bluuebunny/crossref_metadata_2025 huggingface dataset:
Gestational age modulates neural correlates of intentional, but not automatic number magnitude processing in children born preterm
Authors: Klein Elise , Moeller Korbinian , Huber Stefan , Willmes Klaus , Kiechl‐Kohlendorfer Ursula , Kaufmann Liane
Published: October 2017

Premature birth is a significant risk factor for learning disabilities in general and mathematics learning difficulties in particular. However, the exact reasons for this relation are still unknown. While typical numerical development is associated with a frontal‐to‐parietal shift of brain activation with increasing age, influences of gestational age have hardly been considered so far. Therefore, we investigated the influence of gestational age on the neural correlates of number processing in 6‐ and 7‐year‐old children born prematurely (n = 16). Only the numerical distance effect – as a measure of intentional number magnitude processing – elicited the fronto‐parietal activation pattern typically observed for numerical cognition. On the other hand, the size congruity effect – as a measure of automatic number magnitude processing – was associated with activation of brain areas typically attributed to cognitive control. Most importantly, however, we observed that gestational age reliably predicted the frontal‐to‐parietal shift of activation observed for the numerical distance effect. Our findings seem to indicate that human numerical development may start even before birth and prematurity might hamper neural facilitation of the brain circuitry subserving numerical cognition. In turn, this might contribute to the high risk of premature children to develop mathematical learning difficulties.
Early emergence of altered 5‐HT2A receptor‐evoked behavior, neural activation and gene expression following maternal separation
Authors: Sood Ankit , Pati Sthitapranjya , Bhattacharya Amrita , Chaudhari Karina , Vaidya Vidita A.
Published: October 2017

The early stress of Maternal Separation (MS) contributes to the establishment of adult psychopathology. The serotonergic (5‐HT) system is implicated during this temporal window in mediating the development of mood‐related behaviors. MS is reported to evoke altered 5‐HT2A receptor function in adulthood. However, the ontogeny of altered 5‐HT2A receptor responsivity following MS remains unknown. Here, we examined 5‐HT2A receptor agonist, DOI (1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane) (2 mg/kg) evoked responses, namely stereotypical head‐twitch behaviors in control and MS Sprague‐Dawley rat pups at postnatal day 21 (P21). MS involved a separation of pups from the dam for 3 h daily from postnatal day 2–14. MS pups at P21 exhibited significantly enhanced head‐twitch behaviors compared to controls. Using c‐Fos cell counting we examined neural activation in control and MS pups following DOI treatment. MS pups exhibited altered DOI‐evoked c‐Fos expression within all mPFC subdivisions, but not in the hippocampus, lateral septum and hypothalamus, suggesting differential prefrontal neural activation upon 5‐HT2A receptor stimulation following early stress. Gene profiling of 5‐HT2A receptor‐regulated immediate early genes (IEGs) indicated a decline in the expression of Fos, Fra1 and Egr1 mRNA under baseline conditions in the mPFC of MS pups. MS pups also showed an altered pattern in the regulation of several 5‐HT2A receptor‐regulated IEGs (Fos, Fra1, Bdnf, Egr1, Egr3) following DOI treatment. Collectively, these results highlight an early emergence of altered 5‐HT2A receptor‐evoked behavioral responses and neural activation patterns in multiple brain regions in animals with a history of MS.
Composition of brines and mineral zoning of the bottom sediments of soda lakes in the Kulunda steppe (West Siberia)
Authors: Gas’kova O.L. , Strakhovenko V.D. , Ovdina E.A.
Published: October 2017

The diversity of the chemical composition of water in lakes, even those located at a few hundred meters from each other, has long attracted the attention of researchers. Detailed hydrochemical testing of two small soda lakes in the Kulunda steppe, located at 14 km from each other, provided answers to many questions. Although the lakes have pH > 9 and thus are assigned to the soda type, they differ in the composition of saline waters (HCO3–Cl–Na and Cl–SO4–Na–Mg) and bottom sediments. The indicator minerals in the sediments of the lake near Severka Village are pyrite, disordered Ca-smectites, and dolomite (the latter is strongly predominant, especially in the lower part of the sediment section). The minerals in the bottom sediments of the other lake are dominated by terrigenous quartz, feldspars, excess-Ca dolomite, and Mg-calcite, with the portion of carbonates increasing in the lower part of the section. Based on the reported facts, the assumption is made that the landscape position, the influence of groundwaters, and technogenic factors (land plowing) are the main reason for the differences between the two lake systems. The task is set to study biocoenoses and their effect on the diagenesis of the bottom sediments.
Two stages of Neoproterozoic magmatism in the evolution of the Bureya continental massif of the Central Asian Fold Belt
Authors: Sorokin A.A. , Ovchinnikov R.O. , Kudryashov N.M. , Kotov A.B. , Kovach V.P.
Published: October 2017

U–Pb geochronological studies have shown at least two stages of Neoproterozoic magmatism, 940–933 and 804–789 Ma, throughout the geologic evolution of the Bureya continental massif in the east of the Central Asian Fold Belt. The first stage (940–933 Ma) was marked by the formation of the protoliths of metagabbroids and amphibole–biotite gneiss–granites of the Bureya River basin. The geochemical features of these rocks suggest that they formed, most probably, in an island-arc setting on the continental basement or on an active continental margin. The second stage (804–789 Ma) of magmatism was manifested as the formation of biotite leucogranites and hastingsite–lepidomelane granites (A-type granites) in the Chepkan River basin. The latter rocks are similar in geochemical features to within-plate granitoids. The established stages of magmatism are the most ancient for the continental massifs in the east of the Central Asian Fold Belt. It is not ruled out that these magmatism stages were related to the stages of formation and breakup of the Rodinia supercontinent.
Genomic landscape associated with potential response to anti-CTLA-4 treatment in cancers
Authors: Ock Chan-Young , Hwang Jun-Eul , Keam Bhumsuk , Kim Sang-Bae , Shim Jae-Jun , Jang Hee-Jin , Park Sarang , Sohn Bo Hwa , Cha Minse , Ajani Jaffer A. , Kopetz Scott , Lee Keun-Wook , Kim Tae Min , Heo Dae Seog , Lee Ju-Seog
Published: October 2017

Immunotherapy has emerged as a promising anti-cancer treatment, however, little is known about the genetic characteristics that dictate response to immunotherapy. We develop a transcriptional predictor of immunotherapy response and assess its prediction in genomic data from ~10,000 human tissues across 30 different cancer types to estimate the potential response to immunotherapy. The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it. We identify somatic mutations and copy number alterations significantly associated with potential response to immunotherapy, in particular treatment with anti-CTLA-4 antibody. Our findings suggest that tumors may evolve through two different paths that would lead to marked differences in immunotherapy response as well as different strategies for evading immune surveillance. Our analysis provides resources to facilitate the discovery of predictive biomarkers for immunotherapy that could be tested in clinical trials.
Computational design of small transcription activating RNAs for versatile and dynamic gene regulation
Authors: Chappell James , Westbrook Alexandra , Verosloff Matthew , Lucks Julius B.
Published: October 2017

A longstanding goal of synthetic biology has been the programmable control of cellular functions. Central to this is the creation of versatile regulatory toolsets that allow for programmable control of gene expression. Of the many regulatory molecules available, RNA regulators offer the intriguing possibility of de novo design—allowing for the bottom-up molecular-level design of genetic control systems. Here we present a computational design approach for the creation of a bacterial regulator called Small Transcription Activating RNAs (STARs) and create a library of high-performing and orthogonal STARs that achieve up to ~ 9000-fold gene activation. We demonstrate the versatility of these STARs—from acting synergistically with existing constitutive and inducible regulators, to reprogramming cellular phenotypes and controlling multigene metabolic pathway expression. Finally, we combine these new STARs with themselves and CRISPRi transcriptional repressors to deliver new types of RNA-based genetic circuitry that allow for sophisticated and temporal control of gene expression.
The biomechanical origin of extreme wing allometry in hummingbirds
Authors: Skandalis Dimitri A. , Segre Paolo S. , Bahlman Joseph W. , Groom Derrick J. E. , Welch Kenneth C. , Witt Christopher C. , McGuire Jimmy A. , Dudley Robert , Lentink David , Altshuler Douglas L.
Published: October 2017

Flying animals of different masses vary widely in body proportions, but the functional implications of this variation are often unclear. We address this ambiguity by developing an integrative allometric approach, which we apply here to hummingbirds to examine how the physical environment, wing morphology and stroke kinematics have contributed to the evolution of their highly specialised flight. Surprisingly, hummingbirds maintain constant wing velocity despite an order of magnitude variation in body weight; increased weight is supported solely through disproportionate increases in wing area. Conversely, wing velocity increases with body weight within species, compensating for lower relative wing area in larger individuals. By comparing inter- and intraspecific allometries, we find that the extreme wing area allometry of hummingbirds is likely an adaptation to maintain constant burst flight capacity and induced power requirements with increasing weight. Selection for relatively large wings simultaneously maximises aerial performance and minimises flight costs, which are essential elements of humming bird life history.
Normal and inverted regimes of charge transfer controlled by density of states at polymer electrodes
Authors: Rudolph M. , Ratcliff E. L.
Published: October 2017

Conductive polymer electrodes have exceptional promise for next-generation bioelectronics and energy conversion devices due to inherent mechanical flexibility, printability, biocompatibility, and low cost. Conductive polymers uniquely exhibit hybrid electronic–ionic transport properties that enable novel electrochemical device architectures, an advantage over inorganic counterparts. Yet critical structure–property relationships to control the potential-dependent rates of charge transfer at polymer/electrolyte interfaces remain poorly understood. Herein, we evaluate the kinetics of charge transfer between electrodeposited poly-(3-hexylthiophene) films and a model redox-active molecule, ferrocenedimethanol. We show that the kinetics directly follow the potential-dependent occupancy of electronic states in the polymer. The rate increases then decreases with potential (both normal and inverted kinetic regimes), a phenomenon distinct from inorganic semiconductors. This insight can be invoked to design polymer electrodes with kinetic selectivity toward redox active species and help guide synthetic approaches for the design of alternative device architectures and approaches.
Graphitic carbon nitride (g-C3N4)-based photocatalysts for solar hydrogen generation: recent advances and future development directions
Authors: Naseri Amene , Samadi Morasae , Pourjavadi Ali , Moshfegh Alireza Z. , Ramakrishna Seeram
Published: October 2017

Analyzing the commercialization potential of g-C3N4photocatalysts for solar H2generation from an economic viewpoint and for large-scale production.
Toward the low actuation temperature of flexible shape memory polymer composites with room temperature deformabilityviainduced plasticizing effect
Authors: Cai Shenyang , Sun Yu-Chen , Ren Jie , Naguib Hani E.
Published: October 2017

Room temperature deformable PLA/TPU/PEG blends demostrate superior shape memory properties under low temperature environments due to the induced plasticizing effect.
Troposcatter array signal detection based on frequency and spatial fading correlation
Authors: Wang Mengnan , Wang Zhuang
Published: October 2017

Troposcatter propagation mechanism is valuable for beyond‐line‐of‐sight surveillance. However, channel fading caused by multipath scattering limits the sensing performance of the existing equipment. Based on the troposcatter multipath channel fading model on frequency and spatial domain, a modified covariance‐based detector is proposed. The captured array signals are first maximal ratio combined in frequency domain and then weighted in spatial domain before accumulation. The performance of the proposed detector is derived theoretically and verified through simulations, showing significant improvement in the troposcatter scenario.
Photovoltaic–thermoelectric temperature control using a closed‐loop integrated cooler
Authors: Rolley Matthew H. , Sweet Tracy K.N. , Min Gao
Published: October 2017

The closed‐loop integrated cooler (CLIC) is a novel technique deployed on experimental apparatus to accurately measure, monitor and control the temperature of optoelectronic devices. Demonstrated here within a concentrator photovoltaic–thermoelectric (CPV–TE) hybrid device, the thermoelectric module was used as a solid‐state sensor and heat pump in order to control the operational temperature for a triple‐junction solar cell. The technique was used to achieve stable, reproducible and repeatable standard test conditions of 25°C cell temperature, with 1000 W/m2 irradiance and AM1.5G spectrum. During testing with secondary optical element (SOE) optics in a solar simulator, the CLIC enabled accurate temperature control of the CPV cell. This would otherwise be unfeasible due to the spectral, reflective and diffusive effects of the SOE optics. The CLIC was used to obtain temporal and spatial constant temperature of the CPV‐TE hybrid receiver during current–voltage measurement. This method highlights the future potential of the CLIC for accurate temperature control of optoelectronic devices both during testing and in future semiconductor device applications where temperature control is essential to performance or lifetime.
Data association for target tracking rooted in maximum‐likelihood values
Authors: Santos Eduardo , Haykin Simon
Published: October 2017

A modified version of the probabilistic data association (PDA) is proposed for target tracking under measurement uncertainty conditions. This method uses the likelihood of each validated measurement, and selects the best k candidates to be integrated with the PDA. Different computer simulations with a single target under dense‐cluttered environment are presented. Comparison to the standard PDA shows a track loss reduction with the proposed method.
Simulation and analysis of 60 GHz MMW for localisation based on machine learning
Authors: Dou Mingwu , Zhang Wenwu
Published: October 2017

The 60 GHz pulse is more practical for the indoor localisation system due to its better time resolution. Usually, time‐of‐arrival (TOA) estimation with higher accuracy is critical to the indoor localisation. To acquire precise TOA estimations, a novel threshold crossing technique using neural network (NN) is discussed via analysing the characteristics of the received pulses based on the energy detection receiver. The relationship between the optimum thresholds and the signal‐to‐noise ratios (SNRs) are researched. Meanwhile, the influences caused by changing integration periods and channel models are examined. Results show that the proposed NN method can provide better accuracy and robustness to the lower SNR in the models designed by TG 3c.
Facile preparation and dye removal properties of Fe3O4@carbon nanocomposite
Authors: Kong Di , Liu Yunfang , Li Yangyang , Chi Weidong , Huang Qigu , Yu Changyuan
Published: October 2017

Fe3O4@carbon nanocomposite (Fe3O4@C) was continuously prepared by combining microreactor with pyrolysis reactor. The Fe3O4 nanoparticles homogeneously disperse in the carbon matrix with an average size of about 9.2 nm and narrow size distribution. The Fe3O4@C nanocomposite has a Brunauer–Emmett–Teller specific surface area of 71.9 m2/g and total pore volume of 0.37 cm3/g. This nanocomposite has a saturation magnetisation value of 16 emu/g and could be easily separated from water by an external magnet. With the increase of pH value or temperature, the Rhodamine B absorbing capacity of the Fe3O4@C nanocomposite first increases and then decreases after a certain value. The absorbing capacity at pH value 9 is about 169 mg/g when the temperature is 20°C. The above said value also exceeds 150 mg/g at pH value 3. The capacity is still higher than 120 mg/g after four regenerations. The absorbing capacity even reaches to 184 mg/g at 60°C of the absorbing temperature.
Quantum metrology with single spins in diamond under ambient conditions
Authors: Chen Ming , Meng Chao , Zhang Qi , Duan Changkui , Shi Fazhan , Du Jiangfeng
Published: October 2017

The detection of single quantum systems can reveal information that would be averaged out in traditional techniques based on ensemble measurements. The nitrogen-vacancy (NV) centers in diamond have shown brilliant prospects of performance as quantum bits and atomic sensors under ambient conditions, such as ultra-long coherence time, high fidelity control and readout of the spin state. In particular, the sensitivity of the NV center spin levels to external environmental changes makes it a versatile detector capable of measuring various physical quantities, such as temperature, strain, electric fields and magnetic fields. In this paper, we review recent progress in NV-based quantum metrology, and speculate on its future.
Gravitational wave research using pulsar timing arrays
Authors: Hobbs George , Dai Shi
Published: October 2017

A pulsar timing array (PTA) refers to a program of regular, high-precision timing observations of a widely distributed array of millisecond pulsars. Here we review the status of the three primary PTA projects and the joint International Pulsar Timing Array project. We discuss current results related to ultra-low-frequency gravitational wave searches and highlight opportunities for the near future.
Proprotein Convertase Subtilisin/Kexin 9 Levels in Relation to Systemic Immune Activation and Subclinical Coronary Plaque in HIV
Authors: Zanni Markella V , Stone Lauren A , Toribio Mabel , Rimmelin Dodie E , Robinson Jake , Burdo Tricia H , Williams Kenneth , Fitch Kathleen V , Lo Janet , Grinspoon Steven K
Published: October 2017

Background

Proprotein convertase subtilisin/kexin 9 (PCSK9) is known to mediate homeostasis of low-density lipoprotein cholesterol (LDL-c), but it may also participate in immune reactivity and atherogenesis.

Methods

We compared circulating PCSK9 levels among asymptomatic individuals with and without HIV. Further, within each group, we assessed the relationship between PCSK9 levels, traditional cardiovascular disease risk factors, immune activation, and subclinical coronary atherosclerotic plaque.

Results

PCSK9 levels were higher among HIV-infected (n = 149) vs matched non-HIV-infected subjects (n = 69; 332 [272, 412] ng/mL vs 304 [257, 375] ng/mL; P = .047). Among HIV-infected subjects, significant albeit modest positive associations were noted between PCSK9 levels and markers of systemic monocyte activation including sCD14 (rho = 0.22; P = .009) and sCD163 (rho = 0.23; P = .006). In this group, PCSK9 levels related weakly to LDL-c (rho = 0.16; P = .05) and also to Framingham Point Score but did not relate to subclinical coronary atherosclerotic plaque parameters.

Conclusions

Among HIV-infected individuals, circulating PCSK9 levels are elevated and related to systemic markers of monocyte activation but not to coronary plaque parameters. Additional studies are needed to determine the effects of PCSK9 on immune activation and atherogenesis in HIV and to assess whether PCSK9 inhibition reduces immune activation and coronary atherosclerotic plaque burden.

Clinical Trial Registration

NCT00455793.
The McConnell's Capsular Arteries and Their Relevance in Endoscopic Endonasal Approach to the Sellar Region
Authors: Ferrareze Nunes Cristian , Beer-Furlan André , Doglietto Francesco , Carrau Ricardo Luis , Prevedello Daniel Monte-Serrat
Published: October 2017

BACKGROUND

The McConnell's capsular arteries (MCCA) were first described in 1953. They consist of medial branches of the cavernous internal carotid artery (ICA) and are divided in anterior and inferior capsular arteries.

OBJECTIVE

To highlight the anatomy of the MCCA and its importance in the surgical treatment of tuberculum sellae and planum sphenoidale tumors through an endoscopic endonasal approach.

METHODS

Ten cadaveric specimens fixed in formalin and perfused with colored silicone were dissected. Standard endoscopic endonasal transsphenoidal approach to the sellar region was performed. The MCCA were identified and still images were captured for further analysis. We report 1 case to illustrate the importance of the MCCA.

RESULTS

The anterior capsular artery, which originates from the anteromedial aspect of the anterior loop of the cavernous ICA and reaches the suprasellar space, was present in 70% of the specimens with no difference between the right and left sides. The anterior capsular artery plays an important role in the vascularization of tuberculum sellae meningiomas. The inferior capsular artery originates from the inferomedial aspect of the cavernous ICA, at its horizontal portion, and reaches the floor and anterior wall of the sella where it anastomoses to branches of the inferior hypophyseal artery.

CONCLUSION

The MCCA are key structures when performing an endoscopic endonasal approach for tumors of the sellar and suprasellar regions.
Rapid genome sequencing for outbreak analysis of the emerging human fungal pathogenCandida auris
Authors: Rhodes Johanna , Abdolrasouli Alireza , Farrer Rhys A. , Cuomo Christina A. , Aanensen David M. , Armstrong-James Darius , Fisher Matthew C. , Schelenz Silke
Published: October 2017

Background

Candida auriswas first described in 2009, and has since caused nosocomial outbreaks, invasive infections and fungaemia across 11 countries in five continents. An outbreak ofC. aurisoccurred in a specialised cardiothoracic London hospital between April 2015 and November 2016, which to date has been the largest outbreak reported worldwide, involving a total of 72 patients.

Methods

To understand the epidemiology ofC. aurisinfection within this hospital, we sequenced the genomes of outbreak isolates using Oxford Nanopore Technologies and Illumina in order to type antifungal resistance alleles and to explore the outbreak within its local and global context.

Findings

Phylogenomic analysis placed the UK outbreak in the India/Pakistan clade, demonstrating an Asian origin. The outbreak showed similar diversity to that of the entire clade and limited local spatiotemporal clustering was observed. One isolate displayed resistance to both echinocandins and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the geneFKS1, and the latter was associated with a phenylalanine to isoleucine substitution in the geneFUR1. These mutations are novel for this pathogen.

Interpretation

Multiple differential episodic selection of antifungal resistant genotypes has occurred within a genetically heterogenous population across this outbreak, creating a resilient pathogen and making it difficult to define local-scale patterns of transmission as well as implementing outbreak control measures.

Funding

Antimicrobial Research Collaborative, Imperial College London
Quantifying the contribution of recessive coding variation to developmental disorders
Authors: Martin Hilary C. , Jones Wendy D. , Stephenson James , Handsaker Juliet , Gallone Giuseppe , McRae Jeremy F. , Prigmore Elena , Short Patrick , Niemi Mari , Kaplanis Joanna , Radford Elizabeth , Akawi Nadia , Balasubramanian Meena , Dean John , Horton Rachel , Hulbert Alice , Johnson Diana S. , Johnson Katie , Kumar Dhavendra , Ann Lynch Sally , Mehta Sarju G. , Morton Jenny , Parker Michael J. , Splitt Miranda , Turnpenny Peter D. , Vasudevan Pradeep C. , Wright Michael , Wright Caroline F. , FitzPatrick David R. , Firth Helen V. , Hurles Matthew E. , Barrett Jeffrey C. ,   on behalf of the DDD Study
Published: October 2017

Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study, and, for the first time, estimated the causal contribution of recessive coding variation exome-wide. We found that the proportion of cases attributable to recessive coding variants is surprisingly low in patients of European ancestry, at only 3.6%, versus 50% of cases explained byde novocoding mutations. Surprisingly, we found that, even in European probands with affected siblings, recessive coding variants are only likely to explain ~12% of cases. In contrast, they account for 31% of probands with Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes and found three genes that passed stringent Bonferroni correction:EIF3F,KDM5B, andTHOC6.EIF3Fis a novel disease gene, andKDM5Bhas previously been reported as a dominant disease gene.KDM5Bappears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.
FACSanadu: Graphical user interface for rapid visualization and quantification of flow cytometry data
Authors: Bürglin T.R. , Henriksson J.
Published: October 2017

Motivation

Flow cytometry is a fundamental technique in cell biology, yet few open source packages are available to analyse these data. Here we describe FACSanadu, an interactive package for rapid visualization and measurement of flow cytometry data. It is the first open source package that can read length profile data from the COPAS Biosorter.

Availability and Implementation

FACSanadu is implemented in Java and uses the Qt framework for display. Binary distributions are made for all major operating systems (Windows, Macintosh, Linux). The source code and documentation is available as free software athttp://www.facsanadu.org.

Contact:mahogny@areta.org
Detecting T cell receptor rearrangementsin silicofrom non-targeted DNA-sequencing (WGS/WES)
Authors: McGrath Lara Lewis , Lubinski Tristan J. , Barrett J. Carl , Gardner Humphrey
Published: October 2017

To better understand the composition of heterogeneous tissue samples used in generating large genomic datasets, we developed a method for estimating the abundance of T cells within the cellular population. Somatic recombination of chromosomal DNA in T cells creates a vast repertoire of structurally divergent T cell receptors (TCRs) that recognize an array of non-self proteins. It also generates a genomic signature by which TCR sequences can be distinguished from other cell types in non-targeted NGS genomic data. Here we leverage this signature to extract reads with rearranged TCR sequences from a non-targeted population, such as whole genome sequencing (WGS) or whole exome sequencing (WES) datasets. We isolate and confirm T cell rearranged reads from the remainder of the genome (99.9%), accurately estimate relative T cell abundance within a cellular population, and provide a snapshot of the T cell receptor repertoire. This approach is unique from available TCR software options that focus on examining the overall diversity of the TCR repertoire and require prior amplification or selection of this region before sequencing, and has particular utility in immunoscoring clinical patient samples in situations where genomic data exists and other approaches are unavailable.
Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells
Authors: Drobek Ales , Moudra Alena , Mueller Daniel , Huranova Martina , Horkova Veronika , Pribikova Michaela , Ivanek Robert , Oberle Susanne , Zehn Dietmar , McCoy Kathy D. , Draber Peter , Stepanek Ondrej
Published: October 2017

Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute for 10-20% of all peripheral CD8+T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing TCR repertoires and using retrogenic monoclonal T-cell populations, we show that virtual memory T cells originate exclusively from strongly self-reactive T cells. Moreover, we show that the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T-cell clones. We propose a so far unappreciated peripheral T-cell fate decision checkpoint that eventually leads to the differentiation of highly self-reactive T cells into virtual memory T cells. This underlines the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they do not show higher capacity to induce autoimmune diabetes than naïve T cells. Thus, virtual memory T cells are not generally more responsive than naïve T cells, because their activity highly depends on the immunological context.

We conclude that virtual memory T cells are formed from self-reactive CD8+T cells in a process regulated by CD8-Lck stoichiometry. Despite their self-reactivity and partial memory differentiation program, virtual memory T cells did not show a strong autoimmune potential.
GM-CSF negatively regulates early IL-10 mediated responses
Authors: Wilbers Ruud H. P. , Westerhof Lotte B. , van Raaij Debbie R. , Bakker Jaap , Smant Geert , Schots Arjen
Published: October 2017

Inflammatory disorders are becoming more prevalent in the Western world. Treatment of these diseases relies on the intervention in inflammatory responses thereby restoring immune homeostasis. One cytokine that has the potential to restore immune homeostasis is the anti-inflammatory cytokine interleukin-10 (IL-10). But until now IL-10 treatment has not been as successful as anticipated. A reason for this may be that IL-10 responsiveness depends on the environment of the inflamed tissue. In this study we describe that granulocyte-macrophage colony-stimulating factor (GM-CSF) is a key cytokine that negatively regulates IL-10-mediated responses. Dendritic cells differentiated from bone marrow with GM-CSF have a reduced ability to respond to IL-10. Dendritic cells are impaired in their up-regulation of IL-10-induced SOCS3 expression and are unable to suppress LPS-induced TNF-α expression at an early time point. Furthermore, GM-CSF treatment partially replicates this phenotype in macrophages. Surprisingly, GM-CSF seems to regulate IL-10 activity in macrophages without affecting STAT3 activation. Still, GM-CSF induces constitutive phosphorylation of glycogen synthase kinase 3β, a signalling component downstream of the PI3K/Akt pathway. Knowledge on the exact mechanism by which GM-CSF negatively regulates IL-10 activity could give novel insights on the integration of signal transduction pathways elicited by different cytokines. Ultimately this knowledge could provide us with new therapeutic strategies to treat inflammatory disorders.
Coupling of Polo kinase activation to nuclear localization by a bifunctional NLS is required during mitotic entry
Authors: Kachaner David , Garrido Damien , Mehsen Haytham , Normandin Karine , Lavoie Hugo , Archambault Vincent
Published: October 2017

The Polo kinase is a master regulator of mitosis and cytokinesis conserved from yeasts to humans. Polo is composed of an N-term kinase domain (KD) and a C-term Polo-Box Domain (PBD), which regulates its subcellular localizations. The PBD and KD can interact and inhibit each other, and this reciprocal inhibition is relieved when Polo is phosphorylated at its activation loop. How Polo activation and localization are coupled during mitotic entry is unknown. Here we report that PBD binding to the KD masks a nuclear localization signal (NLS). Activating phosphorylation of the KD leads to exposure of the NLS and entry of Polo into the nucleus before nuclear envelope breakdown. Failures of this mechanism result in misregulation of the Cdk1-activating Cdc25 phosphatase and lead to mitotic and developmental defects inDrosophila. These results uncover novel spatiotemporal mechanisms linking master regulatory enzymes during mitotic entry.
Four new induced pluripotent stem cell lines produced from northern white rhinoceros with non-integrating reprogramming factors
Authors: Korody Marisa L. , Pivaroff Cullen , Nguyen Thomas D. , Peterson Suzanne E. , Ryder Oliver A. , Loring Jeanne F.
Published: October 2017

Since we first published methods for generation of induced pluripotent stem cells from endangered species1, we have developed improved non-integrating methods for reprogramming the functionally extinct northern white rhinoceros, and generated iPSCs from four more individuals. Our work is part of a long-term plan for assisted reproduction for conservation of endangered species.
A unified computational framework for modeling genome-wide nucleosome landscape
Authors: Jin Hu , Finnegan Alex I. , Song Jun S.
Published: October 2017

Nucleosomes form the fundamental building blocks of eukaryotic chromatin, and previous attempts to understand the principles governing their genome-wide distribution have spurred much interest and debate in biology. In particular, the precise role of DNA sequence in shaping local chromatin structure has been controversial. This paper rigorously quantifies of the contribution of hitherto-debated sequence features – including G+C content, 10.5-bp periodicity, and poly(dA:dT) tracts – to three distinct aspects of genome-wide nucleosome landscape: occupancy, translational positioning and rotational positioning. Our computational framework simultaneously learns nucleosome number and nucleosome-positioning energy from genome-wide nucleosome maps. In contrast to other previous studies, our model can predict bothin-vitroandin-vivonucleosome maps inS. cerevisiae. We find that although G+C content is the primary determinant of MNase-derived nucleosome occupancy, MNase digestion biases may substantially influence this GC dependence. By contrast, poly(dA:dT) tracts are seen to deter nucleosome formation, regardless of the experimental method used. We further show that the 10.5-bp nucleotide periodicity facilitates rotational but not translational positioning. Applying our method toin-vivonucleosome maps demonstrates that, for a subset of genes, the regularly-spaced nucleosome arrays observed around transcription start sites can be partially recapitulated by DNA sequence alone. Finally,in-vivonucleosome occupancy derived from MNase-seq experiments around transcription termination sites can be mostly explained by the genomic sequence. Implications of these results and potential extensions of the proposed computational framework are discussed
An Mtb-Human Protein-Protein Interaction Map Reveals that Bacterial LpqN Antagonizes CBL, a Host Ubiquitin Ligase that Regulates the Balance Between Anti-Viral and Anti-Bacterial Responses
Authors: Penn Bennett H. , Netter Zoe , Johnson Jeffrey R. , Dollen John Von , Jang Gwendolyn M. , Johnson Tasha , Ohol Yamini M. , Maher Cyrus , Bell Samantha L. , Geiger Kristina , Du Xiaotang , Choi Alex , Parry Trevor , Naramura Mayumi , Chen Chen , Jaeger Stefanie , Shales Michael , Portnoy Dan A. , Hernandez Ryan , Coscoy Laurent , Cox Jeffery S. , Krogan Nevan J.
Published: October 2017

Although macrophages are armed with potent anti-bacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage-intrinsic bacterial control, and the Mtb strategies to overcome them are poorly understood. To further study these processes, we used a systematic affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two new factors involved in Mtb pathogenesis - the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl-/- macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between anti-bacterial and anti-viral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map as a resource for developing a deeper understanding of the intricate interactions between Mtb and its host.
Working memory and reasoning benefit from different modes of large-scale brain dynamics in healthy older adults
Authors: Lebedev Alexander V. , Nilsson Jonna , Lövdén Martin
Published: October 2017

Researchers have proposed that solving complex reasoning problems, a key indicator of fluid intelligence, involves the same cognitive processes as solving working memory tasks. This proposal is supported by an overlap of the functional brain activations associated with the two types of tasks and by high correlations between inter-individual differences in performance. We replicated these findings in fifty-three older subjects but also showed that solving reasoning and working memory problems benefits from different configurations of the functional connectome and that this dissimilarity increases with higher difficulty load. Specifically, superior performance in a typical working memory paradigm (n-back) was associated with up-regulation of modularity (increased between-network segregation), whereas performance in the reasoning task was associated with effective down-regulation of modularity. We also showed that working memory training promotes task-invariant increases in modularity. Since superior reasoning performance is associated with down-regulation of modular dynamics, training may thus have fostered an inefficient way of solving the reasoning tasks. This could help explain why working memory training does little to promote complex reasoning performance. The study concludes that complex reasoning abilities cannot be reduced to working memory and suggests the need to reconsider the feasibility of using working memory training interventions to attempt to achieve effects that transfer to broader cognition.
Towards a neuroscientific understanding of play: A neuropsychological coding framework for analysing infant-adult play patterns
Authors: Neale Dave , Clackson Kaili , Georgieva Stanimira , Dedetas Hatice , Wass Sam , Leong Victoria
Published: October 2017

During early life, play is a ubiquitous activity, and an individual’s propensity for play is positively related to cognitive development and emotional well-being. Play behaviour is diverse and multi-faceted. A challenge for current research is to converge on a common definition and measurement system for play ‒ whether examined at a behavioural, cognitive or neurological level. Combining these different approaches in a multi-level analysis could yield significant advances in understanding the neurocognitive mechanisms of play, and provide the basis for developing biologically-grounded play models. However, there is currently no integrated framework for conducting a multi-level analysis of play that spans brain, cognition and behaviour. The proposed neuropsychological coding framework uses grounded and observable behaviours along three neuropsychological dimensions (sensorimotor, cognitive and socio-emotional), to compute inferences about playful behaviour and related social interactional states. Here, we illustrate the sensitivity and utility of the proposed coding framework using two contrasting dyadic corpora (N=5) of mother-infant object-oriented interactions during experimental conditions that were either conducive (Condition 1) or non-conducive (Condition 2) to the emergence of playful behaviour. We find that the framework accurately identifies the modal form of social interaction as being either playful (Condition 1) or non-playful (Condition 2), and further provides useful insights about differences in the quality of social interaction and temporal synchronicity within the dyad. In conclusion, here, we present a novel neuropsychological framework for analysing the continuous time-evolution of adult-infant play patterns, underpinned by biologically informed state coding along sensorimotor, cognitive and socio-emotional dimensions. We expect that the proposed framework will have wide utility amongst researchers wishing to employ an integrated, multi-level approach to the study of play, and lead towards a greater understanding of the neuroscientific basis of play and may yield insights into a new biologically-grounded taxonomy of play interactions.
Experimental infection of cattle withMycobacterium tuberculosisisolates shows the attenuation of the human tubercle bacillus for cattle
Authors: Villarreal-Ramos Bernardo , Berg Stefan , Whelan Adam , Holbert Sebastien , Carreras Florence , Salguero Francisco J. , Khatri Bhagwati L. , Malone Kerri M. , Rue-Albrecht Kevin , Shaughnessy Ronan , Smyth Alicia , Ameni Gobena , Aseffa Abraham , Sarradin Pierre , Winter Nathalie , Vordermeier Martin , Gordon Stephen V.
Published: October 2017

TheMycobacterium tuberculosiscomplex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported thatM. tuberculosisH37Rv, a standard reference MTBC strain, is attenuated in cattle compared toMycobacterium bovis. However, asM. tuberculosisH37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation ofM. tuberculosisfor cattle by performing a bovine experimental infection with a recentM. tuberculosisisolate. Here we report infection of cattle usingM. bovisAF2122/97,M. tuberculosisH37Rv, andM. tuberculosisBTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that bothM. tuberculosisstrains caused reduced gross and histopathology in cattle compared toM. bovis. UsingM. tuberculosisH37Rv andM. bovisAF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis to explore differences in the peripheral response to infection as a route to identify biomarkers of progressive disease in contrast to a more quiescent, latent infection. Our work shows the attenuation ofM. tuberculosisstrains for cattle, and emphasizes the potential of the bovine model as a ‘One Health’ approach to inform human TB biomarker development and post-exposure vaccine development.
Smc5/6-antagonism by HBx is an evolutionary-conserved function of hepatitis B virus infection in mammals
Authors: Filleton Fabien , Abdul Fabien , Gerossier Laetitia , Paturel Alexia , Hall Janet , Strubin Michel , Etienne Lucie
Published: October 2017

Infection with Hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. HBVs (family Hepadnaviridae) have been associated with mammals for millions of years. Recently, the Smc5/6 complex, known for its essential housekeeping functions in genome maintenance, was identified as an antiviral restriction factor of human HBV. The virus has however developed a counteraction mechanism by degrading the complex via its regulatory HBx protein. Whether the antiviral activity of the Smc5/6 complex against hepadnaviruses is an important and evolutionary-conserved function is unknown. Here, we used a combined evolutionary and functional approach to address this question. We first performed phylogenetic and positive selection analyses of the six Smc5/6 complex subunits and found that they have been highly conserved in primates and mammals. Yet, the Smc6 subunit showed marks of adaptive evolution, potentially reminiscent of virus-host “arms-race” We then functionally tested the HBx from six very divergent hepadnaviruses now naturally infecting primates, rodents, and bats. Despite little sequence homology, we demonstrate that these HBx efficiently degraded mammalian Smc5/6 complexes, independently of the host species and of the sites under positive selection. Importantly, all also rescued the replication of an HBx-deficient HBV in primary human hepatocytes. These findings point to an evolutionary-conserved requirement for Smc5/6 inactivation by HBx, showing that the Smc5/6 antiviral activity has been an important defense mechanism against hepadnaviruses in mammals. Interestingly, Smc5/6 may further be a restriction factor of other yet unidentified viruses that have driven some of its adaptation.

Importance

Infection with hepatitis B virus (HBV) led to 887000 human deaths in 2015. HBV has been co-evolving with mammals for millions of years. Recently, the Smc5/6 complex, known for its essential housekeeping functions, was identified as a restriction factor of human HBV antagonized by the regulatory HBx protein. Here, we address whether the antiviral activity of Smc5/6 is an important evolutionary-conserved function. We found that all six subunits of Smc5/6 have been conserved in primates with only Smc6 showing signatures of “evolutionary arms-race” Using evolutionary-guided functional assays that include infections of primary human hepatocytes, we demonstrate that HBx from very divergent mammalian HBVs could all efficiently antagonize Smc5/6, independently of the host species and sites under positive selection. These findings show that the Smc5/6 antiviral activity against HBV is an important function in mammals. It also raises the intriguing possibility that Smc5/6 restricts other, yet unidentified viruses.