bluuebunny/crossref_metadata_2025 huggingface dataset:
Conformational resolution of nucleotide cycling and effector interactions for multiple small GTPases in parallel
Authors: Killoran Ryan C. , Smith Matthew J.
Published: March 2019

Small GTPase proteins alternatively bind GDP/GTP guanine nucleotides to gate signaling pathways that direct most cellular processes. Numerous GTPases are implicated in oncogenesis, particularly three RAS isoforms HRAS, KRAS and NRAS, and the RHO family GTPase RAC1. Signaling networks comprising small GTPases are highly connected, and there is evidence of direct biochemical crosstalk between the functional G-domains of these proteins. The activation potential of a given GTPase is contingent on a co-dependent interaction with nucleotide and a Mg2+ion, which bind to individual variants via distinct affinities coordinated by residues in the nucleotide binding pocket. Here, we utilize a selective-labelling strategy coupled with real-time nuclear magnetic resonance (NMR) spectroscopy to monitor nucleotide exchange, GTP hydrolysis and effector interactions of multiple small GTPases in a single complex system. We provide new insight on nucleotide preference and the role of Mg2+in activating both wild-type and oncogenic mutant enzymes. Multiplexing reveals GEF, GAP and effector binding specificity in mixtures of GTPases and establishes the complete biochemical equivalence of the three related RAS isoforms. This work establishes that direct quantitation of the nucleotide-bound conformation is required to accurately resolve GTPase activation potential, as GTPases such as RALA or the G12C mutant of KRAS demonstrate fast exchange kinetics but have a high affinity for GDP. Further, we propose that the G-domains of small GTPases behave autonomously in solution and nucleotide cycling proceeds independent of protein concentration but is highly impacted by Mg2+abundance.
Laminar Specific fMRI Reveals Directed Interactions in Distributed Networks During Language Processing
Authors: Sharoh Daniel , van Mourik Tim , Bains Lauren J. , Segaert Katrien , Weber Kirsten , Hagoort Peter , Norris David G.
Published: March 2019

Laminar resolution, functional magnetic resonance imaging (lfMRI) is a noninvasive technique with the potential to distinguish top-down and bottom-up signal contributions on the basis of laminar specific interactions between distal regions. Hitherto, lfMRI could not be demonstrated for either whole-brain distributed networks or for complex cognitive tasks. We show that lfMRI can reveal whole-brain directed networks during word reading. We identify distinct, language critical regions based on their association with the top-down signal stream and establish lfMRI for the noninvasive assessment of directed connectivity during task performance.
Moving microbes: the dynamics of transient microbial residence on human skin
Authors: Vandegrift Roo , Fahimipour Ashkaan K. , Muscarella Mario , Bateman Ashley C. , Van Den Wymelenberg Kevin , Bohannan Brendan J.M.
Published: March 2019

The human skin microbiome interacts intimately with human health, yet the drivers of skin microbiome composition and diversity are not well-understood. The composition of the skin microbiome has been characterized as both highly variable and relatively stable, depending on the time scale under consideration, and it is not clear what role contact with environmental sources of microbes plays in this variability. We experimentally mimicked human skin contact with two common environmental sources of microorganisms — soils and plant leaves — and characterized the dynamics of microbial acquisition and persistence on skin on very short time scales. Repeatable changes in skin community composition following encounters with environmental sources were observed, and these trajectories largely depend on donor community biomass distributions. Changes in composition persisted for at least 24 hours and through a soap and water wash following exposures to relatively high biomass soil communities. In contrast, exposures to lower biomass leaf communities were undetectable after a 24 hour period. Absolute abundances of bacterial taxa in source communities predicted transmission probabilities and residence times, independent of phylogenetic considerations. Our results suggest that variability in the composition of the skin microbiome can be driven by transient encounters with common environmental sources, and that these relatively transient effects can persist when the source is of sufficient biomass.

Importance

Humans come into contact with environmental sources of microbes, such as soil or plants, constantly. Those microbial exposures have been linked to health through training and modulation of the immune system. While much is known about the human skin microbiome, the short term dynamics after a contact event, such as touching soil, have not been well characterized. In this study, we examine what happens after such a contact event, describing trends in microbial transmission to and persistence on the skin. Additionally, we use computational sampling model simulations to interrogate null expectations for these kinds of experiments. This work has broad implications for infection control strategies and therapeutic techniques that rely on modification of the microbiome, such as probiotics and faecal transplantation.
Structural determinants of microtubule minus end preference in CAMSAP CKK domains
Authors: Atherton Joseph , Luo Yanzhang , Xiang Shengqi , Yang Chao , Jiang Kai , Stangier Marcel , Vemu Annapurna , Cook Alexander D. , Wang Su , Roll-Mecak Antonina , Steinmetz Michel O. , Akhmanova Anna , Baldus Marc , Moores Carolyn A.
Published: March 2019

CAMSAP/Patronins regulate microtubule minus-end dynamics. Their end specificity is mediated by their CKK domains, which we proposed recognise specific tubulin conformations found at minus ends. To critically test this idea, we compared the human CAMSAP1 CKK domain (HsCKK) with a CKK domain fromNaegleria gruberi(NgCKK), which has lost minus-end specificity. Near-atomic cryo-electron microscopy structures of HsCKK- and NgCKK-microtubule complexes show that these CKK domains share the same protein fold, bind at the intradimer interprotofilament tubulin junction, but exhibit subtly different footprints on microtubules. Whereas NgCKK binding does not alter the microtubule architecture, HsCKK remodels its microtubule interaction site and changes the underlying polymer structure because the tubulin lattice conformation is not optimal for its binding. NMR experiments show that HsCKK is remarkably rigid, supporting this remodelling ability. Thus, in contrast to many MAPs, CKK domains can differentiate subtly specific tubulin conformations to enable microtubule minus-end recognition.
MCT4 is a high affinity transporter capable of exporting lactate in high-lactate environments
Authors: Contreras-Baeza Y , Sandoval PY , Alarcón R , Galaz A , Cortés-Molina F , Alegría K , Baeza-Lehnert F , Arce-Molina R , Guequén A , Flores CA , San Martín A , Barros LF
Published: March 2019

MCT4 is an H+-coupled transporter expressed in metastatic cancer cells, macrophages, and other highly glycolytic cells, where it extrudes excess lactate generated by the Warburg phenomenon or by hypoxia. Intriguingly, its reported Kmfor lactate, obtained with pH-sensitive probes, is more than an order of magnitude higher than physiological lactate. Here we examined MCT4-rich MDA-MB-231 cells using the FRET sensor Laconic and found a median Kmfor lactate uptake of only 1.7 mM, while parallel estimation in the same cells with a pH probe gave a Kmof 27 mM. The median Kmof MCT4 for lactate was 0.7 mM in MCT4-expressing HEK293 cells and 1.2 mM in human macrophages, suggesting that high substrate affinity is a robust property of the transporter. Probed with the FRET sensor Pyronic, MCT4 showed a Kmfor pyruvate of only 4.2 mM in MDA-MB-231 cells, as opposed to > 150 mM reported previously. We conclude that prior estimates of MCT4 affinity based on pH probes were severely biased by the confounding action of pH regulatory mechanisms. Numerical simulation showed that MCT4, but not MCT1 or MCT2, endows cells with the capability of lactate extrusion in high lactate environments. The revised kinetic properties and novel transport assays may help in developing small-molecule MCT4 blockers for research and therapy.
The complete chloroplast genome of Chinese medicine (Psoralea corylifolia Linn): Molecular Structures, barcoding analysis, and phylogenetic Analysis
Authors: Tan Wei , Gao Han , Zhang Huanyu , Yu Xiaolei , Tian Xiaoxuan , Jiang Weiling , Zhou Kun
Published: March 2019

Psoralea corylifoliais one kind of traditional Chinese medicine used in China widely. In this study, we sequence the complete chloroplast genome ofP. corylifolia, which is 153,114 bp in size and includes a pair of inverted repeats regions of 25,557 bp interspersed by a small single copy of 17,885 bp and a large single copy of 84,115 bp region. Approximately 98 simple sequence repeats, 14 forward, 2 reverse, 2 complement, 32 palindromic and 49 tandem repeats are identified in theP. corylifoliachloroplast genome. The chloroplast genomes ofP. corylifoliaand threeGlycinespecies are conserved in gene order and content, but show high diversity within intergenic spacers.P. corylifoliawith threeGlycinespecies in Papilionoideae fall into the same clade based on 75 conserved coding-protein genes phylogenomic analysis. Moreover, four chloroplast DNA regions (ycf1, matK, accD, ndhF) can serve as the barcodes. In general, our findings will dedicate to better comprehension of the genome aspect as well as evolutionary status ofP. corylifolia.
Bioremediation of soils contaminated with petroleum solid wastes and drill cuttings byPleurotussp. strains under different treatment scales
Authors: Romero-Silva Roberto , Sánchez-Reyes Ayixon , Díaz-Rodríguez Yuletsis , Batista-García Ramón Alberto , Hernández-Hernández Danai , de Robles Judith Tabullo
Published: March 2019

Wastes from the oil industry represent one of the sources of soil pollution with the greatest environmental impact. Both drill cuttings and crude residues are delivered to the soil and produce severe toxic effects, mainly due to the presence of polycyclic aromatic hydrocarbons. Various bioremediation technologies have been implemented in order to restore the soil quality and the natural auto depuration capabilities, amongst them: composting, bioaugmentation and biostimulation. All of these bioremediation techniques promise to be eco-friendlier and cheaper alternatives than other approaches. In this work we have evaluated several strains ofPleurotussp. for their effect on the bioremediation of oil-contaminated wastes and drill cuttings disposed in storage tanks or in open-air soil lots for many years. Our results suggest that combined natural attenuation mechanism and directed fungal biodegradation activities, could be promising strategies to remediate heavily petroleum polluted soils and drilling wastes both at the laboratory and in field conditions. Furthermore, we present new data that supportingPleurotusgenera as able to degrade asphaltenes, the most recalcitrant fraction of petroleum. This study proposes an approach that at the same time can treat soils contaminated with waste from drill cuttings and bottoms of crude storage tanks.
Divergent mitochondrial and nuclear OXPHOS genes are candidates for genetic incompatibilities inFicedulaFlycatchers
Authors: van der heijden Eva , McFarlane S. Eryn , van der Valk Tom , Qvarnström Anna
Published: March 2019

Hybrid dysfunction is an important source of reproductive isolation between emerging species. Bateson-Dobzhansky-Muller incompatibilities are theoretically well-recognized as the underlying cause of low hybrid dysfunction. However, especially in wild populations, little empirical evidence exists for which genes are involved in such incompatibilities. The relative role of ecological divergence in causing the build-up of genetic incompatibilities in relation to other processes such as genomic conflict therefore remains largely unknown. Genes involved in energy metabolism are potential candidates for genetic incompatibilities, since energy metabolism depends on co-expression of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) leading to mitonuclear coadaptation. When mitochondrial and nuclear genes lacking a co-evolutionary history appear together in hybrids, incompatibilities could arise.Ficedulaflycatcher F1 hybrids have a higher resting metabolic rate (RMR) compared to the parental species, which could be a sign of genetic incompatibilities between energy metabolism genes that diverged in response to environmental differences while the species were in allopatry. Based on sequences of 15 mitochondrial genes of 264 individuals, we show that the two species have divergent mtDNA caused by the build-up of mainly synonymous mutations and a few non-synonymous mutations. Pied flycatcher mitogenomes show evidence of non-neutrality, indicating a selective sweep or population expansion. There is little variation in the nuclear OXPHOS-related proteins and no significant deviation from neutrality, however, specific codon identified sites might be under positive selection in both mitochondrial and nuclear genes encoding OXPHOS proteins for complex I and III. Taken together, these diverged mitonuclear genes therefore constitute possible candidates underlying, at least part of the genetic incompatibilities that cause hybrid dysfunction in crosses between collared and pied flycatchers.
Visually evoked responses are enhanced when engaging in a video game
Authors: Ki Jason J. , Parra Lucas C. , Dmochowski Jacek P.
Published: March 2019

While it is well known that vision guides movement, less appreciated is that the motor cortex also provides input to the visual system. Here we asked whether neural processing of visual stimuli is acutely modulated during motor activity, hypothesizing that visual evoked responses are enhanced when engaged in a motor task that depends on the visual stimulus. To test this, we told participants that their brain activity was controlling a video game that was in fact the playback of a prerecorded game. The deception, which was effective in half of participants, aimed to engage the motor system while avoiding evoked responses related to actual movement or somatosensation. In other trials, subjects actively played the game with keyboard control or passively watched a playback. The strength of visually evoked responses was measured as the temporal correlation between the continuous stimulus and the evoked potentials on the scalp. We found reduced correlation during passive viewing, but no difference between active and sham play. Alpha band (8-12 Hz) activity was reduced over central electrodes during sham play, indicating recruitment of motor cortex despite the absence of overt movement. To account for the potential increase of attention during game play, we conducted a second study with subjects counting screen items during viewing. We again found increased correlation during sham play, but no difference between counting and passive viewing. While we cannot fully rule out the involvement of attention, our findings do demonstrate an enhancement of visual evoked responses during active vision.
A logical model of homology for comparative biology
Authors: Mabee Paula M. , Balhoff James P. , Dahdul Wasila M. , Lapp Hilmar , Mungall Christopher J. , Vision Todd J.
Published: March 2019

There is a growing body of research on the evolution of anatomy in a wide variety of organisms. Discoveries in this field could be greatly accelerated by computational methods and resources that enable these findings to be compared across different studies and different organisms and linked with the genes responsible for anatomical modifications. Homology is a key concept in comparative anatomy; two important types are historical homology (the similarity of organisms due to common ancestry) and serial homology (the similarity of repeated structures within an organism). We explored how to most effectively represent historical and serial homology across anatomical structures to facilitate computational reasoning. We assembled a collection of homology assertions from the literature with a set of taxon phenotypes for vertebrate fins and limbs from the Phenoscape Knowledgebase (KB). Using six competency questions, we evaluated the reasoning ramifications of two logical models: the Reciprocal Existential Axioms Homology Model (REA) and the Ancestral Value Axioms Homology Model (AVA). Both models returned the user-expected results for all but one historical homology query and all serial homology queries. Additionally, for each competency question, the AVA model returns the search term and any subtypes. We identify some challenges of implementing complete homology queries due to limitations of OWL reasoning. This work lays the foundation for homology reasoning to be incorporated into other ontology-based tools, such as those that enable synthetic supermatrix construction and candidate gene discovery.
Functional relevance of dual olfactory bulb in olfactory coding
Authors: Kuruppath Praveen , Bai Li , Belluscio Leonardo
Published: March 2019

Bilateral convergence of external stimuli is a common feature of vertebrate sensory systems. This convergence of inputs from the bilateral receptive fields allows higher order sensory perception, such as depth perception in the vertebrate visual system and stimulus localization in the auditory system. The functional role of such bilateral convergence in the olfactory system is mostly unknown. To test whether each olfactory bulb contributes a separate piece of olfactory information, and whether information from the bilateral olfactory bulb is integrated, we synchronized the activation of olfactory bulbs with blue light in mice expressing channelrhodopsin in the olfactory sensory neurons and behaviorally assessed the relevance of dual olfactory bulb in olfactory perception. Our findings suggest that each olfactory bulb contributes separate components of olfactory information and mice integrate the olfactory information from each olfactory bulb to identify an olfactory stimulus.

Significance statement

Identifying an odor is the first step in olfactory coding, as it is critical for the survival of most animals. Previous studies have shown that bilateral olfactory bulbs help rodents to localize the odor source and navigate accordingly. But It is still unclear whether the bilateral olfactory information plays any role in determining odor identity. Here for the first time, using optogenetics and behavioral experiments, we demonstrate that each olfactory bulb provides distinct olfactory information, and rodents integrate information from the two bulbs to identify an odor.
From acoustic to linguistic analysis of temporal speech structure: acousto-linguistic transformation during speech perception using speech quilts
Authors: Overath Tobias , Paik Joon H.
Published: March 2019

Speech perception entails the mapping of the acoustic waveform to linguistic representations. For this mapping to succeed, the speech signal needs to be tracked over various temporal windows at high temporal precision in order to decode linguistic units ranging from phonemes (tens of milliseconds) to sentences (seconds). Here, we tested the hypothesis that cortical processing of speech-specific temporal structure is modulated by higher-level linguistic analysis. Using fMRI, we measured BOLD signal changes to 4-s long speech quilts with variable temporal structure (30, 120, 480, 960 ms segment lengths), as well as natural speech, created from a familiar (English) or foreign (Korean) language. We found evidence for the acoustic analysis of temporal speech properties in superior temporal sulcus (STS): the BOLD signal increased as a function of temporal speech structure in both familiar and foreign languages. However, activity in left inferior gyrus (IFG) revealed evidence for linguistic processing of temporal speech properties: the BOLD signal increased as a function of temporal speech structure only in familiar, but not in foreign speech. Network analyses suggested that left IFG modulates processing of speech-specific temporal structure in primary auditory cortex, which in turn sensitizes processing of speech-specific temporal structure in STS. The results thus reveal a network for acousto-linguistic transformation consisting of primary and non-primary auditory cortex, STS, and left IFG.

Significance Statement

Where and how the acoustic information contained in complex speech signals is mapped to linguistic information is still not fully explained by current speech/language models. We dissociate acoustic from linguistic analyses of speech by comparing the same acoustic manipulation (varying the extent of temporal speech structure) in two languages (native, foreign). We show that acoustic temporal speech structure is analyzed in superior temporal sulcus (STS), while linguistic information is extracted in left inferior frontal gyrus (IFG). Furthermore, modulation from left IFG enhances sensitivity to temporal speech structure in STS. We propose a model for acousto-linguistic transformation of speech-specific temporal structure in the human brain that can account for these results.
Speciation and gene flow across an elevational gradient in New Guinea kingfishers
Authors: Linck Ethan , Freeman Benjamin G. , Dumbacher John P.
Published: March 2019

Closely related species with parapatric elevational ranges are ubiquitous in tropical mountains worldwide. The gradient speciation hypothesis proposes that these series are the result of in situ ecological speciation driven by divergent selection across elevation. Direct tests of this scenario have been hampered by the difficulty inferring the geographic arrangement of populations at the time of divergence. In cichlids, sticklebacks, and Timema stick insects, support for ecological speciation driven by other selective pressures has come from demonstrating parallel speciation, where divergence proceeds independently across replicated environmental gradients. Here, we take advantage of the unique geography of the island of New Guinea to test for parallel gradient speciation in replicated populations of Syma kingfishers that show extremely subtle differentiation across elevation and between historically isolated mountain ranges. We find that currently described high elevation and low elevation species have reciprocally monophyletic gene trees and form nuclear DNA clusters, rejecting this hypothesis. However, demographic modeling suggests selection has likely maintained species boundaries in the face of gene flow following secondary contact. We compile evidence from the published literature to show that while in situ gradient speciation in labile organisms such as birds appears rare, divergent selection and post-speciation gene flow may be an underappreciated force in the origin of elevational series and tropical beta diversity along mountain slopes.
Cardiac structure and function in patients with schizophrenia taking antipsychotic drugs: an MRI study
Authors: Pillinger Toby , Osimo Emanuele F. , de Marvao Antonio , Berry Alaine , Whitehurst Thomas , Statton Ben , Quinlan Marina , Brugger Stefan , Vazir Ali , Cook Stuart A. , O’Regan Declan P. , Howes Oliver D.
Published: March 2019

Cardiovascular disease (CVD) is a major cause of excess mortality in schizophrenia. Preclinical evidence shows antipsychotics can cause myocardial fibrosis and myocardial inflammation in murine models, but it is not known if this is the case in patients. We therefore set out to determine if there is evidence of cardiac fibrosis and/or inflammation using cardiac MRI in medicated patients with schizophrenia compared with matched healthy controls. 31 participants (14 patients and 17 controls) underwent cardiac MRI assessing myocardial markers of fibrosis/inflammation, indexed by native myocardial T1 time, and cardiac structure (left ventricular (LV) mass) and function (left/right ventricular end-diastolic and end-systolic volumes, stroke volumes, and ejection fractions). Participants were physically fit, and matched for age, gender, smoking, blood pressure, BMI, HbA1c, ethnicity, and physical activity. Compared with controls, native myocardial T1 was significantly longer in patients with schizophrenia (effect size, d=0.89; p=0.02). Patients had significantly lower LV mass, and lower left/right ventricular end-diastolic and stroke volumes (effect sizes, d=0.86-1.08; all p-values <0.05). There were no significant differences in left/right end-systolic volumes and ejection fractions between groups (p>0.05). These results suggest an early diffuse fibro-inflammatory myocardial process in patients that is independent of established CVD-risk factors and could contribute to the excess cardiovascular mortality associated with schizophrenia. Future studies are required to determine if this is due to antipsychotic treatment or is intrinsic to schizophrenia.
Spectral graph theory of brain oscillations
Authors: Raj Ashish , Cai Chang , Xie Xihe , Palacios Eva , Owen Julia , Mukherjee Pratik , Nagarajan Srikantan
Published: March 2019

The relationship between the brain’s structural wiring and the functional patterns of neural activity is of fundamental interest in computational neuroscience. We examine a hierarchical, linear graph spectral model of brain activity at mesoscopic and macroscopic scales. The model formulation yields an elegant closed-form solution for the structure-function problem, specified by the graph spectrum of the structural connectome’s Laplacian, with simple, universal rules of dynamics specified by a minimal set of global parameters. The resulting parsimonious and analytical solution stands in contrast to complex numerical simulations of high dimensional coupled non-linear neural field models. This spectral graph model accurately predicts spatial and spectral features of neural oscillatory activity across the brain and was successful in simultaneously reproducing empirically observed spatial and spectral patterns of alpha-band (8-12 Hz) and beta-band (15-30Hz) activity estimated from source localized scalp magneto-encephalography (MEG). This spectral graph model demonstrates that certain brain oscillations are emergent properties of the graph structure of the structural connectome and provides important insights towards understanding the fundamental relationship between network topology and macroscopic whole-brain dynamics.

Significance Statement

The relationship between the brain’s structural wiring and the functional patterns of neural activity is of fundamental interest in computational neuroscience. We examine a hierarchical, linear graph spectral model of brain activity at mesoscopic and macroscopic scales. The model formulation yields an elegant closed-form solution for the structure-function problem, specified by the graph spectrum of the structural connectome’s Laplacian, with simple, universal rules of dynamics specified by a minimal set of global parameters. This spectral graph model demonstrates that certain brain oscillations are emergent properties of the graph structure of the structural connectome and provides important insights towards understanding the fundamental relationship between network topology and macroscopic whole-brain dynamics.
Volumetric two-photon imaging in live cells and embryos via axially gradient excitation
Authors: Gao Yufeng , Xia Xianyuan , Yu Jia , Chen Tingai , Xu Zhili , Xiao Long , Wang Liang , Yan Fei , Du Zhuo , Chu Jun , Zheng Hairong , Li Hui , Zheng Wei
Published: March 2019

Two-photon microscopy(TPM) that features subcellular resolution, intrinsic optical sectioning ability, and deep penetration in sample is a powerful tool of bioimaging. However, the process of layer-by-layer scanning to form a 3D image inherently limits the volumetric imaging speed and significantly increases the phototoxicity. Here we develop a gradient TPM technique that enables rapid volumetric imaging by only acquiring two 2D images. By sequentially exciting the specimen with two axially elongated two-photon beams with complementary gradient intensities, the axial positions of fluorophores can be decoded from the intensity ratio of the paired images. We achieve an axial localization accuracy of 0.728 ± 0.657 μm, which is sufficient for rapid 3D subcellular imaging. We demonstrate the flexibility of the gradient TPM on a variety of sparsely labelled samples, including bead phantoms, mouse brain tissues, live macrophages and live nematode embryos. The results show that, compared with conventional TPM, the 3D imaging speed increases 6 folds while the photobleaching and photodamage are extremely reduced.
MiR-218: A Molecular Switch and Potential Biomarker of Susceptibility to Stress
Authors: Torres-Berrío Angélica , Nouel Dominique , Cuesta Santiago , Parise Eric M. , Restrepo-Lozano José María , Larochelle Pier , Nestler Eric J. , Flores Cecilia
Published: March 2019

Low miR-218 expression in the medial prefrontal cortex (mPFC) is a consistent trait of depression. Here we assessed whether miR-218 in the mPFC confers resilience or susceptibility to depression-like behaviors in adult mice, using the chronic social defeat stress (CSDS) model of depression. We also investigated whether stress-induced variations of miR-218 expression in the mPFC can be detected in blood. We find that downregulation of miR-218 in the mPFC increases susceptibility to a single session of social defeat, whereas overexpression of miR-218 selectively in mPFC pyramidal neurons promotes resilience to CSDS and prevents stress-induced morphological alterations to those neurons. After CSDS, susceptible mice have low levels of miR-218 in the blood as compared to control or resilient groups. We show further that up-and downregulation of miR-218 levels specifically in the mPFC correlates with miR-218 expression in blood. Our results suggest that miR-218 in the adult mPFC might function as a molecular switch that determines susceptibility versus resilience to chronic stress, and that stress-induced variations in mPFC levels of miR-218 could be detected in blood. We propose that blood expression of miR-218 might serve as potential readout of vulnerability to stress and as a proxy of mPFC function.
A Robust Model of Gated Working Memory
Authors: Strock Anthony , Hinaut Xavier , Rougier Nicolas P.
Published: March 2019

Gated working memory is defined as the capacity of holding arbitrary information at any time in order to be used at a later time. Based on electrophysiological recordings, several computational models have tackled the problem using dedicated and explicit mechanisms. We propose instead to consider an implicit mechanism based on a random recurrent neural network. We introduce a robust yet simple reservoir model of gated working memory with instantaneous updates. The model is able to store an arbitrary real value at random time over an extended period of time. The dynamics of the model is a line attractor that learns to exploit reentry and a non-linearity during the training phase using only a few representative values. A deeper study of the model shows that there is actually a large range of hyper parameters for which the results hold (number of neurons, sparsity, global weight scaling, etc.) such that any large enough population, mixing excitatory and inhibitory neurons can quickly learn to realize such gated working memory. In a nutshell, with a minimal set of hypotheses, we show that we can have a robust model of working memory. This suggests this property could be an implicit property of any random population, that can be acquired through learning. Furthermore, considering working memory to be a physically open but functionally closed system, we give account on some counter-intuitive electrophysiological recordings.
Phylogenetic inference of changes in amino acid propensities with single-position resolution
Authors: Klink Galya V. , Kalinina Olga V. , Bazykin Georgii A.
Published: March 2019

Fitness conferred by the same allele may differ between genotypes, and these differences shape variation and evolution. Changes in amino acid propensities at protein sites over the course of evolution have been inferred from sequence alignments statistically, but the existing methods are data-intensive and aggregate multiple sites. Here, we develop an approach to detect individual amino acids that confer different fitness in different groups of species from combined sequence and phylogenetic data. Using the fact that the probability of a substitution to an amino acid depends on its fitness, our method looks for amino acids such that substitutions to them occur more frequently in one group of lineages than in another. We validate our method using simulated evolution of a protein site under different scenarios and show that it has high specificity for a wide range of assumptions regarding the underlying changes in selection, while its sensitivity differs between scenarios. We apply our method to the env gene of two HIV-1 subtypes, A and B, and to the HA gene of two influenza A subtypes, H1 and H3, and show that the inferred fitness changes are consistent with the fitness differences observed in deep mutational scanning experiments. We find that changes in relative fitness of different amino acid variants within a site do not always trigger episodes of positive selection and therefore may not result in an overall increase in the frequency of substitutions, but can still be detected from changes in relative frequencies of different substitutions.

Author summary

Which amino acids are acceptable at a certain protein site can change with time. In viruses, for example, this can be due to changes in mechanisms of drug resistance and immune escape in the course of evolution. Here, we develop a method for detecting such changes from how evolutionary events are distributed over an evolutionary tree. Informally, we infer that a certain amino acid is favored in a certain group of lineages if substitutions giving rise to it repeatedly occur in the evolution of this group, and disfavored if such substitutions are rare. In surface proteins of HIV-1 and influenza A, we find that changes in preferences detected with d-test match those observed in deep mutational scanning experiments. Our purely bioinformatic approach allows inference of changes in selection between lineages from sequences alone, shedding light on the functional differences between strains or species even in the absence of any structural or functional data.
Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma
Authors: Rodríguez-Núñez Pablo , Romero-Pérez Laura , Amaral Ana T. , Puerto-Camacho Pilar , Jordán Carmen , Marcilla David , Grunewald Thomas G. P. , de Alava Enrique , Díaz-Martín Juan
Published: March 2019

YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing Sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involvingEWSR1gene, andFLI1as the most common partner. The fusion protein is a potent driver of oncogenesis but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome.

We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation ofRASSF1locus -a regulator of Hippo pathway- was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation ofRASSF1correlated with the transcriptional silencing of the tumor suppressor isoformRASFF1A, and transcriptional activation of the protumorigenic isoformRASSF1Cpromoting YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells, and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be partly explained by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS.
Childhood socio-economic disadvantage predicts reduced myelin growth across adolescence and young adulthood
Authors: Ziegler Gabriel , Moutoussis Michael , Hauser Tobias U. , Fearon Pasco , Bullmore Edward T. , Goodyer Ian M. , Fonagy Peter , Jones Peter B. ,   NSPN Consortium, Lindenberger Ulman , Dolan Raymond J.
Published: March 2019

Socio-economic disadvantage (SED) increases exposure to life stressors. Animal research suggests early life stressors affect later neurodevelopment, including myelin developmental growth. To determine whether human childhood SED affects myelination in adolescence and early adulthood we measured the developmental increase of a sensitive myelin marker, magnetization transfer (MT), in a longitudinal study. Childhood SED was associated with globally reduced MT, as well as slower intra-cortical MT increase in widespread sensory-motor, cingulate, insular and prefrontal areas and subcortical areas. Parental education partially accounted for the SED effects on MT increase, while positive parenting provided a partial protection against the impact of SED. Thus, early socio-economic disadvantage, a vulnerability factor for a range of ill-health outcomes, is a risk factor for aberrant myelin growth during a critical developmental period that is associated with a high risk of psychiatric disorder.
Automated quantification of synaptic boutons reveals their 3D distribution in the honey bee mushroom body
Authors: Cabirol Amélie , Haase Albrecht
Published: March 2019

Synaptic boutons are highly plastic structures undergoing experience-dependent changes in their number, volume, and shape. Their plasticity has been intensively studied in the insect mushroom bodies by manually counting the number of boutons in small regions of interest and extrapolating this number to the volume of the mushroom body neuropil.

Here we extend this analysis to the synaptic bouton distribution within a larger subregion of the mushroom body olfactory neuropil of honey bees (Apis mellifera). This required the development of an automated method combining two-photon imaging with advanced image post-processing and multiple threshold segmentation. The method was first validated in subregions of the mushroom body olfactory and visual neuropils. Further analyses in the olfactory neuropil suggested that previous studies overestimated the number of synaptic boutons. As a reason for that, we identified boundaries effects in the small volume samples. The application of the automated analysis to larger volumes of the mushroom body olfactory neuropil revealed a corrected average density of synaptic boutons and, for the first time, their 3D spatial distribution. This distribution exhibited a considerable heterogeneity.

This additional information on the synaptic bouton distribution provides the basis for future studies on brain development, symmetry, and plasticity.
Extreme heterogeneity in sex chromosome differentiation and dosage compensation in livebearers
Authors: Darolti Iulia , Wright Alison E. , Sandkam Benjamin A. , Morris Jake , Bloch Natasha I. , Farré Marta , Fuller Rebecca C. , Bourne Godfrey R. , Larkin Denis M. , Breden Felix , Mank Judith E.
Published: March 2019

Once recombination is halted between the X and Y chromosome, sex chromosomes begin to differentiate and transition to heteromorphism. While there is a remarkable variation across clades in the degree of sex chromosome divergence, far less is known about variation in sex chromosome differentiation within clades. Here, we combined whole genome and transcriptome sequencing data to characterise the structure and conservation of sex chromosome systems across Poeciliidae, the livebearing clade that includes guppies. We found that thePoecilia reticulataXY system is much older than previously thought, being shared not only with its sister species,Poecilia wingei, but also withPoecilia picta, which diverged 30 mya. Despite the shared ancestry, we uncovered an extreme heterogeneity across these species in the proportion of the sex chromosome with suppressed recombination, and the degree of Y chromosome decay. The sex chromosomes inP. reticulataare largely homomorphic, with recombination persisting over a substantial fraction. However, the sex chromosomes inP. pictaare completely non-recombining and strikingly heteromorphic. ln addition to being highly divergent, the sex chromosome system inP. pictaincludes a neo-sex chromosome, the result of a fusion between the ancestral sex chromosome and part of chromosome 7. Remarkably, the profound degradation of the ancestral Y chromosome inP. pictais counterbalanced by the evolution of complete dosage compensation in this species, the first such documented case in teleost fish. Our results offer important insight into the initial stages of sex chromosome evolution and dosage compensation.
Single-molecule genome assembly of the BasketWillow, Salix viminalis, reveals earliest stages of sex chromosome expansion
Authors: Almeida Pedro , Proux-Wera Estelle , Churcher Allison , Soler Lucile , Dainat Jacques , Pucholt Pascal , Nordlund Jessica , Martin Tom , Rönnberg-Wästljung Ann Christine , Nystedt Björn , Berlin Sofia , Mank Judith E.
Published: March 2019

Sex chromosomes have evolved independently multiple times in eukaryotes and are therefore considered a prime example of convergent genome evolution. Sex chromosomes are known to emerge after recombination is halted between a homologous pair of chromosomes and this leads to a range of non-adaptive modifications causing the gradual degeneration and gene loss on the sex-limited chromosome. However, because studies on sex chromosomes have primarily focused on old and highly differentiated sex chromosomes, the causes of recombination suppression and the pace at which degeneration subsequently occurs remain unclear. Here, we use long- and short-read single molecule sequencing approaches to assemble and annotate a draft genome of the basket willow,Salix viminalis, a species with a female heterogametic system at the earliest stages of sex chromosome emergence. Our single-molecule approach allowed us to phase the emerging Z and W haplotypes in a female, and we detected very low levels of Z/W divergence, largely the result of the accumulation of single nucleotide polymorphisms in the non-recombining region. Linked-read sequencing of the same female and an additional male (ZZ) revealed the presence of two evolutionary strata supported by both divergence between the Z and W haplotypes and by haplotype phylogenetic trees. Gene order is still largely conserved between the Z and W homologs, although a few genes present on the Z have already been lost from the W. Furthermore, we use multiple lines of evidence to test for inversions, which have long been assumed to halt recombination between the sex chromosomes. Our data suggest that selection against recombination is a more gradual process at the earliest stages of sex chromosome formation than would be expected from an inversion. Our results present a cohesive understanding of the earliest genomic consequences of recombination suppression as well as valuable insights into the initial stages of sex chromosome formation.
Gut Microbiome Functional and Taxonomic Diversity within an Amazonian semi-nomadic hunter-gatherer group
Authors: Conteville LC , Oliveira-Ferreira J , Vicente AC
Published: March 2019

Background

Human gut microbiome profiles have been associated with human health and disease. These profiles have been defined based on microbes’ taxonomy and more recently, on their functionality. Human groups that still maintain traditional modes of subsistence (hunter-gatherers and rural agriculturalists) represent the groups non-impacted by urban-industrialized lifestyles, and therefore study them provide the basis for understanding the human microbiome evolution. The Yanomami is the largest semi-nomadic hunter-gatherer group of the Americas, exploring different niches of the Amazon rainforest in Brazil and Venezuela. In order to extend the analysis of this unique and diverse group, we focused on the gut microbiome of the Yanomami from Brazil and compared with those from Venezuela, and also with other traditional groups from the Amazon, considering taxonomic and functional profiles.

Results

A diversity of taxonomic biomarkers were identified to each South American traditional group studied, including the two Yanomami groups, despite their overall similarity in the taxonomic gut microbiome profiles. Broader levels of functional categories poorly discriminated traditional and urban-industrialized groups. Interestingly, a diversity was observed with the stratification of these categories, clearly segregating those groups. The Yanomami/Brazil gut microbiome presented unique functional features, such as a higher abundance of gene families involved in regulation/cell signaling, motility/chemotaxis, and virulence, contrasting with the microbiomes from the Yanomami/Venezuela and other groups.

Conclusions

Our study revealed biomarkers, taxonomic and functional differences between the gut microbiome of Yanomami/Brazil and Yanomami/Venezuela individuals. This intra-Yanomami group diversity was accessed due to the increase number of individuals and group studied. These differences may reflect their semi-nomadic behavior, as well as, the local and seasonal diversity of the vast rainforest niche they explore, despite their shared cultural and genetic background. Overall, their microbiome profiles are shared with South American and African traditional groups, probably due to their lifestyle. The unique features identified within the Yanomami highlight the bias imposed by underrepresented sampling, and factors such as variations over space and time (seasonality) that impact, mainly, the hunter-gatherers. Therefore, to reach knowledge about human microbiome variations and their implications in human health, it is essential to enlarge data concerning the number of individuals, as well as the groups representing different lifestyles.