associated with Immune Programming
Authors: Antosca Katherine M. , Chernikova Diana A. , Ruoff Kathryn L. , Li Kewei , Guill Margaret F. , MacKenzie Todd A. , Dorman Dana B. , Moulton Lisa A. , Williams Molly A. , Aldrich Brian J. , Yuan Irene H. , Karagas Margaret R. , O’Toole George A. , Madan Juliette C.
Published: June 2018

Previous work from our group indicated a connection between the gastrointestinal microbiota of infants and children with cystic fibrosis (CF) and airway disease in this population. Here we examine the stool microbiota of infants with CF and from the general population who did not have CF over the first year of life. CF children had reduced gastrointestinal Bacteroides and Bifidobacterium beginning in infancy, even after adjusting for antibiotic treatment. We also identify several metabolic pathways that are enriched or under represented among the microbial communities in the stool of these young patients with CF as compared to children without CF. In vitro studies demonstrated that exposure of the apical face of a polarized Intestinal cell line to Bacteroides thetaiotaomicron significantly reduced production of IL-8 secreted from both the apical and basolateral face of these cells, suggesting a mechanism whereby changes in the intestinal microflora could impact systemic inflammation. This work further establishes a link between gastrointestinal microbiota, systemic inflammation and airway disease, and presents the opportunity for therapeutic probiotic interventions.

Significance statement

There is a surprising link between gastrointestinal microbial communities and airway disease progression in CF. Here we show that infants with CF ≤1 year of age show a distinct stool microbiota compared with children of a comparable age from a general population cohort. We detect associations between stool microbes and airway exacerbation events in the cohort of infants with CF, and in vitro studies provide a possible mechanism for this observation. These data argue that current therapeutics do not establish a healthy-like gastrointestinal microbiota in young patients with CF, and we suggest that interventions that direct the gastrointestinal microbiota closer to a healthy state may provide benefit to these patients.
Can Drosophila melanogaster tell who’s who?
Authors: Schneider Jonathan , Murali Nihal , Taylor Graham , Levine Joel
Published: June 2018

Drosophila melanogaster are known to live in a social but cryptic world of touch and odours, but the extent to which they can perceive and integrate visual information is a hotly debated topic. Some researchers fixate on the limited resolution of D. melanogaster’s optics, other’s on their seemingly identical appearance; yet there is evidence of individual recognition and surprising visual learning in flies. Here, we apply machine learning and show that individual D. melanogaster are visually distinct. We also use the striking similarity of Drosophila’s visual system to current convolutional neural networks to theoretically investigate D. melanogaster’s capacity for visual understanding. We find that, despite their limited optical resolution, D. melanogaster’s neuronal architecture has the capability to extract and encode a rich feature set that allows flies to re-identify individual conspecifics with surprising accuracy. These experiments provide a proof of principle that Drosophila inhabit in a much more complex visual world than previously appreciated.

Author summary

In this paper, we determine a proof of principle for inter-individual recognition in two parts; is there enough information contained in low resolution pictures for inter-fly discrimination, and if so does Drosophila’s visual system have enough capacity to use it. We show that the information contained in a 29×29 pixel image (number of ommatidia in a fly eye) is sufficient to achieve 94% accuracy in fly re-identification. Further, we show that the fly eye has the theoretical capacity to identify another fly with about 75% accuracy. Although it is unlikely that flies use the exact algorithm we tested, our results show that, in principle, flies may be using visual perception in ways that are not usually appreciated.
Towards building an automated bioinformatician: more accurate transcript assembly via parameter advising
Authors: DeBlasio Dan , Kim Kwanho , Kingsford Carl
Published: June 2018

Computational tools used for genomic analyses are becoming increasingly sophisticated and complex. While these applications often provide more accurate results than their predecessors, a new problem is emerging in that these pieces of software have a large number of tunable parameters. Choosing the wrong parameter values for an application may lead to significant results being overlooked or false results being reported. We take some first steps towards generating a truly automated genomic analysis pipeline by developing a method for automatically choosing input-specific parameter values for reference-based transcript assembly. We extend the parameter advising framework, first developed for multiple sequence alignment, to optimize parameter choices for the Scallop transcript assembler. In doing so, we provide the first method for finding advisor sets for applications with large numbers of tunable parameters. By choosing parameter values for each input, the area under the curve (AUC) when comparing assembled transcripts to a reference transcriptome is increased by 28.9% over using only the default parameter choices on 1595 RNA-Seq samples in the Sequence Read Archive. This approach is general, and when applied to StringTie it increases AUC by 13.1% on a set of 65 RNA-Seq experiments from ENCODE. Parameter advisors for both Scallop and StringTie are available on Github1.
AlleleAnalyzer: a tool for personalized and allele-specific sgRNA design
Authors: Keough Kathleen C. , Lyalina Svetlana , Olvera Michael P. , Whalen Sean , Conklin Bruce R. , Pollard Katherine S.
Published: June 2018

The CRISPR/Cas system is a highly specific genome editing tool capable of distinguishing alleles differing by even a single base pair. However, current tools only design sgRNAs for a reference genome, not taking into account individual variants which may generate, remove, or modify CRISPR/Cas sgRNA sites. This may cause mismatches between designed sgRNAs and the individual genome they are intended to target, leading to decreased experimental performance. Here we describe AlleleAnalyzer, a tool for designing personalized and allele-specific sgRNAs for genome editing. We leverage >2,500 human genomes to identify optimized pairs of sgRNAs that can be used for human therapeutic editing in large populations in the future.
An Implementation of Empirical Bayesian Inference and Non-Null Bootstrapping for Threshold Selection and Power Estimation in Multiple and Single Statistical Testing
Authors: Nasseroleslami Bahman
Published: June 2018

The majority of conclusions and interpretations in quantitative sciences such as neuroscience are based on statistical tests. However, the statistical inferences, especially in multivariate analyses, commonly rely on the p-values, but not on more expressive measures such as posterior probabilities, false discovery rates (FDR) and statistical power (1 − β). The aim of this report is to make these statistical measures further accessible in single and multiple statistical testing. For multiple testing, the Empirical Bayesian Inference (Efron et al., 2001; Efron, 2007) was implemented using non-parametric test statistics (e.g. the Area Under the Curve of the Receiving Operator Characteristics Curve or Spearman’s rank correlation) and Gaussian Mixture Model estimation of the probability density function of the original and bootstrapped data. For single statistical tests, the same test statistics were used to construct and estimate the null and non-null probability density functions using bootstrapping under null and non-null grouping assumptions. Simulations were used to test the reliability of the results under a wide range of conditions. The results show conformity to the real truth in the simulated conditions, which is held under various conditions imposed on the simulated data. The open-source MATLAB codes are provided and the utility of the approach has been exemplified and discussed for real-world electroencephalographic signals. This implementation of Empirical Bayesian Inference and informed selection of statistical thresholds are expected to facilitate more realistic scientific deductions in versatile fields, especially in neuroscience, neural signal analysis and neuro-imaging.
Signaling dynamics control cell fate in the early Drosophila embryo
Authors: Johnson Heath E. , Shvartsman Stanislav Y. , Toettcher Jared E.
Published: June 2018

The Erk mitogen-activated protein kinase plays diverse roles in animal development, where its activity is associated with phenomena including cell migration, proliferation and differentiation. Its widespread reuse raises a conundrum: when a single kinase like Erk is activated, how does a developing cell know which fate to adopt? Here, we combine precise optogenetic control with genetic perturbations to dissect Erk-dependent cellular responses in the early Drosophila embryo. We find that light-stimulated Erk activity is sufficient to ‘posterior-ize’ the majority of the embryo, leading to massive apical constriction through expression of the autocrine receptor-ligand pairmistandfog. Ectopic contraction at non-terminal positions requires at least 1 h of high-amplitude Erk signaling, whereas a 30 min pulse of Erk activity patterns non-contractile neurogenic ectoderm during the same time window. In contrast to the canonical ‘transient versus sustained’ model, the cell fate switch is triggered by the cumulative load of Erk signaling, not the duration of a single persistent pulse. Our results reveal that the early fly embryo harbors a classic example of dynamic cell fate control, where the total dose of Erk activity selects between two distinct physiological outcomes.