bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating the H+coupled Zn2+transport mechanism of ZIP4; implications inAcrodermatitis Enteropathica
Authors: Hoch Eitan , Sekler Israel 
Published: November 2018

AbstractCellular Zn2+homeostasis is tightly regulated and primarily mediated by designated Zn2+transport proteins, namely ZnTs (SLC30) that shuttle Zn2+efflux, and ZIPs (SLC39) that mediate Zn2+influx. While the functional determinants of ZnT-mediated Zn2+efflux are elucidated, those of ZIP transporters are lesser understood. Previous work has suggested three distinct molecular mechanisms: (I) HCO3−or (II) H+coupled Zn2+transport, or (III) a pH regulated electrodiffusional mode of transport. Here, using live-cell fluorescent imaging of Zn2+and H+, in cells expressing ZIP4, we set out to interrogate its function. Intracellular pH changes or the presence of HCO3−failed to induce Zn2+influx. In contrast, extracellular acidification stimulated ZIP4 dependent Zn2+uptake. Furthermore, Zn2+uptake was coupled to enhanced H+influx in cells expressing ZIP4, thus indicating that ZIP4 is not acting as a pH regulated channel but rather as an H+powered Zn2+co-transporter. We further illustrate how this functional mechanism is affected by genetic variants inSLC39A4that in turn lead toAcrodermatitis Enteropathica, a rare condition of Zn2+deficiency.
Application of UV-cured resin as embedding/mounting media for practical, time-saving otolith specimen preparation
Authors: Strüssmann Carlos Augusto , Miyoshi Kaho , Mitsui Shota 
Published: November 2018

AbstractOtoliths are calcified structures located in the inner ears of fish, as in most vertebrates, that are responsible primarily for the perception of gravity, balance and movement, and secondarily of sound detection. Microstructural and chemical analyzes of the inner otolith growth layers, called increments, constitute powerful tools to estimate fish age and elucidate many life history and demographic traits of fish populations. Otolith analyzes often require the production of a thin cross section that includes in the same plane of view the otolith core and all microscopic layers formed from birth until the moment of collection (otolith edge). Here we report on the usefulness of UV-cured resins that have become recently popular among nail artists and hobbyists for otolith specimen preparation. We show that single-component UV-cured resins can replace successfully and advantageously the commonly used two-component Epoxy resins to obtain otolith cross sections suitable for both microstructural examination and chemical analysis by electron probe microanalysis. UV-cured resins provide on-demand, extremely rapid (minute-order) hardening and high transparency, while providing similar adhesion and mechanical support for the otoliths during processing and analysis as Epoxy resins. UV-cured resins may revolutionize otolith specimen preparation practically- and time-wise, and may be particularly useful in teaching and workshop situations in which time for otolith embedding is a constraint.
Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis
Authors: Ashouri Judith F. , Hsu Lih-Yun , Yu Steven , Rychkov Dmitry , Chen Yiling , Cheng Debra A. , Sirota Marina , Hansen Erik , Lattanza Lisa , Zikherman Julie , Weiss Arthur 
Published: November 2018

AbstractHow pathogenic CD4 T cells in Rheumatoid Arthritis (RA) develop remains poorly understood. We used Nur77—a marker of T cell antigen receptor (TCR) signaling—to identify antigen-activated CD4 T cells in the SKG mouse model of autoimmune arthritis and in patients with RA. Using a fluorescent reporter of Nur77 expression in SKG mice, we found that higher levels of Nur77-eGFP in SKG CD4 T cells marked their autoreactivity, arthritogenic potential, and ability to more readily differentiate into IL-17 producing cells. The T cells with increased autoreactivity, nonetheless had diminishedex vivoinducible TCR signaling, perhaps reflective of adaptive inhibitory mechanisms induced by chronic auto-antigen exposurein vivo. The enhanced autoreactivity was associated with upregulation of IL-6 cytokine signaling machinery, which might in part be attributable to a reduced amount of expression of suppressor of cytokine signaling 3 (SOCS3)—a key negative regulator of IL-6 signaling. As a result, the more autoreactive GFPhiCD4 T cells from SKGNur mice were hyper-responsive to IL-6 receptor signaling. Consistent with findings from SKGNur mice,SOCS3expression was similarly downregulated in RA synovium. This suggests that, despite impaired TCR signaling, autoreactive T cells exposed to chronic antigen stimulation exhibit heightened sensitivity to IL-6 which contributes to the arthritogenicity in SKG mice, and perhaps in patients with RA.Significance StatementHow arthritis-causing T cells trigger rheumatoid arthritis (RA) is not understood since it is difficult to differentiate T cells activated by inflammation in arthritic joints from those activated through their TCR by self-antigens. We developed a model to identify and study antigen-specific T cell responses in arthritis. Nur77—a specific marker of TCR signaling—was used to identify antigen-activated CD4 T cells in the SKG arthritis model and patients with RA. Nur77 could distinguish highly arthritogenic and autoreactive T cells in SKG mice. The enhanced autoreactivity was associated with increased IL-6-receptor-signaling, likely contributing to their arthritogenicity. These data highlight a functional correlate between Nur77 expression, arthritogenic T cell populations, and heightened IL-6 sensitivity in SKG mice with translatable implications for human RA.
Unraveling intratumoral heterogeneity through high-sensitivity single-cell mutational analysis and parallel RNA-sequencing
Authors: Rodriguez-Meira Alba , Buck Gemma , Clark Sally-Ann , Povinelli Benjamin J , Alcolea Veronica , Louka Eleni , McGowan Simon , Hamblin Angela , Sousos Nikolaos , Barkas Nikolaos , Giustacchini Alice , Psaila Bethan , Jacobsen Sten Eirik W , Thongjuea Supat , Mead Adam J 
Published: November 2018

SUMMARYSingle-cell RNA-sequencing has emerged as a powerful tool to resolve transcriptional heterogeneity. However, its application to study cancerous tissues is currently hampered by the lack of coverage across key mutation hotspots in the vast majority of cells, which prevents correlation of genetic and transcriptional readouts from the same single cell. To overcome this, we developed TARGET-seq, a method for the high-sensitivity detection of multiple mutations within single-cells from both genomic and coding DNA, in parallel with unbiased, high-depth whole transcriptome analysis. We demonstrate how this technique uniquely resolves transcriptional and genetic tumor heterogeneity in myeloproliferative neoplasm stem/progenitor cells, providing insights into deregulated pathways of mutant and non-mutant cells. TARGET-seq provides a powerful tool to resolve molecular signatures of genetically distinct subclones of tumor cells.
Prokaryotic genome expansion is facilitated by phages and plasmids but impaired by CRISPR
Authors: Gao Na L. , Chen Jingchao , Lercher Martin J , Chen Wei-Hua 
Published: November 2018

AbstractBacteriophages and plasmids can introduce novel DNA into bacterial cells, thereby creating an opportunity for genome expansion; conversely, CRISPR, the prokaryotic adaptive immune system, which targets and eliminates foreign DNAs, may impair genome expansions. Recent studies presented conflicting results over the impact of CRISPR on genome expansion. In this study, we assembled a comprehensive dataset of prokaryotic genomes and identified their associations with phages and plasmids. We found that genomes associated with phages and/or plasmids were significantly larger than those without, indicating that both phages and plasmids contribute to genome expansion. Genomes were increasingly larger with increasing numbers of associated phages or plasmids. Conversely, genomes with CRISPR systems were significantly smaller than those without, indicating that CRISPR has a negative impact on genome size. These results confirmed that on evolutionary timescales, bacteriophages and plasmids facilitate genome expansion, while CRISPR impairs such a process in prokaryotes. Furthermore, our results also revealed that CRISPR systems show a strong preference for targeting phages over plasmids.
MiR-146a wild-type 3’ sequence identity is dispensable for proper innate immune function in vivo
Authors: Bertolet Grant , Kongchan Natee , Miller Rebekah , Patel Ravi K. , Jain Antrix , Choi Jong Min , Saltzman Alexander , Christenson Amber , Jung Sung Yun , Malovannaya Anna , Grimson Andrew , Neilson Joel R. 
Published: November 2018

AbstractThe prevailing model of microRNA function is that the “seed” region (nucleotides 2-8) is typically sufficient to mediate target recognition and repression. However, numerous recent studies have challenged this model, either by demonstrating extensive 3’ pairing between physically defined miRNA-mRNA pairs or by showing in C. elegans that disrupted 3’ pairing can result in impaired function in vivo. To test the importance of miRNA 3’ pairing in a mammalian system in vivo, we engineered a mutant murine mir-146a allele in which the 5’ half of the mature microRNA retains its wild-type sequence, but the 3’ half has been altered to be anti-complementary. Mice homozygous or hemizygous for this mutant allele are phenotypically indistinguishable from wild-type controls and do not recapitulate any of the immunopathology previously described for mir-146a-null mice. Our results indicate that 3’ pairing is dispensable for the established myeloid function of this key mammalian microRNA.Summary Blurb3’ sequence identity is dispensable for the established function of a mammalian miRNA in vivo.
Heterochromatin protein 1 (HP1) is intrinsically required for post-transcriptional regulation ofDrosophilaGermline Stem Cell (GSC) maintenance
Authors: Casale Assunta Maria , Cappucci Ugo , Fanti Laura , Piacentini Lucia 
Published: November 2018

AbstractA very important open question in stem cells regulation is how the fine balance between GSCs self-renewal and differentiation is orchestrated at the molecular level. In the past several years much progress has been made in understanding the molecular mechanisms underlying intrinsic and extrinsic controls of GSC regulation but the complex gene regulatory networks that regulate stem cell behavior are only partially understood. HP1 is a dynamic epigenetic determinant mainly involved in heterochromatin formation, epigenetic gene silencing and telomere maintenance. Furthermore, recent studies have revealed the importance of HP1 in DNA repair, sister chromatid cohesion and, surprisingly, in positive regulation of gene expression. Here, we show that HP1 plays a crucial role in the control of GSC homeostasis inDrosophila. Our findings demonstrate that HP1 is required intrinsically to promote GSC self-renewal and progeny differentiation by directly stabilizing the transcripts of key genes involved in GSCs maintenance.
Dynamic networks of fighting and mating in a wild cricket population
Authors: Fisher David N. , Rodríguez-Muñoz Rolando , Tregenza Tom 
Published: November 2018

AbstractReproductive success is often highly skewed in animal populations. Yet the processes leading to this are not always clear. Similarly, connections in animal social networks are often non-randomly distributed, with some individuals with many connections and others with few, yet whether there are simple explanations for this pattern has not been determined. Numerous social interactions involve dyads embedded within a wider network. As a result, it may be possible to model which individuals accumulate social interaction through a more general understanding of the social network’s structure, and how this structure changes over time. We analysed fighting and mating interactions across the breeding season in a population of wild field crickets under surveillance from a network of video cameras. We fitted stochastic actor-oriented models to determine the dynamic process by which networks of cricket fighting and mating interactions form, and how they co-influence each other. We found crickets tended to fight those in close spatial proximity to them, and those possessing a mutual connection in the fighting network, and heavier crickets fought more often. We also found that crickets who mate with many others tended to fight less in the following time period. This demonstrates that a mixture of spatial constraints, characteristics of individuals and characteristics of the immediate social environment are key for determining social interactions. The mating interaction network required very few parameters to understand its growth and so structure; only homophily by mating success was required to simulate the skew of mating interactions seen in this population. This demonstrates that relatively simple, but dynamic processes can give highly skewed distributions of mating success.
Risk stratification of allogeneic stem cell recipients with respect to the potential for development of GVHD via their pre-transplant plasma lipid and metabolic signature
Authors: Contaifer Daniel , Roberts Catherine H , Kumar Naren Gajenthra , Natarajan Ramesh , Fisher Bernard J , Leslie Kevin , Reed Jason , Toor Amir A , Wijesinghe Dayanjan S 
Published: November 2018

AbstractThe clinical outcome of allogeneic hematopoietic stem cell transplantation (SCT) is strongly influenced from the complications arising during the post-transplant immune restoration and has been well studied and described. However, the metabolic status of the recipient pre-transplant also has the potential to influence this outcome and has never been studied before and has the potential to enable risk stratification with respect to the development of transplant associated complications such as graft vs. host disease (GVHD). In order to better understand this aspect of transplant related complications we investigated the pre-transplantation metabolic signature to assess the possibility of pre-transplant risk stratification. This pilot study was composed of 14 patients undergoing myeloablative conditioning followed by either HLA matched related, unrelated donor, or autologous stem cell transplantation. Blood samples were taken prior to transplant and the plasma was comprehensively characterized with respect to its lipidome and metabolome via LCMS and GCMS. The results indicated a significantly pro-inflammatory metabolic profile in patients who eventually developed Graft vs. Host Disease (GVHD). The data revealed 5 potential pre-transplant biomarkers (1-monopalmitin, diacylglycerol (DG) 38:5, DG 38:6, 2-aminobutyric acid, and fatty acid (FA) 20:1) that demonstrated high sensitivity and specificity towards predicting post-transplant GVHD development. The predictive model developed demonstrated an estimated predictive accuracy of risk stratification of 100%, with an Area under the Curve of the ROC of 0.995 with 100%. The likelihood ratio of 1-monopalmitin (infinity), DG 38:5 (6.0) and DG 38:6 (6.0) also demonstrated that a patient with a positive test result for these biomarkers pre-transplant will likely have very high odds of developing GVHD post-transplant. Collectively the data demonstrates the possibility of using pre-transplant metabolic signature for risk stratification of SCT recipients with respect to development of GVHD.
Design of a GAK/EGFR inhibitor set to interrogate the relationship of EGFR and GAK in chordoma
Authors: Asquith Christopher R. M. , Naegeli Kaleb M. , East Michael P. , Laitinen Tuomo , Havener Tammy M. , Wells Carrow I. , Johnson Gary L. , Drewry David H. , Zuercher William J. , Morris David C. 
Published: November 2018

ABSTRACTWe describe the design of a set of inhibitors to investigate the relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and using in cell target engagement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstrating narrow spectrum profiles.
Weight statistics controls dynamics in recurrent neural networks
Authors: Krauss Patrick , Schuster Marc , Dietrich Verena , Schilling Achim , Schulze Holger , Metzner Claus 
Published: November 2018

AbstractRecurrent neural networks are complex non-linear systems, capable of ongoing activity in the absence of driving inputs. The dynamical properties of these systems, in particular their long-time attractor states, are determined on the microscopic level by the connection strengths wij between the individual neurons. However, little is known to which extent network dynamics is tunable on a more coarse-grained level by the statistical features of the weight matrix. In this work, we investigate the dynamical impact of three statistical parameters: density (the fraction of non-zero connections), balance (the ratio of excitatory to inhibitory connections), and symmetry (the fraction of neuron pairs with wij = wji). By computing a ‘phase diagram’ of network dynamics, we find that balance is the essential control parameter: Its gradual increase from negative to positive values drives the system from oscillatory behavior into a chaotic regime, and eventually into stationary fix points. Only directly at the border of the chaotic regime do the neural networks display rich but regular dynamics, thus enabling actual information processing. These results suggest that the brain, too, is fine-tuned to the ‘edge of chaos’ by assuring a proper balance between excitatory and inhibitory neural connections.Author summaryComputations in the brain need to be both reproducible and sensitive to changing input from the environment. It has been shown that recurrent neural networks can meet these simultaneous requirements only in a particular dynamical regime, called the edge of chaos in non-linear systems theory. Here, we demonstrate that recurrent neural networks can be easily tuned to this critical regime of optimal information processing by assuring a proper ratio of excitatory and inhibitory connections between the neurons. This result is in line with several micro-anatomical studies of the cortex, which frequently confirm that the excitatory-inhibitory balance is strictly conserved in the cortex. Furthermore, it turns out that neural dynamics is largely independent from the total density of connections, a feature that explains how the brain remains functional during periods of growth or decay. Finally, we find that the existence of too many symmetric connections is detrimental for the above mentioned critical dynamical regime, but maybe in turn useful for pattern completion tasks.
CD8+ lymphocytes modulate Zika virus dynamics and tissue dissemination and orchestrate antiviral immunity
Authors: Schouest Blake , Fahlberg Marissa , Scheef Elizabeth A. , Ward Matthew J. , Headrick Kyra , Szeltner Dawn M. , Blair Robert V. , Gilbert Margaret H. , Doyle-Meyers Lara A. , Danner Victoria W. , Bonaldo Myrna C. , Wesson Dawn M. , Panganiban Antonito T. , Maness Nicholas J. 
Published: November 2018

AbstractCD8+ lymphocytes are critically important in the control of viral infections, but their roles in acute Zika virus (ZIKV) infection remain incompletely explored in a model sufficiently similar to humans immunologically. Here, we use CD8+ lymphocyte depletion to dissect acute immune responses in adult male rhesus and cynomolgus macaques infected with ZIKV. CD8 depletion delayed serum viremia and dysregulated patterns of innate immune cell homing and monocyte-driven transcriptional responses in the blood. CD8-depleted macaques also showed evidence of compensatory adaptive immune responses, with elevated Th1 activity and persistence of neutralizing antibodies beyond the clearance of serum viremia. The absence of CD8+ lymphocytes increased viral burdens in lymphatic tissues, semen, and cerebrospinal fluid, and neural lesions were also evident in both CD8-depleted rhesus macaques. Together, these data support a role for CD8+ lymphocytes in the control of ZIKV dissemination and in maintaining immune regulation during acute infection of nonhuman primates.
Glutamate signaling at cytoneme synapses
Authors: Huang Hai , Liu Songmei , Kornberg Thomas B. 
Published: November 2018

AbstractWe investigated the roles of neuronal synapse components for development of the Drosophila air sac primordium (ASP). The ASP, an epithelial tube, extends specialized signaling filopodia called cytonemes that take up signals such as Dpp from the wing imaginal disc. Dpp signaling in the ASP requires that disc cells express Dpp, Synaptobrevin, Synaptotagmin-1, the glutamate transporter, and a voltage-gated calcium channel, and that ASP cells express the Dpp receptor, Synaptotagmin-4 and the AMPA-type glutamate receptor GluRII. Calcium transients in ASP cytonemes correlate with signaling activity. Calcium transients in the ASP require GluRII, are activated by L-glutamate and by stimulation of an optogenetic ion channel expressed in the wing disc, and are inhibited by EGTA and NASPM. Activation of GluRII is essential but not sufficient for signaling. Cytoneme-mediated signaling is glutamatergic.SummaryParacrine signals transfer between Drosophila epithelial cells at glutamatergic synapses.
Determinants of China’s structural change during the reform era
Authors: Guo Kaiming , Hang Jing , Yan Se 
Published: November 2018

PurposeEconomic theories on structural change focus on factors such as fluctuations in relative prices and income growth. In addition, China’s reform and opening up has also been accompanied by increasing openness, significant fluctuations in investment rates, and frictions in the labor market. Existing literature lacks a unified theoretical framework to assess the relative importance of all these determinants. The paper aims to discuss these issues.Design/methodology/approachTo incorporate all of the potential determinants of China’s structural change, the authors build a two-country four-sector neoclassical growth model that embeds the multi-sector Eaton and Kortum (2002) model of international trade, complete input-output structure, non-homothetic preference and labor market frictions. The authors decompose the sectoral employment shares into six effects: the Baumol, Engel, investment, international trade, factor intensity and labor market friction effects. Using the data of Chinese economy from 1978 to 2011, the authors perform a quantitative investigation of the six determinants’ effects through the decomposition approach and counterfactual exercises.FindingsLow-income elasticity of demand, high labor intensity, and the existence of the switching costs are the reasons for the high employment share in the agricultural sector. Technological progress, investment and international trade have comparatively less influence on the proportion difference of employment in the three sectors.Originality/valueTherefore, to examine the impact on China’s structural change, in addition to Baumol effect and the Engel effect, it is also necessary to consider the impact of three more factors: international trade, investment and switching costs. Therefore, the authors decompose the factors that may influence China’s structural change into the Baumol, Engel, investment, international trade, factor intensity effect and switching cost effects. The authors evaluate these six effects using the decomposition approach and counterfactual exercises.