bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-scale approaches for high-speed imaging and analysis of large neural populations
Authors: Friedrich Johannes , Yang Weijian , Soudry Daniel , Mu Yu , Ahrens Misha B. , Yuste Rafael , Peterka Darcy S. , Paninski Liam 
Published: December 2016

AbstractProgress in modern neuroscience critically depends on our ability to observe the activity of large neuronal populations with cellular spatial and high temporal resolution. However, two bottlenecks constrain efforts towards fast imaging of large populations. First, the resulting large video data is challenging to analyze. Second, there is an explicit tradeoff between imaging speed, signal-to-noise, and field of view: with current recording technology we cannot image very large neuronal populations with simultaneously high spatial and temporal resolution.Here we describe multi-scale approaches for alleviating both of these bottlenecks. First, we show that spatial and temporal decimation techniques provide order-of-magnitude speedups in spatiotemporally demixing calcium video data into estimates of single-cell neural activity. Second, once the shapes of individual neurons have been identified (e.g., after an initial phase of conventional imaging with standard temporal and spatial resolution), we find that the spatial/temporal resolution tradeoff shifts dramatically: after demixing we can accurately recover neural activity from data that has been spatially decimated by an order of magnitude. This offers a cheap method for compressing this large video data, and also implies that it is possible to either speed up imaging significantly, or to “zoom out” by a corresponding factor to image order-of-magnitude larger neuronal populations with minimal loss in accuracy or temporal resolution.Author SummaryThe voxel rate of imaging systems ultimately sets the limit on the speed of data acquisition. These limits often mean that only a small fraction of the activity of large neuronal populations can be observed at high spatio-temporal resolution. For imaging of very large populations with single cell resolution, temporal resolution is typically sacrificed. Here we propose a multi-scale approach to achieve single cell precision using fast imaging at reduced spatial resolution. In the first phase the spatial location and shape of each neuron is obtained at standard spatial resolution; in the second phase imaging is performed at much lower spatial resolution. We show that we can apply a demixing algorithm to accurately recover each neuron’s activity from the low-resolution data by exploiting the high-resolution cellular maps estimated in the first imaging phase. Thus by decreasing the spatial resolution in the second phase, we can compress the video data significantly, and potentially acquire images over an order-of-magnitude larger area, or image at significantly higher temporal resolution, with minimal loss in accuracy of the recovered neuronal activity. We evaluate this approach on real data from light-sheet and 2-photon calcium imaging.
Senescence gives insights into the morphogenetic evolution of anamniotes
Authors: Villiard Éric , Denis Jean-François , Hashemi Faranak Sadat , Igelmann Sebastian , Ferbeyre Gerardo , Roy Stéphane 
Published: December 2016

Summary statementWe report the presence of senescent cells in several transient structures in developing amphibian and teleost fish, suggesting novel mechanisms of morphogenesis that appeared early in vertebrate evolution.AbstractSenescence represents a mechanism to avoid undesired cell proliferation that plays a role in tumor suppression, wound healing and embryonic development. In order to gain insight on the evolution of senescence, we looked at its presence in developing axolotls (urodele amphibians) and in zebrafish (teleost fish), which are both anamniotes. Our data indicate that cellular senescence is present in various developing structures in axolotls (pronephros, olfactory nerve fascicles, lateral organs, gums) and in zebrafish (epithelium of the yolk sac and in the lower part of the gut). Senescence was particularly associated with transient structures (pronephros in axolotls & yolk sac in zebrafish) suggesting that it plays a role in the elimination of these tissues. Our data supports the notion that cellular senescence evolved early in vertebrate evolution to influence embryonic development.
Resonance modulation, annihilation and generation of antiresonance and antiphasonance in 3D neuronal systems: interplay of resonant and amplifying currents with slow dynamics
Authors: Rotstein Horacio G. 
Published: December 2016

AbstractSubthreshold (membrane potential) resonance and phasonance (preferred amplitude and zero-phase responses to oscillatory inputs) in single neurons arise from the interaction between positive and negative feedback effects provided by relatively fast amplifying currents and slower resonant currents. In 2D neuronal systems, amplifying currents are required to be slaved to voltage (instantaneously fast) for these phenomena to occur. In higher dimensional systems, additional currents operating at various effective time scales may modulate and annihilate existing resonances and generate antiresonance (minimum amplitude response) and antiphasonance (zero-phase response with phase monotonic properties opposite to phasonance). We use mathematical modeling, numerical simulations and dynamical systems tools to investigate the mechanisms underlying these phenomena in 3D linear models, which are obtained as the linearization of biophysical (conductance-based) models. We characterize the parameter regimes for which the system exhibits the various types of behavior mentioned above in the rather general case in which the underlying 2D system exhibits resonance. We consider two cases: (i) the interplay of two resonant gating variables, and (ii) the interplay of one resonant and one amplifying gating variables. Increasing levels of an amplifying current cause (i) a response amplification if the amplifying current is faster than the resonant current, (ii) resonance and phasonance attenuation and annihilation if the amplifying and resonant currents have identical dynamics, and (iii) antiresonance and antiphasonance if the amplifying current is slower than the resonant current. We investigate the underlying mechanisms by extending the envelope-plane diagram approach developed in previous work (for 2D systems) to three dimensions to include the additional gating variable, and constructing the corresponding envelope curves in these envelope-space diagrams. We find that antiresonance and antiphasonance emerge as the result of an asymptotic boundary layer problem in the frequency domain created by the different balances between the intrinsic time constants of the cell and the input frequencyfas it changes. For large enough values offthe envelope curves are quasi-2D and the impedance profile decrease with the input frequency. In contrast, forf≪ 1 the dynamics is quasi-1D and the impedance profile increases above the limiting value in the other regime. Antiresonance is created because the continuity of the solution requires the impedance profile to connect the portions belonging to the two regimes. If in doing so the phase profile crosses the zero value, then antiphasonance is also generated.
Mechanism of ribosome rescue by ArfA and RF2
Authors: Demo Gabriel , Svidritskiy Egor , Madireddy Rohini , Diaz-Avalos Ruben , Grant Timothy , Grigorieff Nikolaus , Sousa Duncan , Korostelev Andrei A. 
Published: December 2016

AbstractArfA rescues ribosomes stalled on truncated mRNAs by recruiting the release factor RF2, which normally binds stop codons to catalyze peptide release. We report two 3.2-Å resolution cryo-EM structures – determined from a single sample – of the 70S ribosome with ArfA∙RF2 in the A site. In both states, the ArfA C-terminus occupies the mRNA tunnel downstream of the A site. One state contains a compact inactive RF2 conformation, hitherto unobserved in 70S termination complexes. Ordering of the ArfA N-terminus in the second state rearranges RF2 into an extended conformation that docks the catalytic GGQ motif into the peptidyl-transferase center. Our work thus reveals the structural dynamics of ribosome rescue. The structures demonstrate how ArfA “senses” the vacant mRNA tunnel and activates RF2 to mediate peptide release without a stop codon, allowing stalled ribosomes to be recycled.
Pathways analyses of schizophrenia GWAS focusing on known and novel drug targets
Authors: Gaspar H.A. , Breen G. 
Published: December 2016

ABSTRACTUsing successful genome-wide association results in psychiatry for drug repurposing is an ongoing challenge. Databases collecting drug targets and gene annotations are growing and can be harnessed to shed a new light on psychiatric disorders. We used GWAS summary statistics from the Psychiatric Genetics Consortium (PGC) Schizophrenia working group and a repositioning model for schizophrenia by testing the enrichment of antipsychotics. As sample size increases, schizophrenia GWAS results show increasing enrichment for known antipsychotic drugs, selective calcium channel blockers, and antiepileptics. Each of these therapeutical classes targets different gene subnetworks. We identify 162 Bonferroni-significant druggable genes, and 128 FDR-significant biological pathways related to neurons, synapses, genic intolerance, membrane transport, epilepsy, and mental disorders. These results suggest that, in schizophrenia, current well-powered GWAS results can reliably detect known schizophrenia drugs and thus may hold considerable potential for the identification of new therapeutic leads. Moreover, antiepileptics and calcium channel blockers may provide repurposing opportunities. This study also reveals significant pathways in schizophrenia that were not identified previously, and provides a workflow for pathway analysis and drug repurposing using GWAS results.
Negative regulation of uPAR activity by a GPI-specific phospholipase C
Authors: van Veen Michiel , Matas-Rico Elisa , van de Wetering Koen , Leyton-Puig Daniela , Kedziora Katarzyna M. , Sidenius Nicolai , Jalink Kees , Perrakis Anastassis , Moolenaar Wouter H. 
Published: December 2016

AbstractThe urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins and other receptors. Full-length uPAR is released from the cell surface, but the mechanism and functional significance of uPAR release remain obscure. Here we show that transmembrane glycerophosphodiesterase GDE3 is a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of the proteolytic and non-proteolytic activities of uPAR. In breast cancer cells, high GDE3 expression depletes endogenous uPAR resulting in a less transformed phenotype, correlating with higher survival probability in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, more generally, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior.
CharacterizingXenopus tropicalisendurance capacities with multilevel transcriptomics
Authors: Richards Adam J. , Herrel Anthony , Videlier Mathieu , Paszkiewicz Konrad , Pollet Nicolas , Bonneaud Camille 
Published: December 2016

AbstractVertebrate endurance capacity is a phenotype with considerable genetic heterogeneity. RNA-Seq technologies are an ideal tool to investigate the involved genes and processes, but several challenges exist when the phenotype of interest has a complex genetic background. Difficulties manifest at the level of results interpretation because commonly used statistical methods are designed to identify strongly associated genes. If an observed phenotype can be achieved though multiple distinct genetic mechanisms then typical gene-centric methods come with the attached risk that signal may be lost or misconstrued.Gene set analysis (GSA) methods are now widely accepted as a means to address some of the shortcomings of gene-by-gene analysis methods. We carry out both gene level and gene set level analyses onXenopus tropicalisto identify the genetic factors that contribute to endurance heterogeneity. A typical workflow might consider gene level and pathway level analyses, but in this work we propose an additional focus at the intermediate level of functional modules. We generate functional modules for GSA testing in order to be explicit in how ontology information is used with respect to the functional genomics ofXenopus. Additionally, we make use of multiple assemblies to corroborate implicated genes and processes.We identified 42 core genes, 10 functional modules, and 14 pathways based on gene expression differences between endurant and non-endurant frogs. The majority of the genes and processes are readily associated with muscle contraction or catabolism. A substantial number of these genes are involved in lipid metabolic processes, suggesting an important role in frog endurance heterogeneity. Unsurprisingly, many of the gene expression differences between endurant and non-endurant frogs can be distilled down to the capacity to utilize substrate for energy, but at the individual level frogs appear to make use of diverse machinery to achieve these differences.
Compositional Inductive Biases in Function Learning
Authors: Schulz Eric , Tenenbaum Joshua B. , Duvenaud David , Speekenbrink Maarten , Gershman Samuel J. 
Published: December 2016

AbstractHow do people recognize and learn about complex functional structure? Taking inspiration from other areas of cognitive science, we propose that this is achieved by harnessing compositionality: complex structure is decomposed into simpler building blocks. We formalize this idea within the framework of Bayesian regression using a grammar over Gaussian process kernels, and compare this approach with other structure learning approaches. Participants consistently chose compositional (over non-compositional) extrapolations and interpolations of functions. Experiments designed to elicit priors over functional patterns revealed an inductive bias for compositional structure. Compositional functions were perceived as subjectively more predictable than non-compositional functions, and exhibited other signatures of predictability, such as enhanced memorability and reduced numerosity. Taken together, these results support the view that the human intuitive theory of functions is inherently compositional.
Resource Competition Shapes the Response of Genetic Circuits
Authors: Qian Yili , Huang Hsin-Ho , Jimenéz José I. , Del Vecchio Domitilla 
Published: December 2016

AbstractA common approach to design genetic circuits is to compose gene expression cassettes together. While appealing, this modular approach is challenged by the fact that expression of each gene depends on the availability of transcriptional/translational resources, which is in turn determined by the presence of other genes in the circuit. This raises the question of how competition for resources by different genes affects a circuit’s behavior. Here, we create a library of genetic activation cascades in bacteriaE. coli, where we explicitly tune the resource demand by each gene. We develop a general Hill-function-based model that incorporates resource competition effects through resource demand coefficients. These coefficients lead to non-regulatory interactions among genes that reshape circuit’s behavior. For the activation cascade, such interactions result in surprising biphasic or monotonically decreasing responses. Finally, we use resource demand coefficients to guide the choice of ribosome binding site (RBS) and DNA copy number to restore the cascade’s intended monotonically increasing response. Our results demonstrate how unintended circuit’s behavior arises from resource competition and provide a model-guided methodology to minimize the resulting effects.
Mindboggling morphometry of human brains
Authors: Klein Arno , Ghosh Satrajit S. , Bao Forrest S. , Giard Joachim , Häme Yrjö , Stavsky Eliezer , Lee Noah , Rossa Brian , Reuter Martin , Chaibub Neto Elias , Keshavan Anisha 
Published: December 2016

AbstractMindboggle (http://mindboggle.info) is an open source brain morphometry platform that takes in preprocessed T1-weighted MRI data and outputs volume, surface, and tabular data containing label, feature, and shape information for further analysis. In this article, we document the software and demonstrate its use in studies of shape variation in healthy and diseased humans. The number of different shape measures and the size of the populations make this the largest and most detailed shape analysis of human brains every conducted. Brain image morphometry shows great potential for providing much-needed biological markers for diagnosing, tracking, and predicting progression of mental health disorders. Very few software algorithms provide more than measures of volume and cortical thickness, and more subtle shape measures may provide more sensitive and specific biomarkers. Mindboggle computes a variety of (primarily surface-based) shapes: area, volume, thickness, curvature, depth, Laplace-Beltrami spectra, Zernike moments, etc. We evaluate Mindboggle’s algorithms using the largest set of manually labeled, publicly available brain images in the world and compare them against state-of-the-art algorithms where they exist. All data, code, and results of these evaluations are publicly available.Author SummaryBrains vary in many ways, including their shape. Analysing differences in shape between brains or changes in brain shape over time has been used to characterize morphology of diseased brains, but these analyses conventionally rely on simple volumetric shape measures. We believe that access to a greater variety of shape measures could provide greater sensitivity and specificity to morphological disturbances, and could aid in diagnosis, tracking, and prediction of the progression of mental health disorders. Mindboggle is open source software that provides neuroscientists (and indeed, anyone interested in computing shapes) tools for computing a variety of shape measures, including area, volume, thickness, curvature, geodesic depth, travel depth, Laplace-Beltrami spectra, and Zernike moments. In addition to algorithmic contributions, we conducted evaluations and applied Mindboggle to conduct the most detailed shape analysis of human brains.
Exploring the mutational robustness of nucleic acids by searching genotype neighbourhoods in sequence space
Authors: Zhou Qingtong , Sun Xianbao , Xia Xiaole , Fan Zhou , Luo Zhaofeng , Zhao Suwen , Liang Haojun , Shakhnovich Eugene 
Published: December 2016

AbstractTo assess the mutational robustness of nucleic acids, many genome- and protein-level studies have been performed; in these investigations, nucleic acids are treated as genetic information carriers and transferrers. However, the molecular mechanism through which mutations alter the structural, dynamic and functional properties of nucleic acids is poorly understood. Here, we performed SELEX in silico study to investigate the fitness distribution of the nucleic acid genotype neighborhood in a sequence space for L-Arm binding aptamer. Although most mutants of the L-Arm-binding aptamer failed to retain their ligand-binding ability, two novel functional genotype neighborhoods were isolated by SELEX in silico and experimentally verified to have similar binding affinity (Kd= 69.3 μM and 110.7 μM) as the wild-type aptamer (Kd= 114.4 μM). Based on data from the current study and previous research, mutational robustness is strongly influenced by the local base environment and ligand-binding mode, whereas bases distant from the binding pocket provide potential evolutionary pathways to approach global fitness maximum. Our work provides an example of successful application of SELEX in silico to optimize an aptamer and demonstrates the strong sensitivity of mutational robustness to the site of genetic variation.
Diagnostic usefulness of dermoscopy in differentiating lichen aureus from nummular eczema
Authors: Suh Kee Suck , Park Jong Bin , Yang Myeong Hyeon , Choi Soo Young , Hwangbo Hyun , Jang Min Soo 
Published: December 2016

AbstractLichen aureus (LA) is a variant of pigmented purpuric dermatosis that is characterized clinically by rust macules, papules or plaques, mainly on the legs. In some cases, LA can be difficult to be distinguished from nummular eczema (NE) with the naked eye. Dermoscopy can be applied to skin lesions, revealing additional features that can be highly valuable for correct diagnosis. This study was conducted to investigate characteristic dermoscopic findings of LA and to identify distinctive features that can differentiate it from NE. Fourteen LA patients and 14 NE patients diagnosed by skin biopsy were enrolled. Skin lesions were evaluated via polarized dermoscopy. On dermoscopy, “coppery orange diffuse coloration of background”, “round to oval red globules”, “gray dots”, and “networks of brownish to gray interconnected lines” were more commonly seen in LA (100%, 92.9%, 42.9% and 64.3%, respectively) compared with NE. “Scales”, “shiny yellow clods” and “irregularly distributed brownish‐red globules” were more commonly seen in NE (100%, 85.7% and 57.1%, respectively) compared with LA. Dermoscopy provides valuable information for diagnosis of LA and aids in differentiating it from NE.
Non‐paraneoplastic autoimmune subepidermal bullous disease associated with fatal bronchiolitis obliterans
Authors: Orime Mari , Tomiyama Katsuhiro , Hashidate Hideki , Yoshida Satoru , Hokari Satoshi , Tsuda Akiko , Yokoyama Hisashi , Narita Jun‐ichi , Uchida Youhei , Kanekura Takuro , Abe Riichiro , Ishii Norito , Hashimoto Takashi , Kawai Kazuhiro 
Published: December 2016

AbstractBronchiolitis obliterans is a small‐airway obstructive lung disease for which immunologically mediated pathogenesis is supposed. Frequent association of bronchiolitis obliterans with paraneoplastic pemphigus is well known, but its association with other autoimmune bullous diseases has not been reported except for a case of anti‐laminin‐332‐type mucous membrane pemphigoid in a patient with chronic graft‐versus‐host disease. We report a case of non‐paraneoplastic autoimmune subepidermal bullous disease associated with fatal bronchiolitis obliterans in a patient without transplantation. Although the patient's serum contained immunoglobulin (Ig)A antibodies to the 180‐kDa bullous pemphigoid antigen/type XVII collagen and IgG antibodies to laminin‐332, diagnosis of either linear IgA bullous dermatosis or mucous membrane pemphigoid could not be made because of the failure to detect linear IgA deposition at the basement membrane zone by direct immunofluorescence and the lack of mucous membrane lesions. Physicians should be aware that autoimmune bullous diseases other than paraneoplastic pemphigus can also associate with this rare but potentially fatal lung disease.
Successful treatment of multiple in‐transit melanomas on the leg with intensity‐modulated radiotherapy and immune checkpoint inhibitors: Report of two cases
Authors: Fujimura Taku , Kambayashi Yumi , Furudate Sadanori , Hidaka Takanori , Sato Yota , Tanita Kayo , Tono Hisayuki , Tsukada Akira , Hashimoto Akira , Aiba Setsuya 
Published: December 2016

AbstractBecause the efficacy rates of monotherapy with immune checkpoint inhibitors such as nivolumab or ipilimumab are not sufficient, to enhance the antitumor effects of these reagents is of great interest among dermato‐oncologists. In this report, we describe two cases of multiple in‐transit metastatic melanomas on the leg successfully treated with intensity‐modulated radiotherapy (IMRT) using a CyberKnife in combination with ipilimumab or nivolumab. Our cases suggested that IMRT could enhance the antitumor effects of immune checkpoint inhibitors in patients with multiple in‐transit melanomas.