bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractInflammatory 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

ABSTRACTThe 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

AbstractSince 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

AbstractNucleosomes 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

SUMMARYAlthough 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

AbstractResearchers 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

ABSTRACTDuring 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

AbstractTheMycobacterium 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

AbstractInfection 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.ImportanceInfection 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.
Non-monotonic recruitment of ventromedial prefrontal cortex during remote memory recall
Authors: Barry Daniel N. , Chadwick Martin J. , Maguire Eleanor A. 
Published: October 2017

AbstractSystems-level consolidation refers to the time-dependent reorganisation of memory traces in the neocortex, a process in which the ventromedial prefrontal cortex (vmPFC) has been implicated. Capturing the precise temporal evolution of this crucial process in humans has long proved elusive. Here, we used multivariate methods and a longitudinal functional MRI design to detect, with high granularity, the extent to which autobiographical memories of different ages were represented in vmPFC and how this changed over time. We observed an unexpected time-course of vmPFC recruitment during retrieval, rising and falling around an initial peak of 8-12 months, before re-engaging for older two and five year old memories. This pattern was replicated in two independent sets of memories. Moreover, it was further replicated in a follow-up study eight months later with the same participants and memories, where the individual memory representations had undergone their hypothesised strengthening or weakening over time. We conclude that the temporal engagement of vmPFC in memory retrieval seems to be non-monotonic, revealing a complex relationship between systems-level consolidation and prefrontal cortex recruitment that is unaccounted for by current theories.Author SummaryOur past experiences are captured in autobiographical memories which allow us to recollect events from our lives long after they originally occurred. A part of the brain’s frontal lobe, called the ventromedial prefrontal cortex or vmPFC, is known to be important for supporting autobiographical memories especially as memories become more remote. The precise temporal profile of the vmPFC’s involvement is unclear, yet this information is vital if we are to understand how memories change over time and the mechanisms involved. In this study we sought to establish the time-course of vmPFC engagement in the recollection of autobiographical memories while participants recalled memories of different ages during functional magnetic resonance imaging (fMRI). Using a method that detects brain activity patterns associated with individual memories, we found that memory-specific neural patterns in vmPFC became more distinct over the first few months after a memory was formed, but then this initial involvement of vmPFC subsided after one year. However, more remote memories (two years and older), appeared to re-engage vmPFC once again. This temporal profile is difficult to accommodate within any single existing theory. Consequently, our results provoke a re-think about how memories evolve over time and the role played by the vmPFC.
Base-resolution mapping reveals distinct m1A methylome in nuclear- and mitochondrial-encoded transcripts
Authors: Li Xiaoyu , Xiong Xushen , Zhang Meiling , Wang Kun , Chen Ying , Zhou Jun , Mao Yuanhui , Lv Jia , Yi Danyang , Chen Xiao-Wei , Wang Chu , Qian Shu-Bing , Yi Chengqi 
Published: October 2017

SUMMARYGene expression can be post-transcriptionally regulated via dynamic and reversible RNA modifications. N1-methyladenosine (m1A) is a recently identified mRNA modification; however, little is known about its precise location, regulation and function. Here, we develop a base-resolution m1A profiling method, based on m1A-induced misincorporation during reverse transcription, and report distinct classes of m1A methylome in the human transcriptome. m1A in 5’-UTR, particularly those at the first nucleotide of mRNA, associate with increased translation efficiency. A different subset of m1A exhibit a GUUCRA tRNA-like motif, are evenly distributed in the transcriptome and are dependent on the methyltransferase TRMT6/61A. Additionally, we show for the first time that m1A is prevalent in the mitochondrial-encoded transcripts. Manipulation of m1A level via TRMT61B, a mitochondria-localizing m1A methyltransferase, demonstrates that m1A in mitochondrial mRNA interferes with translation. Collectively, our approaches reveal distinct classes of m1A methylome and provide a resource for functional studies of m1A-mediated epitranscriptomic regulation.
H2S mediates interbacterial communication through the air reverting intrinsic antibiotic resistance
Authors: Thomas-Lopez Daniel , Carrilero Laura , Matrat Stephanie , Montero Natalia , Claverol Stéphane , Filipovic Milos R , Gonzalez-Zorn Bruno 
Published: October 2017

AbstractHydrogen sulfide, a gas classically considered as a by-product of cellular metabolism, is today recognized as a crucial gasotransmitter in Eukaryotes. Moreover, most bacteria harbor the eukaryotic orthologous genes for H2S synthesis, and these genes have been linked to different metabolic pathways.Some bacteria, however, produce high amounts of H2S in their extracellular space, a characteristic classically used for identification purposes. This is the case ofSalmonellaTyphimurium, which produces H2S by itsphsABCoperon. Here we show that extracellular release of H2S byS. Typhimurium is solely dependent on itsphsABCoperon. Furthermore, we show thatS. Typhimurium and other H2S-producing bacteria can interact with physically distant bacteria through H2S production. We demonstrate how H2S can revert intrinsic cephalosporin resistance ofEnterococccus faecalisandEnterococcus faeciumto complete susceptibility. This study constitutes a significant step in the study of bacterial interplay and niche competition. Furthermore, as H2S releasing drugs have already been designed, our results open the way to future therapeutic alternatives for the treatment of infections caused by enterococci, multiresistant pathogens for which no treatments are clinically available.Author SummaryIt has been known for decades that bacteria can communicate with each other through the diffusion of metabolites in the media. However, the capacity of a bacterium to interact with other physically distant cell is a recent discovery of the 21stcentury. In this work we show how some well-studied bacteria, as it isSalmonellaspp., interacts with other bacteria thanks to the compound hydrogen sulfide (H2S) that they produce and release to the environment.In our study we have designed novel techniques that allow us to study the interaction between two bacteria, and we have seen thatSalmonellais able to affect other species that is even 1 cm away,i.e., a distance corresponding to 10.0000 times its own size.What is more astonishing is thatEnterococcus, when exposed to the H2S, is dramatically becomes susceptible to many antibiotics, to which it is supposed to be naturally resistant.Enterococcusspp. are responsible for life-threatening infections in hospitals worldwide. Thus, our observations reveal that bacteria can communicate through the air with H2S, and that this molecule can make bacteria that are highly resistant to antibiotics susceptible to antibiotics, making untreatable infections treatable with current antibiotics.