bluuebunny/crossref_metadata_2025_split huggingface dataset:
In VivoMonitoring of Rare Circulating Tumor Cell and Cluster Dissemination in a Multiple Myeloma Xenograft Model
Authors: Patil Roshani , Tan Xuefei , Bartosik Peter , Detappe Alexandre , Runnels Judith , Ghobrial Irene , Lin Charles P. , Niedre Mark 
Published: January 2019

AbstractWe recently developed ‘Diffusein vivoFlow Cytometry’ (DiFC), a new pre-clinical research tool for enumerating extremely rare fluorescently-labeled circulating cells directlyin vivo. In this paper, we developed a green fluorescent protein (GFP) compatible version of DiFC, and used it to non-invasively monitor the circulating tumor cell (CTC) burden over time in a multiple myeloma disseminated xenograft model. We show that DiFC allowed counting of CTCs at estimated concentrations below 1 cell per mL in peripheral blood with a negligible false alarm rate. DiFC also revealed the presence of CTC clusters in circulation to our knowledge for the first time in this model, and allowed us to calculate their size, kinetics, and frequency of shedding. We anticipate that the unique capabilities of DiFC will have many applications in the study of hematogenous metastasis, and as a powerful complementary methodology to liquid biopsy assays.
Delta/Notch signaling controls neuroepithelial morphogenesis in the zebrafish spinal cord
Authors: Sharma Priyanka , Saraswathy Vishnu Muraleedharan , Xiang Li , Fürthauer Maximilian 
Published: January 2019

ABSTRACTThe morphogenesis of the nervous system requires coordinating the specification and differentiation of neural precursor cells, the establishment of neuroepithelial tissue architecture and the execution of specific cellular movements. How these aspects of neural development are linked is incompletely understood. Here we inactivate a major regulator of embryonic neurogenesis - the Delta/Notch pathway - and analyze the effect on zebrafish central nervous system morphogenesis. While some parts of the nervous system can establish neuroepithelial tissue architecture independently of Notch, Notch signaling is essential for spinal cord morphogenesis. In this tissue, Notch signaling is required to repress neuronal differentiation and promote neuroepithelial apico-basal polarity. Concomitant with a loss of their neuroepithelial properties, Notch signaling deficient cells also alter their morphogenetic behavior. In the wild-type zebrafish neural tube, cells divide at the organ midline to contribute one daughter cell to each organ half. Notch deficient animals fail to display this behavior and therefore form a misproportioned spinal cord. Taken together, our findings show that Notch signaling governs not only the cellular composition but also the morphogenetic shaping of the zebrafish spinal cord.
Hunter-gatherer genomes reveal diverse demographic trajectories following the rise of farming in East Africa
Authors: Gopalan Shyamalika , Berl Richard E.W. , Belbin Gillian , Gignoux Christopher R. , Feldman Marcus W. , Hewlett Barry S. , Henn Brenna M. 
Published: January 2019

AbstractA major outstanding question in human prehistory is the fate of hunting and gathering populations following the rise of agriculture and pastoralism. Genomic analysis of ancient and contemporary Europeans suggests that autochthonous groups were either absorbed into or replaced by expanding farmer populations. Many of the hunter-gatherer populations persisting today live in Africa, perhaps because agropastoral transitions occurred later on the continent. Here, we present the first genomic data from the Chabu, a relatively isolated and marginalized hunting-and-gathering group from the Southwestern Ethiopian highlands. The Chabu are a distinct genetic population that carry the highest levels of Southwestern Ethiopian ancestry of any extant population studied thus far. This ancestry has been in situ for at least 4,500 years. We show that the Chabu are undergoing a severe population bottleneck which began around 40 generations ago. We also study other Eastern African populations and demonstrate divergent patterns of historical population size change over the past 60 generations between even closely related groups. We argue that these patterns demonstrate that, unlike in Europe, Africans hunter-gatherers responded to agropastoralism with diverse strategies.
HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome
Authors: Asquith Mark , Sternes Peter R. , Costello Mary-Ellen , Karstens Lisa , Diamond Sarah , Martin Tammy M. , Spector Timothy D. , Cao Kim-Anh le , Rosenbaum James T. , Brown Matthew A. 
Published: January 2019

ABSTRACTObjectivesHLA alleles affect susceptibility to more than 100 diseases, but the mechanisms to account for these genotype-disease associations are largely unknown. HLA-alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and faecal microbiome signatures. Whether these changes are cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examine the effect ofHLA-B27andHLA-DRB1RA-risk alleles on the composition of the intestinal microbiome in healthy individuals.Methods568 samples from 6 intestinal sites were collected from 107 otherwise healthy unrelated subjects and stool samples from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S rRNA bacterial marker gene. All patients were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data.ResultsAssociation was observed betweenHLA-B27genotype, and RA-riskHLA-DRB1alleles, and overall microbial composition (P=0.0002 and P=0.00001 respectively). These associations were replicated in the TwinsUK cohort stool samples (P=0.023 and P=0.033 respectively).ConclusionsThis study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects ofHLA-B27and –DRB1on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome, and suggest that therapies targeting the microbiome may be effective in their prevention and/or treatment.
Cell Fate Determining Molecular Switches and Signaling Pathway in Pax7-expressing Somitic Mesoderm
Authors: Fung Cheuk Wang , Zhu Han , Zhou Shao Pu , Wu Zhenguo , Wu Angela R. 
Published: January 2019

AbstractPax7-expressing progenitor cells in the somitic mesoderm differentiate into multiple lineages, such as brown adipose tissue, dorsal dermis, as well as muscle in the dorsal trunk and the diaphragm; however, the key molecular switches that determine and control the process of lineage commitment and cell fate are unknown. To probe the mechanisms behind mesoderm development, Pax7creER/R26-stop-EYFP embryos were tamoxifen-induced at E9.5 to label Pax7+ cells for lineage tracing and collected at later time points for analysis. The YFP-labelled cells which belonged to the Pax7 lineage were enriched by fluorescence-activated cell sorting (FACS) and subject to single-cell RNA profiling. We observed that a subpopulation of cells differentiated into the myogenic lineage, showing Myf5 expression as early as E12.5, whereas the rest of the population was fibroblast-like and appeared to be the early stage of the adipogenic and dermal lineages. Cells at E14.5 had distinct myogenic populations that expressed Myod1 and Myog; we also identified other populations with Ebf2 or Twist2 expression, which could belong to adipogenic or dermal lineages, respectively. Cell surface markers were also found for each specific lineage, providing insights in sorting strategy for lineage-of-interest for further functional evaluation. Adipogenic lineage was successfully sorted with a combination of Pdgfra and Thy1 antibodies. In addition, we found that upregulation of Wnt signaling pathway activity is dynamically regulated in dermal lineage. Finally, transcription factors that could potentially drive, or reprogram cell fate, were identified at different developmental time points.Summary statementInvestigation of Pax7 lineage transcriptomic profile at single-cell level identified multiple cell types, fate commitment time point, surface markers, transcription factors and signaling pathways that determine cell fate.
Deep neural networks for interpreting RNA binding protein target preferences
Authors: Ghanbari Mahsa , Ohler Uwe 
Published: January 2019

AbstractDeep learning has become a powerful paradigm to analyze the binding sites of regulatory factors including RNA-binding proteins (RBPs), owing to its strength to learn complex features from possibly multiple sources of raw data. However, the interpretability of these models, which is crucial to improve our understanding of RBP binding preferences and functions, has not yet been investigated in significant detail. We have designed a multitask and multimodal deep neural network for characterizing in vivo RBP binding preferences. The model incorporates not only the sequence but also the region type of the binding sites as input, which helps the model to boost the prediction performance. To interpret the model, we quantified the contribution of the input features to the predictive score of each RBP. Learning across multiple RBPs at once, we are able to avoid experimental biases and to identify the RNA sequence motifs and transcript context patterns that are the most important for the predictions of each individual RBP. Our findings are consistent with known motifs and binding behaviors of RBPs and can provide new insights about the regulatory functions of RBPs.
Structural basis for functional interactions in dimers of SLC26 transporters
Authors: Chang Yung-Ning , Jaumann Eva A. , Reichel Katrin , Hartmann Julia , Oliver Dominik , Hummer Gerhard , Joseph Benesh , Geertsma Eric R. 
Published: January 2019

AbstractThe SLC26 family of transporters maintains anion equilibria in all kingdoms of life. The family shares a 7 + 7 transmembrane segments inverted repeat architecture with the SLC4 and SLC23 families, but holds a regulatory STAS domain in addition. While the only experimental SLC26 structure is monomeric, SLC26 proteins form structural and functional dimers in the lipid membrane. Here we resolve the structure of an SLC26 dimer embedded in a lipid membrane and characterize its functional relevance by combining PELDOR distance measurements and biochemical studies with MD simulations and spin-label ensemble refinement. Our structural model reveals a unique interface different from the SLC4 and SLC23 families. The functionally relevant STAS domain exerts a stabilizing effect on regions central in this dimer. Characterization of heterodimers indicates that protomers in the dimer functionally interact. The combined structural and functional data define the framework for a mechanistic understanding of functional cooperativity in SLC26 dimers.
Potential influence of school-based lifestyle strategies among Australian Aboriginal and non-Aboriginal children: a cross-sectional comparison of adiposity and weight related behaviours between 2010 and 2015
Authors: Hardy Louise L , MacNiven Rona , Esgin Tuguy , Mihrshahi Seema 
Published: January 2019

AbstractBackgroundIn New South Wales (Australia) there has been substantial long term investment in school-based child obesity prevention programs. Whether these programs have led to population level improvements in children’s adiposity and weight-related behaviours in Aboriginal children, who are at greater risk of poorer health outcomes, is yet to be determined. The purpose of this study was to describe changes in adiposity and weight-related behaviours of Aboriginal and non-Aboriginal children and to examine the equality of changes between the two groups.MethodsRepresentative cross-sectional population surveys conducted in 2010 and 2015 among children age 5-16 years (n=15,613), stratified by Aboriginality. Indicators of weight-related behaviour (diet, physical activity, school travel, screen-time) were measured by questionnaire with parents responding for children age <10 years and self-report by children age >10 years. Objective measurements included height, weight, waist circumference, cardiorespiratory fitness, and fundamental movement skills.ResultsAdiposity prevalences were significantly higher in 2015, than 2010 among non-Aboriginal children only, however adiposity prevalences were consistently higher among Aboriginal than non-Aboriginal children. There were positive changes towards adopting healthier weight-related behaviours in all children between surveys, which were consistently significant among non-Aboriginal, but not Aboriginal, children. The magnitude of changes and the 2015 prevalences in weight-related behaviours were generally similar for Aboriginal and non-Aboriginal children, however positive changes in fruit consumption and locomotor skills were significantly larger among Aboriginal than non-Aboriginal children. The prevalence of being driven to school in 2015 was significantly higher than 2010 for both groups.ConclusionsOverall, there are signs that Aboriginal and non-Aboriginal children are shifting towards healthier weight-related behaviours. However, many unhealthy weight-related behaviours remain highly prevalent. Our findings may have utility for the direction of future health policy and service delivery to Aboriginal and non-Aboriginal children and the development of health promotion programs to build on these improvements in health behaviours.
Inflammation and matrix metalloproteinase 9 (Mmp-9) regulate photoreceptor regeneration in adult zebrafish
Authors: Silva Nicholas J. , Nagashima Mikiko , Li Jingling , Kakuk-Atkins Laura , Ashrafzadeh Milad , Hyde David R. , Hitchcock Peter F. 
Published: January 2019

AbstractBrain injury activates complex inflammatory signals in dying neurons, surviving neurons, and glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the zebrafish retina and determine the cellular expression and function of the inflammatory protease, matrix metalloproteinase 9 (Mmp-9), during this regenerative neurogenesis. Following sterile photoreceptor ablation anti-inflammatory treatment suppresses both the number of injury-induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia, the intrinsic retinal stem cell, and Müller glia-derived photoreceptor progenitors. Deleting mmp-9 results in over production of injury-induced progenitors and regenerated photoreceptors, but over time the absence of Mmp-9 compromises the maturation and survival of the regenerated cones. Anti-inflammatory treatment in mutants rescues the defects in cone maturation and survival. These data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function during photoreceptor regeneration and the requirement of Mmp-9 for the survival of regenerated cones.Significance StatementThe innate immune system is activated by neuronal death, and recent studies demonstrate that in zebrafish neuroinflammation is required for neuronal regeneration. The roles of inflammatory cytokines are being investigated, however, the function of the inflammatory protease, matrix metalloprotease Mmp-9, in neuronal regeneration is unknown. We show herein that in adult zebrafish retinal inflammation governs the proliferative phase of the stem cell-based regeneration of rod and cone photoreceptors and determine the specific roles for Mmp-9 in photoreceptor regeneration. This study provides the first mechanistic insights into the potential role of Mmp-9 and serves to link neuroinflammation, stem cell-based regeneration of photoreceptors and human photoreceptor disease.
A heuristic feature cluster search algorithm for precise functional brain mapping
Authors: Asadi Nima , Wang Yin , Olson Ingrid , Obradovic Zoran 
Published: January 2019

ABSTRACTDetecting the most relevant brain regions for explaining the distinction between cognitive conditions is one of the most sought after objectives in neuroimaging research. A popular approach for achieving this goal is the multivariate pattern analysis (MVPA) which is commonly conducted through the searchlight procedure as well as a number of other approaches. This is due to advantages of such methods which include being intuitive and flexible with regards to size of the search space. However, these approaches suffer from a number of limitations that lead to misidentification of truly informative voxels or clusters of voxels which in turn results in imprecise information maps. The limitations of such procedures mainly stem from several factors such as the fact that the information value of the search spheres are assigned to the voxel at the center of them (in case of searchlight), the requirement for manual tuning of parameters such as searchlight radius and shape and other optimization parameters, overlooking the structure and interactions within the regions, and the drawbacks of using regularization methods in analysis of datasets with characteristics of common fMRI data. In this paper, we propose a fully data-driven maximum relevance minimum redundancy search algorithm for detecting precise information value of voxel-level clusters within brain regions while alleviating the above mentioned limitations. In order to make the algorithm efficient, we propose an implementation based on principles of dynamic programming. We evaluate and compare the proposed algorithm with the searchlight procedure using both real and synthetic datasets.
Signal integration and information transfer in an allosterically regulated network
Authors: Shockley Erin M. , Rouzer Carol A. , Marnett Lawrence J. , Deeds Eric J. , Lopez Carlos F. 
Published: January 2019

ABSTRACTA biological reaction network may serve multiple purposes, processing more than one input and impacting downstream processes via more than one output. These networks operate in a dynamic cellular environment in which the levels of network components may change within cells and across cells. Recent evidence suggests that protein concentration variability could explain cell fate decisions. However, systems with multiple inputs, multiple outputs, and changing input concentrations have not been studied in detail due to their complexity. Here, we take a systems biochemistry approach, combining physiochemical modeling and information theory, to investigate how cyclooxygenase-2 (COX-2) processes simultaneous input signals within a complex interaction network. We find that changes in input levels affect the amount of information transmitted by the network, as does the correlation between those inputs. This, and the allosteric regulation of COX-2 by its substrates, allows it to act as a signal integrator that is most sensitive to changes in relative input levels.
Discovering Data Access and Use Requirements Using the Data Tags Suite (DATS) Model1
Authors: Alter George , Gonzalez-Beltran Alejandra , Ohno-Machado Lucila , Rocca-Serra Philippe 
Published: January 2019

AbstractThis article presents elements in the Data Tags Suite (DATS) metadata schema describing data access, data use conditions, and consent information. DATS is a product of the bioCADDIE Project, which created a data discovery index for searching across all types of biomedical data. The “access and use” metadata items in DATS are designed from the perspective of a researcher who wants to find and re-use existing data. Data reuse is often controlled to protect the privacy of subjects and patients. We focus on the impact of data protection procedures on data users. However, these procedures are part of a larger environment around patient privacy protection, and this article puts DATS metadata into the context of the administrative, legal, and technical systems used to protect confidential data.
BAG3 and SYNPO (synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes
Authors: Ji Changyi , Tang Maoping , Zeidler Claudia , Höhfeld Jörg , Johnson Gail VW 
Published: January 2019

AbstractA major cellular catabolic pathway in neurons is macroautophagy/autophagy, through which misfolded or aggregation-prone proteins are sequestered into autophagosomes that fuse with lysosomes, and are subsequently degraded. MAPT (microtubule associated protein tau) is one of the protein clients of autophagy. Given that accumulation of hyperphosphorylated MAPT contributes to the pathogenesis of Alzheimer disease and other tauopathies, decreasing endogenous MAPT levels has been shown to be beneficial to neuronal health in models of these diseases. A previous study demonstrated that the HSPA/HSP70 co-chaperone BAG3 (BCL2 associated athanogene 3) facilitates endogenous MAPT clearance through autophagy. These findings prompted us to further investigate the mechanisms underlying BAG3-mediated autophagy in the degradation of endogenous MAPT. Here we demonstrate for the first time that BAG3 plays an important role in autophagic flux in the neuritic processes of mature neurons (20-24 days in vitro [DIV]) through interaction with the post-synaptic cytoskeleton protein SYNPO (synaptopodin). Loss of either BAG3 or SYNPO impeded the fusion of autophagosomes and lysosomes predominantly in the post-synaptic compartment. A block of autophagy leads to accumulation of the autophagic receptor protein SQSTM1/p62 (sequestosome 1) as well as MAPT phosphorylated at Ser262 (p-Ser262). Furthermore, p-Ser262 appears to accumulate in autophagosomes at post-synaptic densities. Overall these data provide evidence of a novel role for the co-chaperone BAG3 in synapses. In cooperation with SYNPO, it functions as part of a surveillance complex that facilitates the autophagic clearance of MAPT p-Ser262, and possibly other MAPT species at the post-synapse. This appears to be crucial for the maintenance of a healthy, functional synapse.
Attention differentially modulates the amplitude of resonance frequencies in the visual cortex
Authors: Gulbinaite Rasa , Roozendaal Diane H. M. , VanRullen Rufin 
Published: January 2019

ABSTRACTRhythmic visual stimuli (flicker) elicit rhythmic brain responses at the frequency of the stimulus, and attention generally enhances these oscillatory brain responses (steady state visual evoked potentials, SSVEPs). Although SSVEP responses have been tested for flicker frequencies up to 100 Hz [Herrmann, 2001], effects of attention on SSVEP amplitude have only been reported for lower frequencies (up to ~30 Hz), with no systematic comparison across a wide, finely sampled frequency range. Does attention modulate SSVEP amplitude at higher flicker frequencies (gamma band, 30-80 Hz), and is attentional modulation constant across frequencies? By isolating SSVEP responses from the broadband EEG signal using a multivariate spatiotemporal source separation method, we demonstrate that flicker in the alpha and gamma bands elicit strongest and maximally phase stable brain responses (resonance), on which the effect of attention is opposite: positive for gamma and negative for alpha. Finding subject-specific gamma resonance frequency and a positive attentional modulation of gamma-band SSVEPs points to the untapped potential of flicker as a non-invasive tool for studying the causal effects of interactions between visual gamma-band rhythmic stimuli and endogenous gamma oscillations on perception and attention.