bluuebunny/crossref_metadata_2025_split huggingface dataset:
Minimally invasive classification of pediatric solid tumors using reduced representation bisulfite sequencing of cell-free DNA: a proof-of-principle study
Authors: Van Paemel Ruben , De Koker Andries , Vandeputte Charlotte , van Zogchel Lieke , Lammens Tim , Laureys Geneviève , Vandesompele Jo , Schleiermacher Gudrun , Chicard Mathieu , Van Roy Nadine , Vicha Ales , Tytgat G.A.M. , Callewaert Nico , De Preter Katleen , De Wilde Bram 
Published: October 2019

AbstractIn the clinical management of pediatric solid tumors, histological examination of tumor tissue obtained by a biopsy remains the gold standard to establish a conclusive pathological diagnosis. The DNA methylation pattern of a tumor is known to correlate with the histopathological diagnosis across cancer types and is showing promise in the diagnostic workup of tumor samples. This methylation pattern can be detected in the cell-free DNA. Here, we provide proof-of-concept of histopathologic classification of pediatric tumors using cell-free reduced representation bisulfite sequencing (cf-RRBS) from retrospectively collected plasma and cerebrospinal fluid samples. We determined the correct tumor type in 49 out of 60 (81.6%) samples starting from minute amounts (less than 10 ng) of cell-free DNA. We demonstrate that the majority of misclassifications were associated with sample quality and not with the extent of disease. Our approach has the potential to help tackle some of the remaining diagnostic challenges in pediatric oncology in a cost-effective and minimally invasive manner.Translational relevanceObtaining a correct diagnosis in pediatric oncology can be challenging in some tumor types, especially in renal tumors or central nervous system tumors. Furthermore, the diagnostic odyssey can result in anxiety and discomfort for these children. By applying a novel technique, reduced representation bisulfite sequencing on cell-free DNA (cf-RRBS), we show the feasibility of obtaining the histopathological diagnosis with a minimally invasive test on either plasma or cerebrospinal fluid. Furthermore, we were able to derive the copy number profile or tumor subtype from the same assay. Given that primary tumor material might be difficult to obtain, in particular in critically ill children or depending on the tumor location, and might be limited in terms of quantity or quality, our assay could become complementary to the classical tissue biopsy in difficult cases.
Multi-scale spatial genetic structure of a vector-borne plant pathogen in orchards and wild habitat
Authors: Marie-Jeanne Véronique , Bonnot François , Thébaud Gaël , Peccoud Jean , Labonne Gérard , Sauvion Nicolas 
Published: October 2019

ABSTRACTInferring the dispersal processes of vector-borne plant pathogens is a great challenge because the plausible epidemiological scenarios often involve complex spread patterns at multiple scales. European stone fruit yellows (ESFY), a disease caused by ‘CandidatusPhytoplasma prunorum’ and disseminated via planting material and vectors belonging to the speciesCacopsylla pruni, is a major threat for stone fruit production throughout Europe. The spatial genetic structure of the pathogen was investigated at multiple scales by the application of a combination of statistical approaches to a large dataset obtained through the intensive sampling of the three ecological compartments hosting the pathogen (psyllids, wild and cultivatedPrunus) in threePrunus-growing regions in France. This work revealed new haplotypes of ‘Ca. P. prunorum’, and showed that the prevalence of the different haplotypes of this pathogen is highly uneven between all regions, and within two of them. In addition, we identified a significant clustering of similar haplotypes within a radius of at most 50 km, but not between nearby wild and cultivatedPrunus. We also provide evidence that the two species of theC. prunicomplex are unevenly distributed but can spread the pathogen, and that infected plants are transferred between production areas. Altogether, this work supports a main epidemiological scenario where ‘Ca. P. prunorum’ is endemic in, and mostly acquired from, wildPrunusby immatureC. pruni(of both species) who then migrate to “shelter plants” that epidemiologically connect sites less than 50 km apart by later providing infectious matureC. prunito their “migration basins”, which differ in their haplotypic composition. We argue that such multiscale studies would be very useful for other pathosystems.
PRC2 bridges non-adjacent nucleosomes to establish heterochromatin
Authors: Leicher Rachel , Ge Eva J. , Lin Xingcheng , Reynolds Matthew J. , Walz Thomas , Zhang Bin , Muir Tom W. , Liu Shixin 
Published: October 2019

ABSTRACTPolycomb repressive complex 2 (PRC2) maintains transcriptionally silent heterochromatin by installing and spreading repressive histone methylation marks along nucleosome arrays. Despite extensive research, the mechanism by which PRC2 engages with chromatin remains incompletely understood. Here we employ single-molecule force spectroscopy and molecular dynamics simulations to dissect the interactions of PRC2 with polynucleosome substrates. Our results reveal an unexpectedly diverse repertoire of PRC2 binding configurations on chromatin. Besides interacting with bare DNA, mononucleosomes, and neighboring nucleosome pairs, PRC2 is also found to bridge non-adjacent nucleosomes, an activity associated with chromatin compaction. Furthermore, the distribution and stability of these PRC2–chromatin interaction modes are differentially modulated by accessory PRC2 cofactors, oncogenic histone mutations, and the methylation state of chromatin. Overall, this work provides a paradigm for understanding the physical basis of epigenetic maintenance mediated by Polycomb group proteins.
Noise propagation shapes condition-dependent gene expression noise inEscherichia coli
Authors: Urchueguía Arantxa , Galbusera Luca , Bellement Gwendoline , Julou Thomas , Nimwegen Erik van 
Published: October 2019

AbstractAlthough it is well appreciated that gene expression is inherently noisy and that transcriptional noise is encoded in a promoter’s sequence, little is known about the variation in transcriptional noise across growth conditions. Using flow cytometry we here quantify transcriptional noise inE. coligenome-wide across 8 growth conditions, and find that noise and gene regulation are intimately coupled. Apart from a growth-rate dependent lower bound on noise, we find that individual promoters show highly condition-dependent noise and that condition-dependent expression noise is shaped by noise propagation from regulators to their targets. A simple model of noise propagation identifies TFs that most contribute to both condition-specific and condition-independent noise propagation. The overall correlation structure of sequence and expression properties ofE. coligenes uncovers that genes are organized along two principal axes, with the first axis sorting genes by their mean expression and evolutionary rate of their coding regions, and the second axis sorting genes by their expression noise, the number of regulatory inputs in their promoter, and their expression plasticity.
Spans attributed to short-term memory are explained by sensitivity to long-term statistics in both musicians and individuals with dyslexia
Authors: Kimel Eva , Weiss Atalia Hai , Jakoby Hilla , Daikhin Luba , Ahissar Merav 
Published: October 2019

AbstractReduced short-term memory (STM) of individuals with dyslexia (IDDs) and enhanced STM of musicians are well documented, yet their causes are disputed. We hypothesized that their STMs reflect their sensitivities to accumulative long-term stimuli statistics. Indeed, when performing an STM task, IDDs had reduced benefit from syllable frequency, whereas musicians manifested an opposite effect, compared to controls. Interestingly, benefit from sequence-repetition did not significantly differ between groups, suggesting that it relies on different mechanisms. To test the generality of this separation across populations, we recruited a group of good-readers, whose native language contains a smaller fraction of the high-frequency syllables. Their span for these “high-frequency” syllables was small, yet their benefit from sequence-repetition was adequate. These experiments indicate that sensitivity to long-term stimuli distribution, and not to sequential repetition, is reduced in IDDs and enhanced in musicians, and this accounts for differences in their STM performance.
From ridge tops to ravines: landscape drivers of chimpanzee ranging patterns
Authors: Green Samantha J. , Boruff Bryan J. , Grueter Cyril C. 
Published: October 2019

AbstractRecent improvements in tracking technologies have resulted in a growing number of fine-scale animal movement studies in a variety of fields from wildlife management to animal cognition. Most studies assume that an animal’s “optimal” foraging route is linear, ignoring the role the energy landscape can play in influencing movement efficiency. Our objective was to investigate whether landscape features that affect movement costs; topographic variation, and super and substrate, influence the movement of chimpanzees (Pan troglodytes) in a rugged, montane environment. We tested for route re-use and preferential use of human-made trails and ridge tops using 14 months of focal follow data from 14 individuals and maps of established chimpanzee trails. Chimpanzees travelled on human-made trails significantly more than expected and showed weak preference for use of ridge tops for travel. Line density analysis demonstrated route re-use in chimpanzees and uncovered a network of high-use routes across their range. To our knowledge, this is the first study to empirically demonstrate route re-use and preferential use of human-made trails for travel by chimpanzees. We discuss the energetic and cognitive benefits of trail use and the implications for chimpanzee sociality. By applying the latest GIS analytical techniques to fine-scale movement data, this study demonstrates the importance of incorporating landscape features in predictive animal movement models.
Non-Canonical Binding of a Small Molecule to Sortilin Alters Cellular Trafficking of ApoB and PCSK9 in Liver Derived Cells
Authors: Sparks Robert P. , Arango Andres S. , Aboff Zachary L. , Jenkins Jermaine L. , Guida Wayne C. , Tajkhorshid Emad , Sparks Charles E. , Sparks Janet D. , Fratti Rutilio A. 
Published: October 2019

ABSTRACTSortilin regulates hepatic exocytosis and endocytosis of ApoB containing lipoproteins (ApoB-Lp) and mediates the secretion of the subtilase PCSK9. To elucidate connections between these pathways, we previously identified a small molecule (cpd984) that binds to a non-canonical site on Sortilin. In hepatic cells cpd984 augments ApoB-Lp secretion, increases cellular PCSK9 levels, and reduces LDLR expression indicative of reduced secretion of PCSK9. We have shown that insulin-induced ApoB-Lp degradation occurs through Vps34-dependent autophagy. Here we show that the specific Vps34 inhibitor PIK-III enhances ApoB-100 secretion, reducing cellular levels of PCSK9 and Sortilin resulting in reduced LDLR expression, which implicates a role for autophagy in PCSK9 secretion. Results suggest that Sortilin is central to both PCSK9 and ApoB-100 secretion. Finally, we found that cpd984 in yeast blocks CPY secretion while increasing vacuolar homotypic fusion in a Vps10-dependent manner, indicating an evolutionarily conserved mechanism required for lysosomal protease trafficking.
A reciprocal inhibition model of alternations between non-dissociative and dissociative states in patients with PTSD
Authors: Chiba Toshinori , Ide Kentaro , Boku Shuken , Taylor Jessica E. , Toda Hiroyuki , Kanazawa Tetsufumi , Kato Sumie , Horiuchi Yuka , Hishimoto Akitoyo , Maruyama Toru , Yamamoto Taisuke , Shirakawa Miyako , Sora Ichiro , Kawato Mitsuo , Koizumi Ai 
Published: October 2019

ABSTRACTObjectiveTraumatic life-events can leave individuals with contrasting posttraumatic stress disorder (PTSD) symptoms, including re-experiencing and avoidance. Notably, patients with PTSD are known to periodically switch between two opposing attentional biases; namely, toward threat and away from threat. We hypothesized that reciprocal inhibition between the amygdala and ventromedial prefrontal cortex (vmPFC) may induce alternations between these attentional biases, which in turn may contribute to the re-experiencing and avoidance symptoms, respectively.MethodsTo test this reciprocal inhibition model, we performed an experiment to measure the attentional biases of patients with PTSD. We examined the differential relationships between PTSD symptom clusters (re-experiencing/avoidance) and attentional biases (toward/away from threat). Additionally, we performed a meta-regression analysis to examine the role of amygdala reactivity in the imbalance between re-experiencing and avoidance symptoms.ResultsWe found that attentional bias toward threat was selectively associated with re-experiencing symptoms whereas attentional bias away from threat was selectively associated with avoidance symptoms. Meta-regression analysis based on twelve participant populations (total N = 316) revealed that left amygdala activity was positively correlated with the severity of re-experiencing symptoms relative to avoidance symptoms.ConclusionsOur findings support the hypothesis that reciprocal inhibition of common neural circuits may underlie the switch between attentional biases toward and away from threat as well as that between re-experiencing and avoidance symptoms. Re-experiencing and avoidance/emotional numbing are the core symptoms used to distinguish between the non-dissociative and dissociative PTSD subtypes. The reciprocal inhibition mechanism may help elucidate the mechanisms underlying those PTSD subtypes.
Default mode network anatomy and function is linked to pediatric concussion recovery
Authors: Iyer Kartik K. , Zalesky Andrew , Barlow Karen M. , Cocchi Luca 
Published: October 2019

ABSTRACTObjectiveTo determine whether anatomical and functional brain features relate to key persistent post-concussion symptoms (PPCS) in children recovering from mild traumatic brain injuries (mTBI), and whether such brain indices can predict individual recovery from PPCS.Methods110 children with mixed recovery following mTBI were seen at the concussion clinic at Neurology department Alberta Children’s Hospital. The primary outcome was the Post-Concussion Symptom Inventory (PCSI, parent proxy). Sleep disturbance scores (PCSI sub-domain) and the Neurocognition Index (CNS Vital Signs) were also measured longitudinally. PPCS was assessed at 4 weeks post-injury and 8-10 weeks post-injury. Grey matter volumes were assessed using magnetic resonance imaging (MRI) and voxel-based morphometry. Functional connectivity was estimated using resting-state MRI. Two complementary machine learning methods were used to assess if the combination of grey matter and functional connectivity indices carried meaningful prognostic information.ResultsHigher scores on a composite index of sleep disturbance, including fatigue, were associated with converging decreases in grey matter volume and local functional connectivity in two key nodes of the default mode network: the posterior cingulate cortex and the medial prefrontal cortex. Sleep-related disturbances also significantly correlated with reductions in functional connectivity between these brain regions. The combination of structural and functional brain indices associated to individual variations in the default mode network accurately predicted clinical outcomes at follow-up (area under the curve = 0.86).InterpretationThese results highlight that the function-structure profile of core default mode regions underpins sleep-related problems following mTBI and carries meaningful prognostic information for pediatric concussion recovery.
A detailed graphical and computational model of the mammalian renal circadian clock
Authors: Ivy Jessica R. , Shih Barbara , Hogenesch John B. , Mullins John J. , Freeman Tom C. 
Published: October 2019

AbstractHere we describe the construction of a detailed graphical and computational model of the mammalian circadian clock. We use it to simulate the clock activity within the kidney, where it plays a pivotal role in regulating blood pressure. First, we assembled a network-based process diagram, which includes all known components of the clock and the interactions between them. Parameterisation of the model for Petri net-based simulation experiments used mRNA levels in the kidney to define initial conditions. With empirical testing, model parameterisation was further refined such that the simulated activity of core genes closely matched their measured activity. Furthermore, virtual knockout experiments performed on the model were shown to reflect experimental gene knockout data. It also identified points at which canonical clock genes may integrate with downstream genes likely to affect blood pressure and other aspects of kidney function. We believe that the model provides new insights into the complexity and function of this most central of physiological pathways and provides a valuable resource for the research community.
Structural and Dynamic Insights Into α-Synuclein Dimer Conformations
Authors: Zamel Joanna , Chen Jiaxing , Zaer Sofia , Harris Paul David , Drori Paz , Lebendiker Mario , Kalisman Nir , Dokholyan Nikolay V. , Lerner Eitan 
Published: October 2019

AbstractParkinson’s disease is associated with the aggregation of the protein α-synuclein. While α-synuclein can exist in multiple oligomeric states, the dimer has been a subject of extensive debates. Here, using an array of biophysical approaches, we demonstrate that α-synucleinin vitroexhibits primarily a monomer-dimer equilibrium in nanomolar concentrations and up to a few micromolars. We then use spatial information from hetero-isotopic cross-linking mass spectrometry experiments as restrains in discrete molecular dynamics simulations to obtain the ensemble structure of dimeric species. Out of eight structural sub-populations of dimers, we identify one that is compact, stable, abundant, and exhibits partially exposed β-sheet structures. This compact dimer is the only one where the hydroxyls of tyrosine 39 are in proximity that may promote dityrosine covalent linkage upon hydroxyl radicalization, which is implicated in α-synuclein amyloid fibrils. We propose that this α-synuclein dimer features etiological relevance to Parkinson’s disease.
CDR3 binding chemistry controls TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC
Authors: Murray Joseph S. 
Published: October 2019

AbstractThe mechanism which adapts the T-cell antigen receptor (TCR) within a given major histocompatibility complex (MHC/HLA) genotype is essential for protection against pathogens. Historically attributed to relative affinity, genetically vast TCRs are surprisingly focused towards a micromolar affinity for their respective peptide (p) plus MHC (pMHC) ligands. Thus, the somatic diversity of the TCR with respect to MHC-restriction, and (ultimately) to pathogens, remains enigmatic. Here, we derive a triple integral solution (from fixed geometry) for any given V domain in TCR bound to pMHC. Solved complexes involving HLA-DR and HLA-DQ, where genetic linkage to the TCR is most profound, were examined in detail. Certain V domains displayed rare geometry within this panel—specifying a restricted rotational probability/volumetric density (dV). Remarkably, hydrogen (H) bond charge-relays distinguished these structures from the others; suggesting that CDR3 binding chemistry dictates CDR2 contacts on the opposite MHC-II alpha helix. Together, these data suggest that TCR recapitulate dV and specialise target pMHC recognition.
Patients with different cancer types are stratified by CBC data
Authors: Sadovsky Michael G. , Feller Alena A. , Martynova Elena A. , Chernyaev Denis V. , Semenov Edward V. , Slepov Eugene V. , Zukov Ruslan A. 
Published: October 2019

AbstractSearching for informative indices indicating cancer type and cause of the disease is of great importance. Here we tried to identify those indices from the data of complete blood analysis, only. We studied the inhomogeneity in the mutual distribution of a number of oncology patients with various types of tumors in the space of qualitative data provided by the complete blood count. The patients with oncology in hematology system were excluded. Ultimate goal is to reveal the relation between such inhomogeneity issues and the cause of a disease. We used the database on complete blood count comprising oncology patients with various causes of tumor development. The analysis has been carried out both by linear (K-means) and non-linear (elastic map technique) methods. No linear clustering has been found. On the contrary, elastic map technique yields stable clustering identifying not less than three clusters, in the set of patients. No relation of those clusters to sex or age of patients has been found. Four indices (namely, BAS, EOS, WBC and IG) exhibit no relation to the cluster structure, while all others do it. Thus, the patients are stratified according to their respond on the stress caused by cancer tumor. The data on complete blood count may be used for preliminary diagnostics of a tumor and its cause, for oncology patients. This type of analysis is cheap, standard and available at any medical organization.
Changes in Extracellular Matrix Gene and Protein Expressions in Human Trabecular Meshwork Cells in Response to Mechanical Fluid Flow Stimulation
Authors: Yoshida Koichi , Kawai Motofumi , Utsunomiya Tsugiaki , Ishibazawa Akihiro , Song Young-Seok , Udo Mariana Sayuri B. , Tasaki Yoshikazu , Yoshida Akitoshi 
Published: October 2019

AbstractPurposeTo investigate the changes in extracellular matrix (ECM) gene and protein expressions in human trabecular meshwork (HTM) cells in response to mechanical fluid flow stimulation.MethodsHTM cells were cultured on a glass plate and exposed to shear stress (0, 0.2, and 1.0 dyne/cm2) for 12 hours. Changes in gene expressions were evaluated using microarray analysis. The representative genes related to ECM metabolism underwent real-time reverse-transcriptase polymerase chain reaction. Fibronectin (FN) and collagen (COL) IV levels in the supernatant were evaluated using immunoassays. Rho-associated coiled-coil-containing protein kinase (ROCK) activity also was investigated.ResultsAfter stimulation, transforming growth factor β2 mRNA levels were significantly (p < 0.01) lower than that of the static control (0 dyne/cm2 for 12 hours). Matrix metalloproteinase 2 mRNA levels were significantly (p < 0.05) higher than the static control. COL type 1 alpha 2 mRNA, COL type 4 alpha 2 mRNA, and COL type 6 alpha 1 mRNA levels were significantly (p < 0.05, < 0.01, and < 0.05, respectively) higher than the static control. The mean ± standard deviation FN levels (ng/mL) in the supernatant after stimulation (0, 0.2, 1.0 dyne/cm2) were 193.7 ± 7.6, 51.5 ± 21.8, and 34.9 ± 23.6, respectively (p < 0.01). The FN and COL IV levels and ROCK activity were significantly (p < 0.01 and < 0.05, respectively) lower than the static control.ConclusionsChanges in gene and protein expressions related to ECM metabolism occurred in HTM cells after stimulation. Specifically, the suppression of FN and COL IV production might explain the importance of mechanical fluid flow stimulation on maintenance of the normal aqueous humor outflow.