bluuebunny/crossref_metadata_2025_split huggingface dataset:
The developmental changes in intrinsic and synaptic properties of prefrontal neurons enhance local network activity from the second to the third postnatal week in mice
Authors: Kalemaki Katerina , Velli Angeliki , Christodoulou Ourania , Denaxa Myrto , Karagogeos Domna , Sidiropoulou Kyriaki 
Published: January 2020

AbstractThe prefrontal cortex (PFC) is characterized by protracted maturation. The cellular mechanisms controlling the early development of prefrontal circuits are still largely unknown. Our study delineates the developmental cellular processes in the mouse medial PFC (mPFC) during the second and third postnatal weeks and characterizes their contribution to the changes in network activity. We show that spontaneous inhibitory postsynaptic currents (sIPSC) are increased while spontaneous excitatory postsynaptic currents (sEPSC) are reduced from the second to the third postnatal week. Drug application suggested that the increased sEPSC frequency in mPFC at P10 is due to depolarizing GABAAreceptor (GABAAR) function. To further validate this, perforated patch-clamp recordings were obtained and the expression levels of K-Cl co-transporter 2 (KCC2) protein were examined. The reversal potential of IPSCs in response to current stimulation was significantly more depolarized at P10 compared to P20 while KCC2 expression is decreased. Moreover, the number of parvalbumin-expressing GABAergic interneurons increase from P10 to P20 in the mPFC and their intrinsic electrophysiological properties significantly mature. Using computational modeling, we show that the developmental changes in synaptic and intrinsic properties of mPFC neurons contribute to the enhanced network activity in the juvenile compared to neonatal mPFC.
Identification of PIM1 substrates reveals a role for NDRG1 in prostate cancer cellular migration and invasion
Authors: Ledet Russell J. , Ruff Sophie , Wang Yu , Nayak Shruti , Schneider Jeffrey A. , Ueberheide Beatrix , Logan Susan K. , Garabedian Michael J. 
Published: January 2020

ABSTRACTPIM1 is an oncogenic serine/threonine kinase that promotes and maintains prostate tumorigenesis. To more fully understand the mechanism by which PIM1 promotes oncogenesis, we performed a chemical genetic screen to identify direct PIM1 substrates in prostate cancer cells. The PIM1 substrates we identified were involved in a variety of oncogenic processes, and included N-Myc Downstream-Regulated Gene 1 (NDRG1), which has reported roles in the suppression of cancer cell invasion and metastasis. NDRG1 is phosphorylated by PIM1 at serine 330 (pS330), and the level of NDRG1 pS330 is associated with high grade compared to low grade prostate tumors. While NDRG1 pS330 is largely cytoplasmic, total NDRG1 is both cytoplasmic and nuclear. Mechanistically, PIM1 phosphorylation of NDRG1 decreases its stability, reducing its interaction with AR, and thereby lowering expression of AR target genes. PIM1-dependent NDRG1 phosphorylation also reduces NDRG1’s ability to suppress prostate cancer cell migration and invasion. Our study identifies a novel set of PIM1 substrates in prostate cancer cells using a direct, unbiased chemical genetic screen. It also provides key insights into the mechanisms by which PIM1-mediated phosphorylation of NDRG1 impairs its function, resulting in enhanced cell migration and invasion.
Shared and specific signatures of locomotor ataxia in mutant mice
Authors: Machado Ana S. , Marques Hugo G. , Duarte Diogo F. , Darmohray Dana M. , Carey Megan R. 
Published: January 2020

AbstractSeveral spontaneous mouse mutants with deficits in motor coordination and associated cerebellar neuropathology have been described. Intriguingly, both visible gait alterations and neuroanatomical abnormalities throughout the brain differ across mutants. We previously used the LocoMouse system to quantify specific deficits in locomotor coordination in mildly ataxicPurkinje cell degenerationmice (pcd;Machado et al., 2015). Here, we analyze the locomotor behavior of severely ataxicreelermutants and compare and contrast it with that ofpcd. Despite clearly visible gait differences, direct comparison of locomotor kinematics and linear discriminant analysis reveal a surprisingly similar pattern of impairments in multijoint, interlimb, and whole-body coordination in the two mutants. These findings capture both shared and specific signatures of gait ataxia and provide a quantitative foundation for mapping specific locomotor impairments onto distinct neuropathologies in mice.
Synchrony and perturbation transmission in trophic metacommunities
Authors: Quévreux Pierre , Barbier Matthieu , Loreau Michel 
Published: January 2020

AbstractIn a world where natural habitats are ever more fragmented, the dynamics of meta-communities is essential to properly understand species responses to perturbations. If species’ populations fluctuate asynchronously, the risk of their simultaneous extinction is low, thus reducing the species’ regional extinction risk. We propose a metacommunity model consisting of two food chains connected by dispersal to study the transmission of small perturbations affecting populations in the vicinity of an equilibrium. We show that perturbing a species in one patch can lead to asynchrony between patches if the perturbed species is not the most affected by dispersal. Dispersal affects rare species the most, thus making biomass distribution critical to understand the response of trophic metacommunities to perturbations. We further partition the effect of each perturbation on species synchrony when several independent perturbations are applied. Our approach allows disentangling and predicting the responses of simple trophic metacommunities to perturbations, thus providing a theoretical foundation for future studies considering more complex spatial ecological systems.
Environmental heterogeneity ruling the action of ecological processes over the bacterial metacommunity assembly
Authors: Huber Paula , Metz Sebastian , Unrein Fernando , Mayora Gisela , Sarmento Hugo , Devercelli Melina 
Published: January 2020

ABSTRACTDetermining which processes take place in the spatial distribution of bacterioplankton metacommunities has been a central goal of microbial ecology. In freshwater ecosystems, selection has been spotted as the main driver shaping bacterial community. However, its relative importance compared with others processes (dispersal, drift, diversification) may depend on spatial heterogeneity and dispersal rates within a metacommunity. Still, a decrease in the role of selection is expected with increasing dispersal homogenization. Here, we investigate the main ecological processes modulating the bacterial assembly in contrasting scenarios of environmental heterogeneity. We carried out a spatiotemporal survey in the floodplain system of Paraná River. The bacterioplankton metacommunity was studied by a step-forward analysis combining different statistical inferences based on the phylogenetic and taxa turnover as well as co-occurrence networks. We found that selection was the main process even at both extremes of environmental heterogeneity and homogeneity, challenging the general view that the strength of selection is weakened due to dispersal homogenization. The ecological processes acting on the community also determined the complexity and randomness of bacterial networks. The heterogeneous selection promoted greater network complexity increasing the β-diversity, and bacterial associations were more random with the increasing influence of stochasticity. Finally, the spatiotemporal heterogeneity was an important factor determining the number and identity of keystone taxa in the system. Integrating all these empirical evidences we propose a new conceptual model that elucidates how the environmental heterogeneity guides the action of ecological processes shaping the bacterial metacommunity.
Automated Workflow For Peptide-level Quantitation From DIA/ SWATH-MS Data
Authors: Gupta Shubham , Röst Hannes 
Published: January 2020

AbstractData Independent Acquisition (DIA) is a powerful method to acquire spectra from all ionized precursors of a sample. Considering the complexity of the highly multiplexed spectral data, sophisticated workflows have been developed to obtain peptides quantification. Here we describe an open-source and easy-to-use workflow to obtain a quantitative matrix from multiple DIA runs. This workflow requires as prior information an “assay library”, which contains the MS coordinates of peptides. It consists of OpenSWATH, pyProphet and DIAlignR software. For the ease of installation and to isolate operating system related dependency, docker-based containerization is utilized in this workflow.
Genome-wide scale analyses identify novel BMI genotype-environment interactions using a conditional false discovery rate
Authors: Moore R. , Georgatou-Politou L. , Liley J. , Stegle O. , Barroso I. 
Published: January 2020

AbstractGenotype-environment interaction (G×E) studies typically focus on variants with previously known marginal associations. While such two-step filtering greatly reduces the multiple testing burden, it can miss loci with pronounced G×E effects, which tend to have weaker marginal associations. To test for G×E effects on a genome-wide scale whilst leveraging information from marginal associations in a flexible manner, we combine the conditional false discovery rate with interaction test results obtained from StructLMM. After validating our approach, we applied this strategy to UK Biobank (UKBB) data to probe for G×E effects on BMI. Using 126,077 UKBB individuals for discovery, we identified known (FTO, MC4R, SEC16B) and novel G×E signals, many of which replicated (FAM150B/ALKAL2,TMEM18, EFR3B, ZNF596-FAM87A, LIN7C-BDNF, FAIM2, UNC79, LAT)in an independent subset of UKBB (n=126,076). Finally, when analysing the full UKBB cohort, we identified 140 candidate loci with G×E effects, highlighting the advantages of our approach.
Fluorescence Labeling of Circulating Tumor Cells with Folate Receptor Targeted Molecular Probes for DiffuseIn VivoFlow Cytometry
Authors: Patil Roshani , Srinivasarao Madduri , Amiji Mansoor , Low Philip S. , Niedre Mark 
Published: January 2020

AbstractPurposeWe recently developed a new instrument called ‘diffusein vivoflow cytometry’ (DiFC) for enumeration of rare fluorescently-labeled circulating tumor cells (CTCs) in small animals without drawing blood samples. Until now, we have used cell lines that express fluorescent proteins, or were pre-labeled with a fluorescent dyeex-vivo. In this work, we investigated the use of two folate receptor (FR)-targeted fluorescence molecular probes forin vivolabeling of FR+ CTCs for DiFC.MethodsWe used EC-17 and Cy5-PEG-FR fluorescent probes. We studied the affinity of these probes for L1210A and KB cancer cells, both of which over-express FR. We tested the labeling specificity in cells in culturein vitro, in whole blood, and in micein vivo. We also studied detectability of labeled cells with DiFC.ResultsBoth EC-17 and Cy5-PEG-FR probes had high affinity for FR+ CTCs in cell culturein vitro. However, only EC-17 had sufficient specificity for CTCs in whole blood. EC-17 labeled CTCs were also readily detectable in circulation in mice with DiFC.ConclusionsThis work demonstrates the feasibility of labeling CTCs for DiFC with a cell surface receptor targeted probe, greatly expanding the utility of the method for pre-clinical animal models. Because DiFC uses diffuse light, this method could be also used to enumerate CTCs in larger animal models and potentially even in humans.
Automatic Three-Dimensional Reconstruction of Fascicles in Peripheral Nerves from Histological Images
Authors: Tovbis Daniel , Agur Anne , Mogk Jeremy P.M. , Zariffa José 
Published: January 2020

AbstractComputational studies can be used to support the development of peripheral nerve interfaces, but currently use simplified models of nerve anatomy, which may impact the applicability of simulation results. To better quantify and model neural anatomy across the population, we have developed an algorithm to automatically reconstruct accurate peripheral nerve models from histological cross-sections. We acquired serial median nerve cross-sections from human cadaveric samples, staining one set with hematoxylin and eosin (H&E) and the other using immunohistochemistry (IHC) with anti-neurofilament antibody. We developed a four-step processing pipeline involving registration, fascicle detection, segmentation, and reconstruction. We compared the output of each step to manual ground truths, and additionally compared the final models to commonly used extrusions, via intersection-over-union (IOU). Fascicle detection and segmentation required the use of a neural network and active contours in H&E-stained images, but only simple image processing methods for IHC-stained images. Reconstruction achieved an IOU of 0.42±0.07 for H&E and 0.37±0.16 for IHC images, with errors partially attributable to global misalignment at the registration step, rather than poor reconstruction. This work provides a quantitative baseline for fully automatic construction of peripheral nerve models. Our models provided fascicular shape and branching information that would be lost via extrusion.
Lineage reversion drives WNT independence in intestinal cancer
Authors: Han Teng , Goswami Sukanya , Hu Yang , Tang Fanying , Zafra Maria Paz , Murphy Charles , Cao Zhen , Poirier John T , Khurana Ekta , Elemento Olivier , Hechtman Jaclyn F. , Yaeger Rona , Dow Lukas E. 
Published: January 2020

ABSTRACTThe WNT pathway is a fundamental regulator of intestinal homeostasis and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer (CRC). To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that while WNT suppression blocks tumor growth in most organoid and in vivo CRC models, the accumulation of CRC-associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of p53 and SMAD4, transient TGFβ exposure drives YAP/ TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work delineates genetic and microenvironmental factors that drive WNT inhibitor resistance, identifies a new mechanism for WNT-independent CRC growth and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.
Cerebellar and Prefrontal-Cortical Engagement During Higher-Order Rule Learning in Older Adulthood
Authors: Jackson T. Bryan , Maldonado Ted , Eakin Sydney M. , Orr Joseph M. , Bernard Jessica A. 
Published: January 2020

ABSTRACTTo date most aging research has focused on cortical systems and networks, ignoring the cerebellum which has been implicated in both cognitive and motor function. Critically, older adults (OA) show marked differences in cerebellar volume and functional networks, suggesting it may play a key role in the behavioral differences observed in advanced age. OA may be less able to recruit cerebellar resources due to network and structural differences. Here, 26 young adults (YA) and 25 OA performed a second-order learning task, known to activate the cerebellum in the fMRI environment. Behavioral results indicated that YA performed significantly better and learned more quickly compared to OA. Functional imaging detailed robust parietal and cerebellar activity during learning (compared to control) blocks within each group. OA showed increased activity (relative to YA) in the left inferior parietal lobe in response to instruction cues during learning (compared to control); whereas, YA showed increased activity (relative to OA) in the left anterior cingulate to feedback cues during learning, potentially explaining age-related performance differences. Visual interpretation of effect size maps showed more bilateral posterior cerebellar activation in OA compared to YA during learning blocks, but early learning showed widespread cerebellar activation in YA compared to OA. There were qualitatively large age-related differences in cerebellar recruitment in terms of effect sizes, yet no statistical difference. These findings serve to further elucidate age-related differences and similarities in cerebellar and cortical brain function and implicate the cerebellum and its networks as regions of interest in aging research.
Breastmilk-promoted bifidobacteria produce aromatic amino acids in the infant gut
Authors: Laursen Martin F. , Sakanaka Mikiyasu , von Burg Nicole , Mörbe Urs , Andersen Daniel , Moll Janne Marie , Pekmez Ceyda T. , Rivollier Aymeric , Michaelsen Kim F. , Mølgaard Christian , Lind Mads Vendelbo , Dragsted Lars O. , Katayama Takane , Frandsen Henrik L. , Vinggaard Anne Marie , Bahl Martin I. , Brix Susanne , Agace William , Licht Tine R. , Roager Henrik M. 
Published: January 2020

ABSTRACTBreastfeeding profoundly shapes the infant gut microbiota, which is critical for early life immune development. However, few breastmilk-dependent microbial metabolites mediating host-microbiota interactions are currently known. We here demonstrate that breastmilk-promotedBifidobacteriumspecies convert aromatic amino acids (tryptophan, phenylalanine and tyrosine) into their respective aromatic lactic acids (indolelactate, phenyllactate and 4-hydroxyphenyllactate) via a previously unrecognised aromatic lactate dehydrogenase. By longitudinal profiling of the gut microbiota composition and metabolome of stool samples of infants obtained from birth until 6 months of age, we show that stool concentrations of aromatic lactic acids are determined by the abundance of human milk oligosaccharide degradingBifidobacteriumspecies containing the aromatic lactate dehydrogenase. We demonstrate that stool concentrations ofBifidobacterium-derived indolelactate, the most abundant aromatic lactic acidin vivo, are associated with the capacity of infant stool samples to activate the aryl hydrocarbon receptor (AhR), a receptor important for controlling intestinal homeostasis and immune responses. Finally, we show that indolelactate modulatesex vivoimmune responses of human CD4+ T-cells and monocytes in a dose-dependent manner by acting as an agonist of both, the AhR and hydroxycarboxylic acid receptor 3 (HCAR3). Our findings reveal that breastmilk-promotedBifidobacteriumproduce aromatic lactic acids in the gut of infants and suggest that these microbial metabolites may impact immune function in early life.
Tagsteady: a metabarcoding library preparation protocol to avoid false assignment of sequences to samples
Authors: Carøe Christian , Bohmann Kristine 
Published: January 2020

AbstractMetabarcoding of environmental DNA (eDNA) and DNA extracted from bulk specimen samples is a powerful tool in studies of biodiversity, diet and ecological interactions as its inherent labelling of amplicons allows sequencing of taxonomically informative genetic markers from many samples in parallel. However, the occurrence of so-called ‘tag-jumps’ can cause incorrect assignment of sequences to samples and artificially inflate diversity. Two steps during library preparation of pools of 5’ nucleotide-tagged amplicons have been suggested to cause tag-jumps; i) T4 DNA polymerase blunt-ending in the end-repair step and ii) post-ligation PCR amplification of amplicon libraries. The discovery of tag-jumps has led to recommendations to only carry out metabarcoding PCR amplifications with primers carrying twin-tags to ensure that tag-jumps cannot result in false assignments of sequences to samples. As this increases both cost and workload, a metabarcoding library preparation protocol which circumvents the two steps that causes tag-jumps is needed. Here, we demonstrate Tagsteady, a metabarcoding Illumina library preparation protocol for pools of nucleotide-tagged amplicons that enables efficient and cost-effective generation of metabarcoding data with virtually no tag-jumps. We use pools of twin-tagged amplicons to investigate the effect of T4 DNA polymerase blunt-ending and post-ligation PCR on the occurrence of tag-jumps. We demonstrate that both blunt-ending and post-ligation PCR, alone or together, can result in detrimental amounts of tag-jumps (here, up to ca. 49% of total sequences), while leaving both steps out (the Tagsteady protocol) results in amounts of sequences carrying new combinations of used tags (tag-jumps) comparable to background contamination.
Linguistic input drives brain network configuration during language comprehension
Authors: Quiñones Ileana , Molinaro Nicola , Caballero-Gaudes César , Mancini Simona , Hernández-Cabrera Juan Andrés , Barber Horacio , Carreiras Manuel 
Published: January 2020

AbstractAssessing the synchrony and interplay between distributed neural regions is critical to understanding how language is processed. Here, we investigated possible neuro-functional links between form and meaning during sentence comprehension combining a classical whole-brain approach, which characterizes patterns of brain activation resulting from our experimental manipulation, and a novel multivariate network-based approach, which uses graph-theory measures to unravel the architectural configuration of the language system. Capitalizing on the Spanish gender agreement system, we experimentally manipulated formal and conceptual factors: whether the noun-adjective grammatical gender relationship was congruent or not and whether the noun gender type was semantically informative or strictly formal. Left inferior and middle frontal gyri, as well as left MTG/STG emerged as critical areas for the computation of grammatical relations. We demonstrate how the interface between formal and conceptual features depends on the synergic articulation of brain areas divided in three subnetworks that extend beyond the classical left-lateralized perisylvian language circuit. Critically, we isolated a subregion of the left angular gyrus showing a significant interaction between gender congruency and gender type. The functional interplay between the angular gyrus and left perisylvian language-specific circuit proves crucial for constructing coherent and meaningful messages. Importantly, using graph theory we show that this complex system is functionally malleable: the role each node plays within the network changes depending on the available linguistic cues.Significance StatementNeural networks can be described as graphs comprising distributed and interconnected nodes. These nodes share functional properties but also differ in terms of functional specialization and the number of interconnections mediating the efficient transfer of information. Previous work has shown functional connectivity differences based on graph-theory properties between typical and atypical samples. However, here we have used concepts from graph theory to characterize connectivity during language processing using task-related fMRI. This approach allowed us to demonstrate how linguistic input drives brain network configuration during language comprehension. This is the first evidence of functional flexibility in language networks: the communicative capacity of each hub changes depending on whether the linguistic input grants access to meaning or is purely formal.