bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methylation and survival differences associated with the type of IDH mutation in 1p/19q non-codeleted astrocytomas
Authors: Tesileanu C Mircea S , Vallentgoed Wies R , Sanson Marc , Taal Walter , Clement Paul M , Wick Wolfgang , Brandes Alba Ariela , Baurain Jean Francais , Chinot Olivier L , Wheeler Helen , Gill Sanjeev , Griffin Matthew , Rogers Leland , Rudà Roberta , Weller Michael , McBain Catherine , Reijneveld Jaap , Enting Roelien H , Caparrotti Francesca , Lesimple Thierry , Clenton Susan , Gijtenbeek Anja , Lim Elisabeth , de Vos Filip , Mulholland Paul J , Taphoorn Martin J B , de Heer Iris , Hoogstrate Youri , de Wit Maurice , Boggiani Lorenzo , Venneker Sanne , Oosting Jan , Bovée Judith VMG , Erridge Sara , Vogelbaum Michael A , Nowak Anna K , Mason Warren P , Kros Johan M , Wesseling Pieter , Aldape Ken , Jenkins Robert B , Dubbink Hendrikus J , Baumert Brigitta , Golfinopoulos Vassilis , Gorlia Thierry , van den Bent Martin , French Pim J 
Published: December 2020

AbstractSomatic mutations in the isocitrate dehydrogenase genesIDH1andIDH2occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132Hmutations. This high prevalence is important as IDH1R132His presumed to be relatively poor at producing D-2-hydroxyglutarate (D-2HG) whereas high concentrations of this oncometabolite are required to inhibit TET2 DNA demethylating enzymes. Indeed, patients harbouring IDH1R132Hmutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of site of origin. For 1p/19q non-codeleted glioma patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring non-R132H mutated tumours have better outcome (HR 0.41, 95% CI [0.24, 0.71], p=0.0013). Non-R132H mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p<0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H mutated 1p/19q non-codeleted gliomas have a more favourable prognosis than their IDH1R132Hmutated counterpart is clinically relevant and should be taken into account for patient prognostication.Single sentence summaryAstrocytoma patients with tumours harbouring IDH mutations other than p.R132H have increased DNA methylation levels and longer survival
Chill coma onset and recovery fail to reveal true variation in thermal performance among populations ofDrosophila melanogaster
Authors: Davis Hannah E. , Cheslock Alexandra , MacMillan Heath A. 
Published: December 2020

AbstractSpecies from colder climates tend to be more chill tolerant regardless of the chill tolerance trait measured, but forDrosophila melanogaster, population-level differences in chill tolerance among populations are not always found when a single trait is measured in the laboratory.We measured chill coma onset temperature, chill coma recovery time, and survival after chronic cold exposure in replicate lines derived from multiple paired African and EuropeanD. melanogasterpopulations. The populations in our study were previously found to differ in chronic cold survival ability, which is believed to have evolved independently in each population pair.To our surprise, the populations did not differ in chill coma onset temperature and chill coma recovery time in a manner that reflected their geographic origins, even though these traits are known to vary with origin latitude amongDrosophilaspecies and among the most common metrics of thermal tolerance in insects. The populations did, however, still differ in their ability to survive chronic cold exposure.While it is common practice to measure only one chill tolerance trait when comparing chill tolerance among insect populations, our results emphasise the importance of measuring more than one thermal tolerance trait to minimize the risk of missing real adaptive variation in insect thermal tolerance.
A 4-lineage statistical suite to evaluate the support of large-scale retrotransposon insertion data to reconstruct evolutionary trees
Authors: Churakov G , Kuritzin A , Chukharev K , Zhang F , Wünnemann F , Ulyantsev V , Schmitz J 
Published: December 2020

AbstractRetrophylogenomics makes use of genome-wide retrotransposon presence/absence insertion patterns to resolve questions in phylogeny and population genetics. In the genomics era, evaluating high-throughput data requires the associated development of appropriately powerful statistical tools. The currently used KKSC 3-lineage statistical test for estimating the significance of retrophylogenomic data is limited by the number of possible tree topologies it can assess in one step. To improve on this, we have extended the analysis to simultaneously compare 4-lineages, enabling us to evaluate ten distinct presence/absence insertion patterns for 26 possible tree topologies plus 129 trees with different incidences of hybridization or introgression. The new tool provides statistics for cases involving multiple ancestral hybridizations/introgressions, ancestral incomplete lineage sorting, bifurcation, and polytomy. The test is embedded in a user-friendly web R-application (http://retrogenomics.uni-muenster.de:3838/hammlet/) and is available for use by the scientific community.
Novelty at second glance: A critical appraisal of the novel-object paradigm based on meta-analysis
Authors: Takola E. , Krause E. T. , Müller C. , Schielzeth H. 
Published: December 2020

ABSTRACTThe study of consistent individual differences in behaviour has become an important focus in research on animal behaviour. Behavioural phenotypes are typically measured through standardized testing paradigms and one frequently used paradigm is the novel object test. In novel object tests, animals are exposed to new (unknown) objects and their reaction is quantified. When repeating trials to assess the temporal consistency of individual differences, researchers face the dilemma of whether to use the same or different ‘novel’ objects, since the same stimulus can result in habituation, while exposure to different objects can result in context-dependent responses. We performed a quantitative assessment of 254 effect sizes from 113 studies on novel-object trials to evaluate the properties of this testing paradigm, in particular the effect of object novelty and time interval between novel-object trials on estimates of individual consistency. We found an increase of sample sizes and an increase of estimates of repeatabilities with time. The vast majority of short-term studies (<one month) used different novel objects, while long-term studies (>one month) used either the same or different novel objects about equally often. The average estimate for individual consistency was r = 0.47 (short-term r = 0.52, long-term r = 0.44). Novelty, time interval between trials and their interaction together explained only 3% of the total heterogeneity. Overall, novelobject trials reliably estimate individual differences in behaviour, but results were very heterogeneous even within the same study species, suggesting susceptibility to unknown details in testing conditions. Most studies that measure novel-object responses in association with food label the trait as neophobia, while novel-object trials in a neutral context are labelled variously as boldness/shyness, exploratory behaviour or neophobia/neophilia. Neophobia/neophilia is also the term most specific to novel object presentations. To avoid ambiguity, we suggest object neophobia/neophilia as the most specific label for novel-object responses.
Aiming off the target: studying repetitive DNA using target capture sequencing reads
Authors: Costa Lucas , Marques André , Buddenhagen Chris , Thomas William Wayt , Huettel Bruno , Schubert Veit , Dodsworth Steven , Houben Andreas , Souza Gustavo , Pedrosa-Harand Andrea 
Published: December 2020

SUMMARYWith the advance of high-throughput sequencing (HTS), reduced-representation methods such as target capture sequencing (TCS) emerged as cost-efficient ways of gathering genomic information. As the off-target reads from such sequencing are expected to be similar to genome skims (GS), we assessed the quality of repeat characterization using this data.For this, repeat composition from TCS datasets of fiveRhynchospora(Cyperaceae) species were compared with GS data from the same taxa.All the major repetitive DNA families were identified in TCS, including repeats that showed abundances as low as 0.01% in the GS data. Rank correlation between GS and TCS repeat abundances were moderately high (r= 0.58-0.85), increasing after filtering out the targeted loci from the raw TCS reads (r= 0.66-0.92). Repeat data obtained by TCS was also reliable to develop a cytogenetic probe and solve phylogenetic relationships ofRhynchosporaspecies with high support.In light of our results, TCS data can be effectively used for cyto- and phylogenomic investigations of repetitive DNA. Given the growing availability of HTS reads, driven by global phylogenomic projects, our strategy represents a way to recycle genomic data and contribute to a better characterization of plant biodiversity.
Signal processing capacity of the cellular sensory machinery regulates the accuracy of chemotaxis under complex cues
Authors: Moon Hye-ran , Saha Soutick , Mugler Andrew , Han Bumsoo 
Published: December 2020

SummaryChemotaxis is ubiquitous in many biological processes, but it still remains elusive how cells sense and decipher multiple chemical cues. In this study, we postulate a hypothesis that the chemotactic performance of cells under complex cues is regulated by the signal processing capacity of the cellular sensory machinery. The underlying rationale is that cellsin vivoshould be able to sense and process multiple chemical cues, whose magnitude and compositions are entangled, to determine their migration direction. We experimentally show that the combination of TGF-β and EGF suppresses the chemotactic performance of cancer cells using independent receptors to sense the two cues. Based on this observation, we develop a biophysical framework suggesting that the antagonism is caused by the saturation of the signal processing capacity, but not by the mutual repression. Our framework suggests the significance of the signal processing capacity in the cellular sensory machinery.
Coiled coil control of growth factor and inhibitor-dependent EGFR trafficking and degradation
Authors: Mozumdar Deepto , Chang Sol Hsun-Hui , Quach Kim , Doerner Amy , Schepartz Alanna 
Published: December 2020

AbstractEGFR exhibits biased signaling, whereby growth factor or mutation-dependent changes in receptor conformation and/or dynamics elicit distinct intracellular outcomes. We report that many outcomes associated with activated EGFR are controlled by a two-state coiled coil switch located within the juxtamembrane segment (JM), an essential component of the cytosolic dimer interface. The position of this switch defines the path of endocytic trafficking and whether or not EGFR is degraded within lysosomes. JM coiled coil identity also predicts kinase-independent effects of oncogenic EGFR mutations and clinically relevant tyrosine kinase inhibitors (TKIs) that promote efficient, lysosome-based EGFR degradation. These findings provide a model for biased EGFR signaling, insights into kinase-independent activities of EGFR and clinically relevant TKIs, and identify new strategies for modulating protein lifetime.
Regions of Highly Recurrent Electrogram Morphology at Sites of Low Cycle Length Accurately Reflect Arrhythmogenic Substrate for Atrial Fibrillation – Implications For a New, Mechanism Guided Therapeutic Approach for Atrial Fibrillation
Authors: Yoo Shin , Rottmann Markus , Ng Jason , Johnson David , Shanab Bassel , Pfenniger Anna , Geist Gail Elizabeth , Mandawa Suman , Burrell Amy , Zhang Wenwei , Wasserstrom J Andy , Knight Bradley P , Passman Rod , Goldberger Jeffrey J , Arora Rishi 
Published: December 2020

ABSTRACTBackgroundAlthough atrial electrograms (EGMs) are thought to reflect pathophysiological substrate for atrial fibrillation (AF), it is not known which electrograms are suitable targets during AF ablation. We hypothesized that electrogram morphology recurrence (EMR) better reflects arrhythmogenic AF substrate than traditional frequency and complexity measures of AF. In a canine rapid atrial pacing (RAP) model of AF, we assessed the relationship between EMR and traditional AF electrogram measures, rotational activity in the atria, fibrosis, myofiber orientation and parasympathetic innervation.MethodsPersistent AF was induced in 13 dogs by RAP for 6-8 weeks. High-density epicardial mapping (117 electrodes) was performed in six atrial sub-regions. EMR measures Recurrence percentage (Rec%) and cycle length of the most frequent electrogram morphology (CLR), Fractionated Interval (FI), Organization Index (OI), Dominant Frequency (DF) and Shannon’s Entropy (ShEn) were analyzed before and after atropine administration. Myocyte fiber orientation, amount of fibrosis and spatial distribution of parasympathetic nerve fibers were quantified.ResultsRec% was greatest in the appendages, and CLRwas lowest in the posterior left atrium. Rec%/CLRcorrelated with FI, OI and the complexity measure ShEn, but not with DF. All electrogram measures were poorly correlated with fibrosis and myofiber anisotropy. Rec% correlated closely with stability of rotational activity. Unlike other measures, Rec% correlated closely with spatial heterogeneity of parasympathetic nerve fibers; this was reflected in CLRresponse to atropine.ConclusionEMR correlates closely with stability of rotational activity and with the pattern of atrial parasympathetic innervation. CLRmay therefore be a viable therapeutic target in persistent AF.
AIM: A Network Model of Attention in Auditory Cortex
Authors: Chou Kenny F. , Sen Kamal 
Published: December 2020

AbstractAttentional modulation of cortical networks is critical for the cognitive flexibility required to process complex scenes. Current theoretical frameworks for attention are based almost exclusively on studies in visual cortex, where attentional effects are typically modest and excitatory. In contrast, attentional effects in auditory cortex can be large and suppressive. A theoretical framework for explaining attentional effects in auditory cortex is lacking, preventing a broader understanding of cortical mechanisms underlying attention. Here, we present a cortical network model of attention in primary auditory cortex (A1). A key mechanism in our network is attentional inhibitory modulation (AIM) of cortical inhibitory neurons. In this mechanism, top-down inhibitory neurons disinhibit bottom-up cortical circuits, a prominent circuit motif observed in sensory cortex. Our results reveal that the same underlying mechanisms in the AIM network can explain diverse attentional effects on both spatial and frequency tuning in A1. We find that a dominant effect of disinhibition on cortical tuning is suppressive, consistent with experimental observations. Functionally, the AIM network may play a key role in solving the cocktail party problem. We demonstrate how attention can guide the AIM network to monitor an acoustic scene, select a specific target, or switch to a different target, providing flexible outputs for solving the cocktail party problem.
The RNA binding protein Nab2 regulates the proteome of the developingDrosophilabrain
Authors: Corgiat Edwin B. , List Sara M. , Rounds J. Christopher , Corbett Anita H. , Moberg Kenneth H. 
Published: December 2020

AbstractThe humanZC3H14gene, which encodes a ubiquitously expressed polyadenosine zinc finger RNA binding protein, is mutated in an inherited form of autosomal recessive, non-syndromic intellectual disability. To gain insight into ZC3H14 neurological functions, we previously developed aDrosophila melanogastermodel of ZC3H14 loss by deleting the fly ortholog, Nab2. Studies in this invertebrate model reveal that Nab2 controls final patterns of neuron projection within fully developed adult brains. Here, we examine earlier pupal stages and define roles for Nab2 in controlling the dynamic growth of axons into the developing brain mushroom bodies (MBs), which support olfactory learning and memory, and in regulating abundance of a small fraction of the total brain proteome, a portion of which is rescued by overexpression ofNab2specifically in brain neurons. The group of Nab2-regulated brain proteins, identified by quantitative proteomic analysis, includes the microtubule binding protein Futsch, the neuronal Ig-family transmembrane protein Turtle, the glial:neuron adhesion protein Contactin, the RacGAP Tumbleweed, and the planar cell polarity factor Van Gogh, which collectively link Nab2 to a the processes of brain morphogenesis, neuroblast proliferation, circadian sleep/wake cycles, and synaptic development. Overall, these data indicate that Nab2 controls abundance of a subset of brain proteins during the active process of wiring the pupal brain mushroom body, and thus provide a window into potentially conserved functions of the Nab2/ZC3H14 RNA binding proteins in neurodevelopment and function.
The Laplacian eigenmaps dimensionality reduction of fMRI data for discovering stimulus-induced changes in the resting-state brain activity
Authors: Pospelov Nikita , Tetereva Alina , Martynova Olga , Anokhin Konstantin 
Published: December 2020

AbstractThe resting brain at wakefulness is active even in the absence of goal-directed behavior or salient stimuli. However, patterns of this resting-state (RS) activity can undergo alterations following exposure to meaningful stimuli. This study aimed to develop an unbiased method to detect such changes in the RS activity after exposure to emotionally meaningful stimuli. For this purpose, we used functional magnetic resonance imaging (fMRI) of RS brain activity before and after the acquisition and extinction of experimental conditioned fear. A group of healthy volunteers participated in three fMRI sessions: a RS before fear conditioning, a fear extinction session, and a RS immediately after fear extinction. The fear-conditioning paradigm consisted of three neutral visual stimuli paired with a partial reinforcement by a mild electric current. We used both linear and non-linear dimensionality reduction approaches to distinguish between the initial RS and the RS after stimuli exposure. The principal component analysis (PCA) as a linear dimensionality reduction method did not differentiate these states. Using the non-linear Laplacian eigenmaps manifold learning method, we were able to show significant differences between the two RSs at the level of individual participants. This detection was further improved by smoothing the BOLD signal with the wavelet multiresolution analysis. The developed method can improve the discrimination of functional states collected in longitudinal fMRI studies.
Alzheimer’s Aβ assembly binds sodium pump and blocks endothelial NOS activity via ROS-PKC pathway
Authors: Sasahara Tomoya , Satomura Kaori , Tada Mari , Kakita Akiyoshi , Hoshi Minako 
Published: December 2020

AbstractAmyloid β-protein (Aβ) may contribute to worsening of Alzheimer’s disease (AD) through vascular dysfunction, but the actual molecular mechanisms remain controversial. Usingex-vivoblood vessels and primary endothelial cells derived from human brain microvessels, we revealed that patient-derived Aβ assemblies, termed amylospheroids (ASPD), exist on the microvascular surface in patient brains and inhibit vasorelaxation through binding to the α3 subunit of sodium, potassium-ATPase (NAKα3) on endothelial cells. Interestingly, NAKα3 also serves as the toxic target of ASPD in neurons. ASPD elicit neurodegeneration through calcium overload, while ASPD suppress vasorelaxation by inhibiting nitric oxide (NO) production. ASPD-NAKα3 interaction on cerebrovascular endothelial cells disturbs the NO release by inactivating endothelial NO synthase through mitochondrial reactive oxygen species and protein kinase C. The findings suggest that ASPD may dually contribute to neuronal and vascular pathologies through binding to NAKα3. Thus, blocking the ASPD-NAKα3 interaction may be a useful target for AD therapy.
Fate mapping analysis reveals a novel dermal migratory Langerhans-like cell population
Authors: Sheng Jianpeng , Qi Chen , Wen Dong Yu , Xiaoting Wu , Mayer Johannes , Lin Wang , Xueli Bai , Tingbo Liang , Ho Sung Yang , Goh Wilson Wen Bin , Ronchese Franca , Ruedl Christiane 
Published: December 2020

AbstractDendritic cells residing in the skin represent a large family of antigen presenting cells, ranging from long-lived Langerhans cells (LC) in the epidermis to various distinct classical dendritic cell subsets in the dermis. Through genetic fate mapping analysis and single cell RNA sequencing we have identified a novel separate population of LC-independent CD207+CD326+LClikecells in the dermis that homed at a slow rate to the LNs. These LClikecells were long-lived and radioresistant but, unlike LCs, they were gradually replenished by bone-marrow-derived precursors under steady state. LClikecells together with cDC1s were the main migratory CD207+CD326+cell fractions present in the LN and not, as currently assumed, LCs, which were barely detectable, if at all. These findings bring new insights into the dynamism of cutaneous dendritic cells and opens novel avenues in the development of treatments to cure inflammatory skin disorders.
Joint modeling of zero-inflated longitudinal proportions and time-to-event data with application to a gut microbiome study
Authors: Hu Jiyuan , Wang Chan , Blaser Martin J. , Li Huilin 
Published: December 2020

SUMMARYRecent studies have suggested that the temporal dynamics of the human microbiome may have associations with human health and disease. An increasing number of longitudinal microbiome studies, which record time to disease onset, aim to identify candidate microbes as biomarkers for prognosis. Owing to the ultra-skewness and sparsity of microbiome proportion (relative abundance) data, directly applying traditional statistical methods may result in substantial power loss or spurious inferences. We propose a novel joint modeling framework [JointMM], which is comprised of two sub-models: a longitudinal sub-model called zero-inflated scaled-Beta generalized linear mixed-effects regression to depict the temporal structure of microbial proportions among subjects; and a survival sub-model to characterize the occurrence of an event and its relationship with the longitudinal microbiome proportions. JointMM is specifically designed to handle the zero-inflated and highly skewed longitudinal microbial proportion data and examine whether the temporal pattern of microbial presence and/or the non-zero microbial proportions are associated with differences in the time to an event. The longitudinal sub-model of JointMM also provides the capacity to investigate how the (time-varying) covariates are related to the temporal microbial presence/absence patterns and/or the changing trend in non-zero proportions. Comprehensive simulations and real data analyses are used to assess the statistical efficiency and interpretability of JointMM.