bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for face selectivity in early vision
Authors: Campana Florence , Martin Jacob G. , Bokeria Levan , Thorpe Simon , Jiang Xiong , Riesenhuber Maximilian 
Published: March 2020

AbstractThe commonly accepted “simple-to-complex” model of visual processing in the brain posits that visual tasks on complex objects such as faces are based on representations in high-level visual areas. Yet, recent experimental data showing the visual system’s ability to localize faces in natural images within 100ms (Crouzet et al., 2010) challenge the prevalent hierarchical description of the visual system, and instead suggest the hypothesis of face-selectivity in early visual areas. In the present study, we tested this hypothesis with human participants in two eye tracking experiments, an fMRI experiment and an EEG experiment. We found converging evidence for neural representations selective for upright faces in V1/V2, with latencies starting around 40 ms post-stimulus onset. Our findings suggest a revision of the standard “simple-to-complex” model of hierarchical visual processing.Significance statementVisual processing in the brain is classically described as a series of stages with increasingly complex object representations: early visual areas encode simple visual features (such as oriented bars), and high-level visual areas encode representations for complex objects (such as faces). In the present study, we provide behavioral, fMRI, and EEG evidence for representations of complex objects – namely faces – in early visual areas. Our results challenge the standard “simple-to-complex” model of visual processing, suggesting that it needs to be revised to include neural representations for faces at the lowest levels of the visual hierarchy. Such early object representations would permit the rapid and precise localization of complex objects, as has previously been reported for the object class of faces.
Simplified model assumptions artificially constrain the parameter range in which selection at the holobiont level can occur
Authors: Daybog Itay , Kolodny Oren 
Published: March 2020

AbstractVan Vliet & Doebeli (1) (henceforth VVD) present a multi-level selection framework simulating host-microbiome evolutionary dynamics. The model explores the conditions under which the association between hosts and their “helper” microbiome – microbes that developed a trait that provides a benefit to the host at a cost to themselves – is strong enough to allow for selection at the holobiont level. The model is an important contribution to the holobiont debate, making the notion quantifiable and highlighting the involved parameters.In the study, VVD conclude that the parameter space in which selection occurs at the level of the holobiont is extremely restricted (Fig 1). Here we show that this result stems from specific model assumptions. Although these assumptions are reasonable as a modeling starting point, slight biologically-reasonable modifications of the assumptions lead to qualitatively different outcomes.
Integrated Molecular Characterisation of the MAPK Pathways in Human Cancers
Authors: Sinkala Musalula , Nkhoma Panji , Mulder Nicola , Martin Darren Patrick 
Published: March 2020

AbstractThe mitogen-activated protein kinase (MAPK) pathways are a crucial regulator of the cellular processes that fuel the malignant transformation of normal cells. The genetic underpinnings of molecular aberrations which lead to cancer involve mutations in and, transcription variations of, various MAPK pathway genes. Here, we use datasets of 40,848 patient-derived tumours representing 101 distinct human cancers to identify cancer-associated mutations in MAPK signalling pathway genes. We identify the subset of these genes within which mutations tend to be associated with the worst disease outcomes. Furthermore, by integrating information extracted from various large-scale molecular datasets, we expose the relationship between the fitness of cancer cells after CRISPR mediated gene knockout of MAPK pathway genes, and their dose-responses to MAPK pathway inhibitors. Besides providing new insights into MAPK pathways, we unearth vulnerabilities in specific pathway genes that are reflected in the responses of cancer cells to MAPK drug perturbations: a revelation with great potential for guiding the development of innovative therapeutic strategies.
Locus coeruleus MRI contrast is associated with cortical thickness in older adults
Authors: Bachman Shelby L. , Dahl Martin J. , Werkle-Bergner Markus , Düzel Sandra , Forlim Caroline Garcia , Lindenberger Ulman , Kühn Simone , Mather Mara 
Published: March 2020

AbstractThere is growing evidence that neuronal integrity of the noradrenergic locus coeruleus (LC) is important for later-life cognition. Less understood is how LC integrity relates to brain correlates of cognition, such as brain structure. Here, we examined the relationship between cortical thickness and a measure reflecting LC integrity in older (n = 229) and younger adults (n = 67). Using a magnetic resonance imaging sequence which yields high signal intensity in the LC, we assessed the contrast between signal intensity of the LC and that of neighboring pontine reference tissue. The Freesurfer software suite was used to quantify cortical thickness. LC contrast was positively related to cortical thickness in older adults, and this association was prominent in parietal, frontal, and occipital regions. Brain regions where LC contrast was related to cortical thickness include portions of the frontoparietal network which have been implicated in noradrenergically modulated cognitive functions. These findings provide novel evidence for a link between LC structure and cortical brain structure in later adulthood.
Semantic and syntactic composition of minimal adjective-noun phrases in Dutch: an MEG study
Authors: Kochari Arnold , Lewis Ashley , Schoffelen Jan-Mathijs , Schriefers Herbert 
Published: March 2020

AbstractThe possibility to combine smaller units of meaning (e.g., words) to create new and more complex meanings (e.g., phrases and sentences) is a fundamental feature of human language. In the present project, we investigated how the brain supports the semantic and syntactic composition of two-word adjective-noun phrases in Dutch, using magnetoencephalography (MEG). The present investigation followed up on previous studies reporting a composition effect in the left anterior temporal lobe (LATL) when comparing neural activity at nouns combined with adjectives, as opposed to nouns in a non-compositional context. The first aim of the present study was to investigate whether this effect, as well as its modulation by noun specificity and adjective class, can also be observed in Dutch. A second aim was to investigate to what extent these effects may be driven by syntactic composition rather than primarily by semantic composition as was previously proposed. To this end, a novel condition was administered in which participants saw nouns combined with pseudowords lacking meaning but agreeing with the nouns in terms of grammatical gender, as real adjectives would. We failed to observe a composition effect or its modulation in both a confirmatory analysis (focused on the cortical region and time-window where it has previously been reported) and in exploratory analyses (where we tested multiple regions and an extended potential time-window of the effect). A syntactically driven composition effect was also not observed in our data. We do, however, successfully observe an independent, previously reported effect on single word processing in our data, confirming that our MEG data processing pipeline does meaningfully capture language processing activity by the brain. The failure to observe the composition effect in LATL is surprising given that it has been previously reported in multiple studies. Reviewing all previous studies investigating this effect, we propose that materials and a task involving imagery might be necessary for this effect to be observed. In addition, we identified substantial variability in the regions of interest analysed in previous studies, which warrants additional checks of robustness of the effect. Further research should identify limits and conditions under which this effect can be observed. The failure to observe specifically a syntactic composition effect in such minimal phrases is less surprising given that it has not been previously reported in MEG data.
Comparing basal dendrite branches in human and mouse hippocampal CA1 pyramidal neurons with Bayesian networks
Authors: Mihaljević Bojan , Larrañaga Pedro , Benavides-Piccione Ruth , DeFelipe Javier , Bielza Concha 
Published: March 2020

ABSTRACTPyramidal neurons are the most common cell type in the cerebral cortex. Understanding how they differ between species is a key challenge in neuroscience. A recent study provided a unique set of human and mouse pyramidal neurons of the CA1 region of the hippocampus, and used it to compare the morphology of apical and basal dendritic branches of the two species. The study found inter-species differences in the magnitude of the morphometrics and similarities regarding their variation with respect to morphological determinants such as branch type and branch order. We use the same data set to perform additional comparisons of basal dendrites. In order to isolate the heterogeneity due to intrinsic differences between species from the heterogeneity due to differences in morphological determinants, we fit multivariate models over the morphometrics and the determinants. In particular, we use conditional linear Gaussian Bayesian networks, which provide a concise graphical representation of the independencies and correlations among the variables. We also extend the previous study by considering additional morphometrics and by formally testing test whether a morphometric increases or decreases with the distance from the soma. This study introduces a multivariate methodology for inter-species comparison of morphology.
SNAPflex: a paper-and-plastic device for instrument-free RNA and DNA extraction from whole blood
Authors: Kolluri Nikunja , Albarran Nikolas , Fan Andy , Olson Alex , Sagar Manish , Young Anna , Gomez-Marquez José , Klapperich Catherine M. 
Published: March 2020

AbstractNucleic acid amplification tests (NAATs), which amplify and detect pathogen nucleic acids, are vital methods to diagnose diseases, particularly in cases where patients exhibit low levels of infection. For many blood-borne pathogens such as HIV or Plasmodium, it is necessary to first extract pathogen RNA or DNA from patient blood prior to analysis with NAATs. Traditional nucleic acid extraction methods are expensive, resource-intensive and are often difficult to deploy to resource-limited areas where many blood-borne infections are widespread. Here, we describe a portable, paper-and-plastic device for instrument-free nucleic acid extraction from whole blood, which we call SNAPflex, that builds upon our previous work extracting RNA in a 2D platform from nasopharyngeal swabs. We demonstrated improved extraction of HIV RNA from simulated patient samples compared to traditional extraction methods and long-term stability of extracted RNA without the need for cold storage. We further demonstrated successful extraction and recovery of Plasmodium falciparum DNA from simulated patient samples with superior recovery compared to existing extraction methods. The SNAPflex device extracts and purifies DNA and RNA from whole blood which can be amplified with traditional NAATs, and was designed to easily manufacture and integrate into existing health systems.
Genome editing in mammals using CRISPR type I-D nuclease
Authors: Osakabe Keishi , Wada Naoki , Murakami Emi , Osakabe Yuriko 
Published: March 2020

SUMMARYAdoption of the CRISPR-Cas system has revolutionized genome engineering in recent years; however, application of genome editing with CRISPR type I—the most abundant CRISPR system in bacteria—has been less developed. Type I systems in which Cas3 nuclease degrades the target DNA are known; in contrast, for the sub-type CRISPR type I-D (TiD), which lacks a typical Cas3 nuclease in its cascade, the mechanism of target DNA degradation remains unknown. Here, we found that Cas10d—a nuclease in TiD—is multi-functional in PAM recognition, stabilization and target DNA degradation. TiD can be used for targeted mutagenesis of genomic DNA in human cells, directing both bi-directional long-range deletions and short insertions/deletions. TiD off-target effects, which were dependent on the mismatch position in the protospacer of TiD, were also identified. Our findings suggest TiD as a unique effector pathway in CRISPR that can be repurposed for genome engineering in eukaryotic cells.
CHD8Suppression Impacts on Histone H3 Lysine 36 Trimethylation and Alters RNA Alternative Splicing
Authors: Kerschbamer Emanuela , Tripathi Takshashila , Erdin Serkan , Salviato Elisa , Di Leva Francesca , Sebestyén Endre , Arnoldi Michele , Benelli Matteo , Gusella James F. , Piazza Silvano , Demichelis Francesca , Talkowski Michael E. , Ferrari Francesco , Biagioli Marta 
Published: March 2020

AbstractDisruptive mutations in the chromodomain helicase DNA binding protein 8 (CHD8) have been recurrently associated with Autism Spectrum Disorders (ASD). In normal cellular physiology, CHD8 co-purifies with MLL1 and MOF transcriptional activation complex, with elongating RNAPII and directly binds to DNA promoters and enhancers regions, thus a regulatory role in transcriptional initiation and elongation could be postulated.Here we investigated how chromatin landscape reacts toCHD8suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. We interrogated transcriptionally active and repressed regions, as well as active and poised enhancers.CHD8suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states. H3K36me3 reduction specifically affects highly expressed, CHD8-bound genes. Histone H3K36me3 reduction associated toCHD8-suppression does not functionally impact on global transcriptional levels, but correlated with altered alternative splicing patterns of ∼ 2000 protein coding genes implicated in “RNA splicing”, “mitotic cell cycle phase transition” and “mRNA processing”, especially affecting alternative first exon and exon skipping events.In summary, our results point toward broad molecular consequences ofCHD8suppression, implicating altered histone deposition/maintenance and RNA processing regulation as important regulatory processes in ASD.
Rational Design of Aptamer Switches with Programmable pH Response
Authors: Thompson Ian A.P. , Zheng Liwei , Eisenstein Michael , Soh H. Tom 
Published: March 2020

AbstractAptamer switches that respond sensitively to local variations in pH could enable the development of molecular devices that greatly enhance diagnostic accuracy and therapeutic efficacy. Previous design strategies relied on inserting a known pH-sensitive DNA motif into the aptamer structure. Unfortunately, their performance was ultimately governed by the intrinsic pH-response of the inserted motif and could not be readily tuned to operate across arbitrary pH ranges. In this work, we present a general methodology for converting virtually any aptamer into a pH-responsive switch that can be modulated to undergo a strong change in affinity - in acidic, neutral, or alkaline conditions. This was achieved by inserting two orthogonal motifs that can be manipulated in parallel to tune sensitivity to different pH conditions without altering the core sequence of the aptamer itself. Using a single ATP aptamer, we achieve pH-dependent target binding and release under diverse pH conditions, producing as much as 1,000-fold pH-induced change in affinity. Importantly, we also demonstrate the novel capability to predictably engineer aptamer switches that only exhibit strong target affinity within a narrowly defined pH range. Our approach should offer a highly generalizable strategy for integrating pH-responsiveness into molecular devices.
Histone dynamics within the nucleosome play a critical role in SNF2h-mediated nucleosome sliding
Authors: Gamarra Nathan , Narlikar Geeta J. 
Published: March 2020

AbstractElucidating the mechanisms by which ATP-dependent chromatin remodeling enzymes disrupt nucleosome structure is essential to understanding how chromatin states are established and maintained. A key finding informing remodeler mechanism is the observation that the dynamics of protein residues buried within the histone core of the nucleosome are used by specific remodelers to mobilize the nucleosome1. Recently, a study obtaining cryo-electron microscopy (cryo-EM) structures of ISWI-family remodelernucleosome complexes failed to observe stable conformational rearrangements in the histone octamer2. The authors of this study also failed to replicate the earlier finding that site-specifically restraining histone dynamics inhibits nucleosome sliding by ISWI-family remodelers1,2. In contrast, a recent cryo-EM structure detected asymmetric histone dynamics in an ISWI-nucleosome complex3. Here, using two different protocols, we replicate the original finding in Sinha et al.1that dynamics within the histone core are important for nucleosome sliding by the human ISWI remodeler, SNF2h. These results firmly establish histone dynamics as an essential feature of ISWI-mediated nucleosome sliding and highlight the care required in designing and performing biochemical experiments investigating nucleosome dynamics using disulfide linkages.
Efferent Synaptic Transmission at the Vestibular Type II Hair Cell Synapse
Authors: Yu Zhou , McIntosh J. Michael , Sadeghi Soroush , Glowatzki Elisabeth 
Published: March 2020

ABSTRACTIn the vestibular peripheral organs, type I and type II hair cells (HCs) transmit incoming signals via glutamatergic quantal transmission onto afferent nerve fibers. Additionally, type I HCs transmit via ‘non-quantal’ transmission to calyx afferent fibers, by accumulation of glutamate and potassium in the synaptic cleft. Vestibular efferent inputs originating in the brainstem contact type II HCs and vestibular afferents. Here, we aimed at characterizing the synaptic efferent inputs to type II HCs using electrical and optogenetic stimulation of efferent fibers combined within vitrowhole-cell patch clamp recording from type II HCs in the rodent vestibular crista. Properties of efferent synaptic currents in type II HCs were similar to those found in cochlear hair cells and mediated by activation of α9/α10 nicotinic acetylcholine receptors (AChRs) and SK potassium channels. While efferents showed a low probability of release at low frequencies of stimulation, repetitive stimulation resulted in facilitation and increased probability of release. Notably, the membrane potential of type II HCs measured during optogenetic stimulation of efferents showed a strong hyperpolarization even in response to single pulses and was further enhanced by repetitive stimulation. Such efferent-mediated inhibition of type II HCs can provide a mechanism to adjust the contribution of signals from type I and type II HCs to vestibular nerve fibers. As a result, the relative input of type I hair cells to vestibular afferents will be strengthened, emphasizing the phasic properties of the incoming signal that are transmitted via fast non-quantal transmission.New and NoteworthyType II vestibular hair cells (HCs) receive inputs from efferent fibers originating in the brainstem. We usedin vitrooptogenetic and electrical stimulation of efferent fibers to study their synaptic inputs to type II HCs. Efferent inputs inhibited type II HCs, similar to cochlear efferent effects. We propose that efferent inputs adjust the contribution of signals from type I and type II HCs that report different components of the incoming signal to vestibular nerve fibers.
Structures of a P4-ATPase lipid flippase in lipid bilayers
Authors: He Yilin , Xu Jinkun , Wu Xiaofei , Li Long 
Published: March 2020

AbstractType 4 P-type ATPases (P4-ATPases) are a group of key enzymes maintaining lipid asymmetry of eukaryotic membranes. Phospholipids are actively and selectively flipped by P4-ATPases from the exoplasmic leaflet to the cytoplasmic leaflet. How lipid flipping is coupled with ATP-hydrolysis by P4-ATPases is poorly understood. Here, we report the electron cryo-microscopy structures of a P4-ATPase, Dnf1-Cdc50 fromChaetomium thermophilum, which had been reconstituted into lipid nanodiscs and captured in two transport intermediate states. The structures reveal that transmembrane segment 1 of Dnf1 becomes highly flexible during lipid transport. The local lipid bilayers are distorted to facilitate the entry of the phospholipid substrates from the exoplasmic leaflet to a cross-membrane groove. During transport, the lipid substrates are relayed through four binding sites in the groove which constantly shields the lipid polar heads away from the hydrophobic environment of the membranes.
Identification and functional analysis of long non-coding RNAs in autism spectrum disorders
Authors: Tong Zhan , Zhou Yuan , Wang Juan 
Published: March 2020

ABSTRACTBackgroundGenetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now been identified as disease risk genes for ASD, a detailed illustration of long non-coding RNAs (lncRNAs) associated with ASD remains elusive. In this study, our aim was to identify ASD-related lncRNAs and explore their functions and associated biological pathways in autism.MethodsASD-related lncRNAs were identified based on genomic variant data of individuals with ASD from a twin study, and further validated using an independent copy number variant (CNV) dataset. The functions and associated biological pathways of ASD-related lncRNAs were explored by enrichment analysis of three different types of functional neighbor genes (i.e. genomic neighbors, competing endogenous RNA (ceRNA) neighbors and gene co-expression neighbors in the cortex). The differential functions of ASD-related lncRNAs in distinct brain regions were demonstrated by using gene co-expression network analysis based on tissue-specific gene expression profiles. Moreover, a functional network analysis were conducted for highly reliable functional neighbor genes of ASD-related lncRNAs. Finally, several potential drugs were predicted based on the enrichment of drug-induced pathway sets in ASD-altered biological pathway list.ResultsIn total, 532 ASD-related lncRNAs were identified, and 86.7% of these ASD-related lncRNAs were further validated by a copy number variant (CNV) dataset. Most of functional neighbor genes of ASD-related lncRNAs were enriched in several functions and biological pathways, including nervous system development, inflammatory response and transcriptional regulation. As a set, ASD-related lncRNAs were mainly associated with nervous system development and dopaminergic synapse in the cortex, but associated with transcriptional regulation in the cerebellum. Moreover, all highly reliable functional neighbor genes were connected in a single functional network. Finally, several potential drugs were predicted and partly supported by the previous reports.ConclusionsWe concluded that ASD-related lncRNAs participate in the pathogenesis of ASD through various known biological pathways, which may be differential in distinct brain regions. And detailed investigation of ASD-related lncRNAs also provided clues for developing potential ASD diagnosis biomarker and therapy.