bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cortico-striatal activity driving compulsive reward seeking
Authors: Harada Masaya , Pascoli Vincent , Hiver Agnes , Flakowski Jérôme , Lüscher Christian 
Published: October 2019

AbstractAddicted individuals compulsively seek drugs. Cortico-striatal projections have been implicated in persevering to seek rewards even when punished. The temporo-spatial determinants of the activity underlying the compulsive reward seeking however remains elusive. Here we trained mice in a seek-take chain, rewarded by optogenetic dopamine neuron self-stimulation (oDASS). Mice that persevered when seeking was punished, exhibited an increased AMPA/NMDA ratio selectively at orbitofrontal cortex (OFC) to dorsal striatum (DS) synapses. In addition, an activity peak of spiny projection neurons (SPNs) in the DS at the moment of signalled reward availability was detected. Chemogenetic inhibition of OFC neurons curbed the activity peak and reduced punished reward seeking, as did optogenetic hyperpolarization of SPNs time locked to the cue predicting reward availability, establishing a causal link. Taken together, we conclude that the strengthening of OFC-DS synapses drives SPNs activity when a reward predictive cue is delivered, thus encouraging reward seeking in subsequent trials.
In Breast Cancer ZMIZ1 Co-Regulates E2F2 as Part of the Estrogen Receptor-Mediated Cell-Cycle Response
Authors: Zhao Weiye , Rose Susanna F , Blake Ryan , Godicelj Anže , Cullen Amy E , Stenning Jack , Beevors Lucy , Gehrung Marcel , Kumar Sanjeev , Kishore Kamal , Sawle Ashley , Eldridge Matthew , Giorgi Federico M , Bridge Katherine S , Markowetz Florian , Holding Andrew N 
Published: October 2019

AbstractThe Estrogen Receptor (ER) drives 75% of breast cancers. On activation, the ER recruits co-factors to form a transcriptionally active complex. These co-factors can modulate tumour growth, and understanding their roles can help to identify new therapeutic targets.Here, we present the discovery of an ER-ZMIZ1 interaction by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating that targeting ZMIZ1 results in the reduction of ER transcriptional activity at estrogen response elements and a significant decrease in the proliferation of ER-positive cancer cell lines.To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 hours. GSEA analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell-cycle genes.Integration of ENCODE data with our RNA-seq results identified ER and ZMIZ1 binding at the promoter of E2F2. We therefore propose that ER and ZMIZ1 co-regulate an important subset of cell cycle genes via a novel ER-ZMIZ1-E2F2 signalling axis.Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA, METABRIC, and the proteins are co-localised within the nuclei of tumours cell in patient biopsies.In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER-ZMIZ1 interaction ER+ patient tumours, supporting potential clinical relevance.
PDGFRA Defines the Mesenchymal Stem Cell Kaposi’s Sarcoma Progenitors by Enabling KSHV Oncogenesis in an Angiogenic Environment
Authors: Naipauer Julian , Rosario Santas , Gupta Sachin , Premer Courtney , Mendez Omayra , Schlesinger Mariana , Ponzinibbio Virginia , Jain Vaibhav , Gay Lauren , Renne Rolf , Chan Ho Lam , Morey Lluis , Salyakina Daria , Abba Martin , Williams Sion , Hare Joshua M. , Goldschmidt-Clermont Pascal J , Mesri Enrique A. 
Published: October 2019

ABSTRACTKaposi’s sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pα(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected Pα(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pα(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.AUTHOR SUMMARYIdentification of the KS progenitor cell creates the possibility of studying viral oncogenesis and its determinants from its initial steps as a continuum. It also increases our understanding of pathogenic mechanisms and disease preferential tropism. Hereby we identify Pα(+)S-MSCs as KS progenitors, in which KSHV infection has oncogenic consequences; only when these cells are in a pro-angiogenic environment in which PDGFRA activation enables an oncogenic de-repressed KSHV epigenome. These results identify a KS-progenitor population in the Pα(+)S-MSCs and point to pro-angiogenic environmental conditions as essential for oncogenic viral gene expression and transformation. We designed a novel model of KSHV oncogenesis, creating a very robust platform to identify KSHV oncogenic pathways and their relationship with cellular lineages and extracellular growth environments.
Anthropogenic disturbance drives dispersal syndromes, demography, and gene flow in spatially structured amphibian populations
Authors: Cayuela Hugo , Besnard Aurélien , Cote Julien , Laporte Martin , Bonnaire Eric , Pichenot Julian , Schtickzelle Nicolas , Bellec Arnaud , Joly Pierre , Léna Jean-Paul 
Published: October 2019

AbstractThere is growing evidence that anthropogenic landscapes can strongly influence the evolution of dispersal, particularly through fragmentation, and may drive organisms into an evolutionary trap by suppressing dispersal. However, the influence on dispersal evolution of anthropogenic variation in habitat patch turnover has so far been largely overlooked. In this study, we examined how human-driven variation in patch persistence affects dispersal rates and distances, determines dispersal-related phenotypic specialization, and drives neutral genetic structure in spatially structured populations. We addressed this issue in an amphibian,Bombina variegata, using an integrative approach combining capture–recapture modeling, demographic simulation, common garden experiments, and population genetics.B. variegatareproduces in small ponds that occur either in habitat patches that are persistent (i.e. several decades or more), located in riverine environments with negligible human activity, or in patches that are highly temporary (i.e. a few years), created by logging operations in intensively harvested woodland. Our capture–recapture models revealed that natal and breeding dispersal rates and distances were drastically higher in spatially structured populations (SSPs) in logging environments than in riverine SSPs. Population simulations additionally showed that dispersal costs and benefits drive the fate of logging SSPs, which cannot persist without dispersal. The common garden experiments revealed that toadlets reared in laboratory conditions have morphological and behavioral specialization that depends on their habitat of origin. Toadlets from logging SSPs were found to have higher boldness and exploration propensity than those from riverine SSPs, indicating transgenerationally transmitted dispersal syndromes. We also found contrasting patterns of neutral genetic diversity and gene flow in riverine and logging SSPs, with genetic diversity and effective population size considerably higher in logging than in riverine SSPs. In parallel, intra-patch inbreeding and relatedness levels were lower in logging SSPs. Controlling for the effect of genetic drift and landscape connectivity, gene flow was found to be higher in logging than in riverine SSPs. Taken together, these results indicate that anthropogenic variation in habitat patch turnover may have an effect at least as important as landscape fragmentation on dispersal evolution and the long-term viability and genetic structure of wild populations.
Access to unexplored regions of sequence space in directed enzyme evolutionviainsertion/deletion mutagenesis
Authors: Emond Stephane , Petek Maya , Kay Emily , Heames Brennen , Devenish Sean , Tokuriki Nobuhiko , Hollfelder Florian 
Published: October 2019

ABSTRACTInsertions and deletions (InDels) are frequently observed in natural protein evolution, yet their potential remains untapped in laboratory evolution. Here we introduce a transposon mutagenesis approach (TRIAD) to generate libraries of random variants with short in-frame InDels, and screen TRIAD libraries to evolve a promiscuous arylesterase activity in a phosphotriesterase. The evolution exhibits features that are distinct from previous point mutagenesis campaigns: while theaverage activityof TRIAD variants is more deleterious, alarger proportionhas successfully adapted for the new activity, exhibiting different functional profiles: (i) both strong and weak trade-off in original vs promiscuous activity are observed; (ii) trade-off is more severe (10- to 20-fold increasedkcat/KMin arylesterase with ∼100-fold decreases in the original phosphotriesterase activity) and (iii) improvements show up inkcatrather than KM, suggesting novel adaptive solution. These distinct features make TRIAD an alternative to widely used point mutagenesis, providing access to functional innovations and traversing unexplored fitness landscape regions.
CellWell: A micropatterned biphasic nanocomposite platform for culturing chondrocytes
Authors: Saraswat Ram , Ratnayake Ishara , Perez E. Celeste , Schutz William M. , Zhu Zhengtao , Ahrenkiel S. Phillip , Wood Scott T. 
Published: October 2019

Graphical AbstractAbstractWe present a unique micropatterned nanocomposite cell culture platform to model articular cartilage that is suitable for high-throughput single-cell analyses using standard imaging techniques. This platform, the CellWell, is constructed out of a thin, optically transparent substrate that is lithographically micropatterned with a network of wells sized to fit individual cells. The substrate material consists of a thin layer of agarose hydrogel embedded with polyvinyl alcohol nanofibers. The geometries of the wells are designed to reinforce a physiological morphology, thereby combining the physiological advantages of 3D culture systems with the practical advantages of 2D systems. CellWells were found to have compressive moduli of 144 ± 11.5 kPa and 158 ± 0.6 kPa at strain rates of 5 μm/s and 15 μm/s. The compressive moduli were determined at two different strain rates to allow for comparison of CellWell stiffness with published values of pericellular matrix and with observed values of articular cartilage, which could not be indented at the same rate. Articular chondrocytes seeded in a CellWell were found to maintain their spheroidal morphology more effectively than those seeded in monolayer cultures and to be more easily imaged than those seeded in a 3D scaffold of identical thickness. Through its ease of use and ability to maintain the physiological morphology of chondrocytes, we expect that the CellWell will enhance the clinical translatability of future studies conducted using this culture platform.
Social behavioral deficits in NF1 emerge from peripheral chemosensory neuron dysfunction
Authors: Moscato Emilia H. , Dubowy Christine , Walker James A. , Kayser Matthew S. 
Published: October 2019

AbstractNeurofibromatosis type 1 (NF1) is a neurodevelopmental disorder commonly associated with social and communicative disabilities. The cellular and circuit mechanisms by which loss of neurofibromin 1 (Nf1) function results in social deficits are unknown. Here, we identify social behavioral dysregulation with loss of Nf1 in Drosophila. These deficits map to primary dysfunction of a small group of peripheral sensory neurons, rather than central brain circuits. Specifically, Nf1 regulation of Ras signaling in adult, Ppk23+ chemosensory cells is required for normal social behaviors in flies. Loss of Nf1 results in attenuated ppk23+ neuronal activity in response to pheromonal cues, and circuit-specific manipulation of Nf1 expression or neuronal activity in ppk23+ neurons rescues social deficits. Unexpectedly, this disrupted sensory processing gives rise to persistent changes in behavior lasting beyond the social interaction, indicating a sustained effect of an acute sensory misperception. Together our data identify a specific circuit mechanism through which Nf1 acts to regulate social behaviors, and suggest social deficits in NF1 arise from propagation of sensory misinformation.
Geographic Generalization in Airborne RGB Deep Learning Tree Detection
Authors: Weinstein Ben. G. , Marconi Sergio , Bohlman Stephanie A. , Zare Alina , White Ethan P. 
Published: October 2019

AbstractTree detection is a fundamental task in remote sensing for forestry and ecosystem ecology applications. While many individual tree segmentation algorithms have been proposed, the development and testing of these algorithms is typically site specific, with few methods evaluated against data from multiple forest types simultaneously. This makes it difficult to determine the generalization of proposed approaches, and limits tree detection at broad scales. Using data from the National Ecological Observatory Network we extend a recently developed semi-supervised deep learning algorithm to include data from a range of forest types, determine whether information from one forest can be used for tree detection in other forests, and explore the potential for building a universal tree detection algorithm. We find that the deep learning approach works well for overstory tree detection across forest conditions, outperforming conventional LIDAR-only methods in all forest types. Performance was best in open oak woodlands and worst in alpine forests. When models were fit to one forest type and used to predict another, performance generally decreased, with better performance when forests were more similar in structure. However, when models were pretrained on data from other sites and then fine-tuned using a small amount of hand-labeled data from the evaluation site, they performed similarly to local site models. Most importantly, a universal model fit to data from all sites simultaneously performed as well or better than individual models trained for each local site. This result suggests that RGB tree detection models that can be applied to a wide array of forest types at broad scales should be possible.
longfincausescis-ectopic expression of thekcnh2a ether-a-go-goK+channel to autonomously prolong fin outgrowth
Authors: Stewart Scott , Le Bleu Heather K. , Yette Gabriel A. , Henner Astra L. , Robbins Amy E. , Braunstein Joshua A. , Stankunas Kryn 
Published: October 2019

ABSTRACTOrgans stop growing to achieve a characteristic size and shape in scale with the animal’s body. Likewise, regenerating organs sense injury extents to instruct appropriate replacement growth. Fish fins exemplify both phenomena through their tremendous diversity of form and remarkably robust regeneration. The classic zebrafish mutantlongfint2develops and regenerates dramatically elongated fins and underlying ray skeleton. We showlongfint2chromosome 2 overexpresses theether-a-go-go-related voltage-gated potassium channelkcnh2a.Genetic disruption ofkcnh2a in cisrescueslongfint2,indicatinglongfint2is a regulatorykcnh2aallele. We findlongfint2fin overgrowth originates from prolonged outgrowth periods including by showing Kcnh2a chemical inhibition during late stage regeneration fully suppresses overgrowth. Cell transplantations demonstratelongfint2-ectopickcnh2aacts tissue autonomously within the fin intra-ray mesenchymal lineage. Temporal inhibition of the Ca2+-dependent phosphatase calcineurin indicates it likewise entirely acts late in regeneration to attenuate fin outgrowth. Epistasis experiments suggestlongfint2-expressed Kcnh2a inhibits calcineurin output to supersede growth cessation signals. We conclude ion signaling within the growth-determining mesenchyme lineage controls fin size by tuning outgrowth periods rather than altering positional information or cell-level growth potency.
Pain-free resting-state functional brain connectivity predicts individual pain sensitivity
Authors: Spisak Tamas , Kincses Balint , Schlitt Frederik , Zunhammer Matthias , Schmidt-Wilcke Tobias , Kincses Zsigmond T. , Bingel Ulrike 
Published: October 2019

AbstractIndividual differences in pain perception are of key interest in basic and clinical research as altered pain sensitivity is both a characteristic and a risk factor for many pain conditions. It is, however, unclear how individual susceptibility to pain is reflected in the pain-free resting-state brain activity and functional connectivity.Here, we identified and validated a network pattern in the pain-free resting-state functional brain connectome that is predictive of interindividual differences in pain sensitivity. Our predictive network signature (https://spisakt.github.io/RPN-signature) allows assessing the individual susceptibility to pain without applying any painful stimulation, as might be valuable in patients where reliable behavioural pain reports cannot be obtained. Additionally, as a direct, non-invasive readout of the supraspinal neural contribution to pain sensitivity, it may have broad implications for translational research and the development and assessment of analgesic treatment strategies.
Transgenerational dispersal plasticity and its fitness consequences are under genetic control
Authors: Cayuela Hugo , Jacob Staffan , Schtickzelle Nicolas , Verdonck Rik , Philippe Hervé , Laporte Martin , Huet Michèle , Bernatchez Louis , Legrand Delphine 
Published: October 2019

AbstractPhenotypic plasticity, the ability of one genotype to produce different phenotypes in different environments, plays a central role in species’ response to environmental changes. Transgenerational plasticity (TGP) allows the transmission of this environmentally-induced phenotypic variation across generations, and can influence adaptation. To date, the genetic control of TGP, its long-term stability, and its potential costs remain largely unknown, mostly because empirical demonstrations of TGP across many generations in several genetic backgrounds are scarce. Here, we examined how genotype determines the TGP of dispersal, a fundamental process in ecology and evolution. We used an experimental approach involving ~200 clonal generations in a model-species of ciliate to determine if and how TGP influences the expression of dispersal-related traits in several genotypes. Our results show that morphological and movement traits associated with dispersal are plastic, and that these modifications are inherited over at least 35 generations. We also highlight that genotype modulates the fitness costs and benefits associated with plastic dispersal strategies. Our study suggests that genotype-dependent TGP could play a critical role in eco-evolutionary dynamics as dispersal determines gene flow and the long-term persistence of natural populations. More generally, it outlines the tremendous importance that genotype-dependent TGP could have in the ability of organisms to cope with current and future environmental changes.SignificanceThe genetic control of the transgenerational plasticity is still poorly understood despite its critical role in species responses to environmental changes. We examined how genotype determines transgenerational plasticity of a complex trait (i.e., dispersal) in a model-species of ciliate across ~200 clonal generations. Our results provide evidence that plastic phenotypic variation linked to dispersal is stably inherited over tens of generations and that cell genotype modulates the expression and fitness cost of transgenerational plasticity.
Single cell map of the human ovarian cortex
Authors: Wagner Magdalena , Yoshihara Masahito , Douagi Iyadh , Damdimopoulos Anastasios , Panula Sarita , Petropoulos Sophie , Lu Haojiang , Pettersson Karin , Palm Kerstin , Katayama Shintaro , Hovatta Outi , Kere Juha , Lanner Fredrik , Damdimopoulou Pauliina 
Published: October 2019

ABSTRACTThe human ovary orchestrates sex hormone production and undergoes monthly structural changes to release mature oocytes. The outer lining of the ovary (cortex) has a key role in defining fertility in women as it harbors the ovarian reserve. It has been postulated that putative oogonial stem cells exist in the ovarian cortex and that these can be captured by DDX4 antibody isolation. We analysed on a single cell level the transcriptome and cell surface antigen profiles of over 24,000 cells from high quality ovarian cortex samples from 21 patients. Our single cell mapping reveals transcriptional profiles of six main cell types; oocytes, granulosa cells, immune cells, endothelial cells, perivascular cells, and stromal cells. Cells captured by DDX4 antibody are perivascular cells, not oogonial stem cells. Our data does not support the existence of germline stem cells in adult human ovaries thereby reinforcing the dogma of a limited ovarian reserve.
Using experiential learning of NGOs to enhance active citizenship education in school curriculum
Authors: Chong King Man Eric 
Published: October 2019

Purpose
The purpose of this paper is to analyse and evaluate the implementation of an empathy model of experiential learning in real-life sites, with the help of NGOs, for developing students’ active citizenship in two Hong Kong Chinese secondary schools.

Design/methodology/approach
This study employs a case study in which teachers and the researcher engage in planning, implementing and evaluating an experiential learning unit which combines together both classed-based learning activities and experiential learning activities provided by NGOs in real-life settings. Qualitative interview findings are collected from teachers and students.

Findings
Incorporating experiential learning activities in thematic learning units provided by NGOs for the active citizenship of students can facilitate teachers to develop student learning outcomes of empathy and perspective taking derived from authentic experience. In particular, teachers’ reflect on how to facilitate Chinese students’ reflect on disadvantaged people and ethnic minorities. This action research study recommends that students’ conceptual understanding of concepts such as poverty and ethnic minorities should be developed before they participate in NGO’s experiential learning activities, so that the experiential experiences can add something on what they have already learnt.

Originality/value
This study found some useful implications for exploring ways for teacher development by applying an experiential learning model in combination with classroom-based learning for active citizenship. This research study recommends implementing pre-experiential conceptual building activities and post-experiential classroom-based enquiry and reflection activities to help students consolidate their learning experiences through verbal and written reflection, as well as on what actions that they can take.