bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leveraging prior concept learning improves ability to generalize from few examples in computational models of human object recognition
Authors: Rule Joshua S. , Riesenhuber Maximilian 
Published: February 2020

AbstractHumans quickly learn new visual concepts from sparse data, sometimes just a single example. Decades of prior work have established the hierarchical organization of the ventral visual stream as key to this ability. Computational work has shown that networks which hierarchically pool afferents across scales and positions can achieve human-like object recognition performance and predict human neural activity. Prior computational work has also reused previously acquired features to efficiently learn novel recognition tasks. These approaches, however, require magnitudes of order more examples than human learners and only reuse intermediate features at the object level or below. None has attempted to reuse extremely high-level visual features capturing entire visual concepts. We used a benchmark deep learning model of object recognition to show that leveraging prior learning at the concept level leads to vastly improved abilities to learn from few examples. These results suggest computational techniques for learning even more efficiently as well as neuroscientific experiments to better understand how the brain learns from sparse data. Most importantly, however, the model architecture provides a biologically plausible way to learn new visual concepts from a small number of examples, and makes several novel predictions regarding the neural bases of concept representations in the brain.Author summaryWe are motivated by the observation that people regularly learn new visual concepts from as little as one or two examples, far better than, e.g., current machine vision architectures. To understand the human visual system’s superior visual concept learning abilities, we used an approach inspired by computational models of object recognition which: 1) use deep neural networks to achieve human-like performance and predict human brain activity; and 2) reuse previous learning to efficiently master new visual concepts. These models, however, require many times more examples than human learners and, critically, reuse only low-level and intermediate information. None has attempted to reuse extremely high-level visual features (i.e., entire visual concepts). We used a neural network model of object recognition to show that reusing concept-level features leads to vastly improved abilities to learn from few examples. Our findings suggest techniques for future software models that could learn even more efficiently, as well as neuroscience experiments to better understand how people learn so quickly. Most importantly, however, our model provides a biologically plausible way to learn new visual concepts from a small number of examples.
The intriguing dynamics of chromatin folding and assembly
Authors: Yang Z. , Miao W. , Mofrad M. R.K. 
Published: February 2020

ABSTRACTWe investigate the dynamics of chromatin folding based on the “strings and binders” (SBS) model with molecular dynamics simulation. SBS model is a coarse-grained model considering a self-avoiding chain interacting with diffusive binders. By introducing transition among different categories of beads with specific transition cycles and transition probabilities, our model is capable of introducing different dynamics quantitatively during the folding process, thus capturing variety of phenomena related to chromatin dynamics. Firstly, roles of dynamics in the process of chromatin folding were examined. We discovered that there is a minimum gyration of chromatin under varying characteristic times of transition which indicates neither dramatically dynamic nor static folding process is optimal for chromatin to reach stable states with relatively low free energy. Secondly, it is noticeable that when beads transit from or into others in distinct dynamics, the equilibrium concentrations are distinct as well. As a consequence, the distribution of chromatin loop length is relevant to the dynamics of binders which can be modified by complex such as Wings apart-like protein homolog (Wapl) and SCC2/SCC4 cohesin loader complex (SCC2/SCC4). Finally, our model is able to reproduce contact matrices of both wild type HAP1 cell and ΔWAPL HAP1 cell obtained from Hi-C technology with a relatively high accuracy. Our model recapitulate the accumulating contacts at the corners of TADs and vanishing short-range contacts along the diagonal, manifesting the difference of chromatin structures before and after eliminating WAPL.STATEMENT OF SIGNIFICANCEOur model includes reciprocal transition among beads in SBS model to introduce different dynamics in chromatin folding process. Our model is able to examine the roles of dynamics in chromatin folding, reveal the loop length variation due to the concentration imbalance caused by distinct dynamics and reproduce contact matrices of both wild type and WAPL-deficient cells. Our research work provides a model to investigate the dynamics of chromatin folding quantitatively and displays its significance of revealing multiple experimental results using computational tools.
Floating frogs sound larger: environmental constraints on signal production drives call frequency changes
Authors: Goutte Sandra , Muñoz Matías I. , Ryan Michael J. , Halfwerk Wouter 
Published: February 2020

AbstractIn animal communication, receivers benefit from signals providing reliable information on signallers’ traits of interest. Individuals involved in conflicts, such as competition between rivals, should pay particular attention to cues that are ‘unfakeable’ by the senders due to the intrinsic properties of the production process. In bioacoustics, the best-known example of such ‘index signals’ is the relationship between a sender’s body size and the dominant frequency of their vocalizations. Dominant frequency may however not only depend on an animal’s morphology but also on the interaction between the sound production system and its immediate environment. Here, we experimentally altered the environment surrounding calling frogs and assessed its impact on the signal produced. More specifically, we altered water level, which forced frogs to float on the surface and tested how this manipulation affected the shuttling of air between the lungs and the vocal sac, and how this in turn impacted the calls’ dominant frequency. Our results show that frogs that are floating are able to fully inflate their lungs and vocal sacs, and that the associated change in airflow or air pressure is correlated with a decrease of call dominant frequency.
Yaphaploinsufficiency leads to Müller cell dysfunction and late-onset cone dystrophy
Authors: Masson Christel , García-García Diana , Bitard Juliette , Grellier Élodie-Kim , Roger Jérôme E. , Perron Muriel 
Published: February 2020

ABSTRACTHippo signalling regulates eye growth during embryogenesis through its effectors YAP and TAZ. Taking advantage of aYapheterozygous mouse line, we here sought to examine its function in adult neural retina, where YAP expression is restricted to Müller glia. We first discovered an unexpected temporal dynamic of gene compensation. At post-natal stages,Tazupregulation occurs, leading to a gain of function-like phenotype characterized by EGFR signalling potentiation and delayed cell cycle exit of retinal progenitors. In contrast,Yap+/-adult retinas no longer exhibit TAZ-dependent dosage compensation. In this context,Yaphaploinsufficiency in aged individuals results in Müller glia dysfunction, late-onset cone degeneration and reduced cone-mediated visual response. Alteration of glial homeostasis and altered patterns of cone opsins were also observed in Müller cell specific conditionalYapknockout mice. Together, this study highlights a novel YAP function in Müller cells for the maintenance of retinal tissue homeostasis and the preservation of cone integrity. It also suggests that YAP haploinsufficiency should be considered and explored as a cause of cone dystrophies in human.Main PointsThis study finds unsuspected dynamics of YAP compensatory mechanisms in the retina ofYap+/-miceYaphaploinsufficiency results in Müller glia dysfunction in aged mice, leading to late-onset cone dystrophy
Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differential modulation of ABC transporters on chronic myeloid leukemias
Authors: Salustiano Eduardo J. , da Costa Kelli M. , Freire-de-Lima Leonardo , Mendonça-Previato Lucia , Previato José O. 
Published: February 2020

ABSTRACTMultidrug resistance (MDR) in cancer manifests due to cross-resistance to chemotherapeutic drugs with neither structural nor functional relationship, markedly by increased expression and activity of ABC superfamily transporters. Evidences indicate sphingolipids as substrates to ABC proteins in processes such as cell signaling, membrane biosynthesis and inflammation, and products of its biosynthetic route were shown to favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key cell regulator enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Under stress, cells increasede novobiosynthesis of ceramides, which return to sub-toxic levels after assimilation into GlcCer by UGCG. Given that cancer cells seem to mobilize UGCG and increase GSL contents for the clearance of ceramides ultimately contributing to treatment failure, we studied how inhibiting GSL biosynthesis would affect the MDR phenotype of chronic myeloid leukemias. Results indicate that MDR associates to higher expression of UGCG and to a complex GSL profile. Inhibition of this glucosyltransferase greatly reduced GM1 expression, and cotreatment with standard chemotherapeutics sensitized cells leading to mitochondrial membrane potential loss and apoptosis. Despite reducing ABCB1 expression, only the ABCC-mediated efflux activity was affected. Consistently, efflux of C6-ceramide, one byproduct of UGCG downregulation, was reduced after inhibition of ABCC-mediated transport. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, overcoming drug resistance through distinct mechanisms. This work brings more comprehension about the involvement of GSL for chemotherapy failure, and modulation of its contents emerges as an intervention targeted to MDR leukemias.
TERT-mediated induction of MIR500A contributes to tumor invasiveness by targeting Hedgehog pathway
Authors: Bernabé-García Manuel , Martínez-Balsalobre Elena , García-Moreno Diana , García-Castillo Jesús , Revilla-Nuin Beatriz , Blanco-Alcaina Elena , Mulero Victoriano , Alcaraz-Pérez Francisca , Cayuela María L. 
Published: February 2020

AbstractThe classical activity of telomerase (TERT) is to maintain telomere homeostasis, ensuring chromosome stability and cellular proliferation. However, increasing evidences of telomere-independent human TERT functions have been lastly obtained. We report here that TERT directly binds to the TCF binding elements (TBE) located upstream the oncomiRMIR500Ainducing its expression and promoting cancer invasiveness. This function is independent of telomerase activity, since catalytic inactive TERT also inducesMIR500Aexpression and telomerase inhibitors directed against TERT, but not to its RNA componentTERC, inhibit telomerase-inducedMIR500Aexpression and cancer invasiveness. Mechanistically, telomerase-inducedMIR500Adown-regulates key genes of the Hedgehog signaling pathway, namely patched 1 (PTCH1), Gli family zinc finger 3 (GLI3) and cullin 3 (CUL3), increasing tumor invasiveness. Our results show a crucial role of the TERT/MIR500A/Hedgehog axis is tumor aggressiveness, pointing out to the relevance of inhibiting the extracurricular functions of telomerase to fight cancer.
An alternative miRISC targeting a coding mutation site inFOXL2links to granulosa cell tumor
Authors: Shin Eunkyoung , Jin Hanyong , Suh Dae-Shik , Luo Yongyang , Ha Hye-Jeong , Kim Tae Heon , Hahn Yoonsoo , Hyun Seogang , Lee Kangseok , Bae Jeehyeon 
Published: February 2020

ABSTRACTRecent evidence suggests that animal microRNAs (miRNAs) can target coding sequences (CDSs); however, the pathophysiological importance of such targeting remains unknown. Here, we show that a somatic heterozygous missense mutation (c.402C>G; p.C134W) inFOXL2, a feature shared by virtually all adult-type granulosa cell tumors (AGCTs), introduces a target site for miR-1236, which induces haploinsufficiency of the tumor-suppressorFOXL2. This miR-1236-mediated selective degradation of the variantFOXL2mRNA is preferentially conducted by a distinct miRNA-loaded RNA-induced silencing complex (miRISC) directed by the Argonaute3 (AGO3) and DHX9 proteins. In both patients and mouse model of AGCT, the inversely regulated variantFOXL2abundance with the miR-1236 levels was highly correlated with malignant features of AGCT. Our study provides a molecular basis for understanding the conservedFOXL2CDS mutation-mediated etiology of AGCT, revealing the existence of a previously unidentified mechanism of miRNA-targeting disease-associated mutations in the CDS by forming a non-canonical miRISC.
NFκB dynamics determine the stimulus-specificity of epigenomic reprogramming in macrophages
Authors: Cheng Quen J. , Ohta Sho , Sheu Katherine M. , Spreafico Roberto , Adelaja Adewunmi , Taylor Brooks , Hoffmann Alexander 
Published: February 2020

SummaryThe epigenome defines the cell type, but also shows plasticity that enables cells to tune their gene expression potential to the context of extracellular cues. This is evident in immune sentinel cells such as macrophages, which can respond to pathogens and cytokines with phenotypic shifts that are driven by epigenomic reprogramming1. Recent studies indicate that this reprogramming arises from the activity of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), which binds not only to available enhancers but may producede novoenhancers in previously silent areas of the genome2. Here, we show that NFκB reprograms the macrophage epigenome in a stimulus-specific manner, in response only to a subset of pathogen-derived stimuli. The basis for these surprising differences lies in the stimulus-specific temporal dynamics of NFκB activity. Testing predictions of a mathematical model of nucleosome interactions, we demonstrate through live cell imaging and genetic perturbations that NFκB promotes open chromatin and formation ofde novoenhancers most strongly when its activity is non-oscillatory. Thesede novoenhancers result in the activation of additional response genes. Our study demonstrates that the temporal dynamics of NFκB activity, which encode ligand identity3, can be decoded by the epigenome throughde novoenhancer formation. We propose a mechanistic paradigm in which the temporal dynamics of transcription factors are a key determinant of their capacity to control epigenomic reprogramming, thus enabling the formation of stimulus-specific memory in innate immune sentinel cells.
Are pangolins the intermediate host of the 2019 novel coronavirus (2019-nCoV) ?
Authors: Liu Ping , Jiang Jing-Zhe , Wan Xiu-Feng , Hua Yan , Wang Xiaohu , Hou Fanghui , Chen Jing , Zou Jiejian , Chen Jinping 
Published: February 2020

AbstractThe outbreak of 2019-nCoV pneumonia (COVID-19) in the city of Wuhan, China has resulted in more than 70,000 laboratory confirmed cases, and recent studies showed that 2019-nCoV (SARS-CoV-2) could be of bat origin but involve other potential intermediate hosts. In this study, we assembled the genomes of coronaviruses identified in sick pangolins. The molecular and phylogenetic analyses showed that pangolin Coronaviruses (pangolin-CoV) are genetically related to both the 2019-nCoV and bat Coronaviruses but do not support the 2019-nCoV arose directly from the pangolin-CoV. Our study also suggested that pangolin be natural host ofBetacoronavirus, with a potential to infect humans. Large surveillance of coronaviruses in pangolins could improve our understanding of the spectrum of coronaviruses in pangolins. Conservation of wildlife and limits of the exposures of humans to wildlife will be important to minimize the spillover risks of coronaviruses from wild animals to humans.
Comparing the Fate of Brain Metastatic Breast Cancer Cells in Different Immune Compromised Mice with Cellular Magnetic Resonance Imaging
Authors: Knier Natasha N. , Hamilton Amanda M. , Foster Paula J. 
Published: February 2020

AbstractMetastasis is the leading cause of mortality in breast cancer patients, with brain metastases becoming increasingly prevalent. Studying this disease is challenging due to the limited experimental models and methods available. Here, we used iron-based cellular MRI to track the fate of a mammary carcinoma cell line (MDA-MB-231-BR)in vivoto characterize the growth of brain metastases in the nude and severely immune-compromised NOD/SCID/ILIIrg−/− (NSG) mouse.Nude and NSG mice received injections of iron-labeled MDA-MB-231-BR cells. Images were acquired with a 3T MR system and assessed for signal voids and metastases. The percentage of signal voids and the number and volume of metastases were quantified.Ex vivoimaging of the liver, histology, and immunofluorescence labeling was performed.On day 0, iron-labeled cells were visualized as signal voids throughout the brain. The percentage of voids decreased significantly between day 0 and endpoint. At endpoint, there was no difference in the number of brain metastases or tumour burden in NSG mice compared to nudes. Tumour volumes in nude mice were significantly larger than in NSG mice. Body images indicated that the NSG mice had metastases in the liver, lungs, and lymph nodes.Characterization of the NSG and nude mouse is necessary to study breast cancer brain metastasisin vivo. Here, we show that the 231BR cell line grew differently in NSG mice compared to nude mice. This work demonstrates the role that imaging can play toward credentialing these models that cannot be done with otherin vitroor histopathologic methods alone.
Highly specific, multiplexed isothermal pathogen detection with fluorescent aptamer readout
Authors: Aufdembrink Lauren M. , Khan Pavana , Gaut Nathaniel J , Adamala Katarzyna P. , Engelhart Aaron E. 
Published: February 2020

AbstractIsothermal, cell-free, synthetic biology-based approaches to pathogen detection leverage the power of tools available in biological systems, such as highly active polymerases compatible with lyophilization, without the complexity inherent to live-cell systems, of which Nucleic Acid Sequence Based Amplification (NASBA) is well known. Despite the reduced complexity associated with cell-free systems, side reactions are a common characteristic of these systems. As a result, these systems often exhibit false positives from reactions lacking an amplicon. Here we show that the inclusion of a DNA duplex lacking a promoter and unassociated with the amplicon, fully suppresses false positives, enabling a suite of fluorescent aptamers to be used as NASBA tags (Apta-NASBA). Apta-NASBA has a 1 pM detection limit and can provide multiplexed, multicolor fluorescent readout. Furthermore, Apta-NASBA can be performed using a variety of equipment, for example a fluorescence microplate reader, a qPCR instrument, or an ultra-low-cost Raspberry Pi-based 3D-printed detection platform employing a cell phone camera module, compatible with field detection.
Tracing animal genomic evolution with the chromosomal-level assembly of the freshwater sponge Ephydatia muelleri
Authors: Kenny Nathan J , Francis Warren R. , Rivera-Vicéns Ramón E. , Juravel Ksenia , de Mendoza Alex , Díez-Vives Cristina , Lister Ryan , Bezares-Calderon Luis , Grombacher Lauren , Roller Maša , Barlow Lael D. , Camilli Sara , Ryan Joseph F. , Wörheide Gert , Hill April L , Riesgo Ana , Leys Sally P. 
Published: February 2020

AbstractThe genomes of non-bilaterian metazoans are key to understanding the molecular basis of early animal evolution. However, a full comprehension of how animal-specific traits such as nervous systems arose is hindered by the scarcity and fragmented nature of genomes from key taxa, such as Porifera. Ephydatia muelleri is a freshwater sponge found across the northern hemisphere. Here we present its 326 Mb genome, assembled to high contiguity (N50: 9.88 Mb) with 23 chromosomes on 24 scaffolds. Our analyses reveal a metazoan-typical genome architecture, with highly shared synteny across Metazoa, and suggest that adaptation to the extreme temperatures and conditions found in freshwater often involves gene duplication. The pancontinental distribution and ready laboratory culture of E. muelleri make this a highly practical model system, which with RNAseq, DNA methylation and bacterial amplicon data spanning its development and range allows exploration of genomic changes both within sponges and in early animal evolution.
A Src family kinase maintains latent sensitization in rats, a model of inflammatory and neuropathic pain
Authors: Chen Wenling , Marvizón Juan Carlos 
Published: February 2020

AbstractLatent sensitization is a long-term model of chronic pain in which hyperalgesia is continuously suppressed by opioid receptors. This is demonstrated by the induction of mechanical allodynia by opioid antagonists. Different intracellular signals may mediate the initiation, maintenance and expression of latent sensitization. Our criterion for the involvement of a signal in the maintenance of latent sensitization is that it inhibitors should permanently eliminate the allodynia produced by an opioid antagonist. We hypothesized that Src family kinases (SFKs) maintain latent sensitization and tested this hypothesis in rats with latent sensitization induced by complete Freund’s adjuvant (CFA) or by spared nerve injury. After measures of mechanical allodynia returned to baseline, the SFK inhibitor PP2 or vehicle were injected intrathecally. The opioid antagonist naltrexone injected intrathecally 15 min later produced allodynia in control rats but not in rats injected with PP2. PP2 or vehicle were injected daily for two more days and naltrexone was injected five days later. Again, naltrexone induced allodynia in the control rats but not in the rats injected with PP2. Results were similar when latent sensitization was induced either with CFA or spared nerve injury. We concluded that an SFK, likely Fyn, maintains latent sensitization induced by inflammation or nerve injury.PerspectiveThis article presents evidence that a Src family kinase, likely Fyn, maintains latent sensitization induced by inflammation or nerve injury. If latent sensitization is a valid model of chronic pain, inhibiting its maintenance with Src family kinase inhibitors may cure chronic pain.