bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dimensionality Reduction on Spatio-Temporal Maximum Entropy Models of Spiking Networks
Authors: Herzog Rubén , Escobar María-José , Cofre Rodrigo , Palacios Adrián G. , Cessac Bruno 
Published: March 2018

AbstractMaximum entropy models (MEM) have been widely used in the last 10 years to characterize the statistics of networks of spiking neurons. A major drawback of this approach is that the number of parameters used in the statistical model increases very fast with the network size, hindering its interpretation and fast computation. Here, we present a novel framework of dimensionality reduction for generalized MEM handling spatio-temporal correlations. This formalism is based on information geometry where a MEM is a point on a large-dimensional manifold. We exploit the geometrical properties of this manifold in order to find a projection on a lower dimensional space that best captures the high-order statistics. This allows us to define a quantitative criterion that we call the “degree of compressibility” of the neuronal code. A powerful aspect of this method is that it does not require fitting the model. Indeed, the matrix defining the metric of the manifold is computed directly via the data without parameters fitting. The method is first validated using synthetic data generated by a known statistics. We then analyze a MEM having more parameters than the underlying data statistics and show that our method detects the extra dimensions. We then test it on experimental retinal data. We record retinal ganglion cells (RGC) spiking data using multi-electrode arrays (MEA) under different visual stimuli: spontaneous activity, white noise stimulus, and natural scene. Using our method, we report a dimensionality reduction up to 50% for retinal data. As we show, this is quite a huge reduction compared to a randomly generated spike train, suggesting that the neuronal code, in these experiments, is highly compressible. This additionally shows that the dimensionality reduction depends on the stimuli statistics, supporting the idea that sensory networks adapt to stimuli statistics by modifying the level of redundancy.Author SummaryMaximum entropy models (MEM) have been widely used to characterize the statistics of networks of spiking neurons. However, as the network size increases, the number of model parameters increases rapidly, hindering its interpretation and fast computation. Here, we propose a method to evaluate the dimensionality reduction of MEM, based on the geometrical properties of the manifold best capturing the network high-order statistics. Our method is validated with synthetic data using independent or correlated neural responses. Importantly, we show that dimensionality reduction depends on the stimuli statistics, supporting the idea that sensory networks adapt to stimuli statistics modifying the level of redundancy.
Cellular cooperation shapes tumor growth: a statistical mechanics mathematical model
Authors: West Jeffrey , Newton Paul K. 
Published: March 2018

AbstractA tumor is made up of a heterogeneous collection of cell types all competing on a fitness landscape mediated by micro-environmental conditions that dictate their interactions. Despite the fact that much is known about cell signaling and cellular cooperation, the specifics of how the cell-to-cell coupling and the range over which this coupling acts affect the macroscopic tumor growth laws that govern total volume, mass, and carrying capacity remain poorly understood. We develop a statistical mechanics approach that focuses on the total number of possible states each cell can occupy, and show how different assumptions on correlations of these states gives rise to the many different macroscopic tumor growth laws used in the literature. Although it is widely understood that molecular and cellular heterogeneity within a tumor is a driver of growth, here we emphasize that focusing on the functional coupling of these states at the cellular level is what determines macroscopic growth characteristics.Significance statementA mathematical model relating tumor heterogeneity at the cellular level to tumor growth at the macroscopic level is described based on a statistical mechanics framework. The model takes into account the number of accessible states available to each cell as well as their long-range coupling (population cooperation) to other cells. We show that the degree to which cell populations cooperate determine the number of independent cell states, which in turn dictates the macroscopic (volumetric) growth law. It follows that targeting cell-to-cell interactions could be a way of mitigating and controlling tumor growth.
Behavioral phenotyping of an improved mouse model of Phelan-McDermid Syndrome with a complete deletion of the Shank3 gene
Authors: Drapeau Elodie , Riad Mohammed , Kajiwara Yuji , Buxbaum Joseph D. 
Published: March 2018

AbstractPhelan-McDermid Syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability, and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms. Here, we report the production and thorough behavioral characterization of a new mouse model in which all Shank3 isoforms are disrupted. Our mice are more severely affected than previously published models. While the deficits were typically more pronounced in homozygotes, an intermediate phenotype was observed for heterozygotes in many paradigms. As in other Shank3 mouse models, stereotypies, including increased grooming, were observed. Additionally, both sensory and motor deficits were detected in neonatal and adult mice. While social behaviors were not strongly impacted, Shank3-deficient mice displayed a strong escape behavior and avoidance of inanimate objects indicating increased novelty-induced anxiety. Similarly, increased freezing was observed during fear conditioning training and amygdala-dependent cued retrieval. Finally, deficits were observed in both initial training and reversal in the Barnes maze and in contextual fear memory that are memory tasks involving hippocampal-prefrontal circuits. This new mouse model of PMS, engineered to most closely represent human mutations, recapitulates core symptoms of PMS providing improvements for both construct and face validity, compared to previous models.Significant statementPhelan-McDermid syndrome, caused by happloinsufficiency of Shank3, is a severe and complex neurodevelopmental disorder. This study investigates the behavioral consequences of a disruption of all Shank3 isoforms in neonatal and adult mice using a detailed battery of tests tailored to investigate core symptoms and usual comorbidities of PMS. We found that our new model is more severely affected than previously published mouse models with only partial deletions of Shank3 and more closely recapitulates symptoms of PMS thus providing improvements for both construct and face validity. Our results highlight the significance of using a mouse model with a complete deletion of Shank3 for studying mechanisms underlying autism spectrum disorder and PMS, carrying preclinical studies and testing test novel therapeutic approaches.
Fasting prevents hypoxia-induced defects of proteostasis inC. elegans
Authors: Iranon Nicole N , Jochim Bailey E , Miller Dana L 
Published: March 2018

AbstractLow oxygen conditions (hypoxia) can impair essential physiological processes and cause cellular damage and death. We have shown that specific hypoxic conditions disrupt protein homeostasis inC. elegans, leading to protein aggregation and proteotoxicity. Here, we show that nutritional cues regulate this effect of hypoxia on proteostasis. Animals fasted prior to hypoxic exposure develop dramatically fewer protein aggregates compared to their fed counterparts, indicating that the effect of hypoxia is abrogated. Fasting is effective at protecting against hypoxia-induced proteostasis defects in multiple developmental stages, tissues, and in different models of misfolded or aggregation prone proteins. Our data also demonstrate that the effect of fasting is induced and reversed quite rapidly, suggesting that the nutritional environment experienced at the onset of hypoxia dictates at least some aspects of the physiological response to hypoxia. We further demonstrate that the insulin/IGF-like signaling pathway plays a role in mediating the protective effects of fasting in hypoxia. Animals with mutations indaf-2, theC. elegansinsulin-like receptor, display wild-type levels of hypoxia-induced protein aggregation upon exposure to hypoxia when fed, but are not protected by fasting. However, we found that DAF-2 acts independently of the FOXO transcription factor, DAF-16, to mediate the protective effects of fasting. These results suggest a non-canonical role for the insulin/IGF-like signaling pathway in coordinating the effects of hypoxia and nutritional state on proteostasis.Author SummaryWhen blood flow to various parts of the body becomes restricted, those tissues suffer from a lack of oxygen, a condition called hypoxia. Hypoxia can cause cellular damage and death, such as is observed as a result of stroke and cardiovascular disease. We have found that in the model organismC. elegans(a roundworm) specific concentrations of hypoxia cause aggregation of polyglutamine proteins – the same kind of proteins that are found in an aggregated state in the neurodegenerative disorder Huntington’s disease. Here, we show that that worms can be protected from hypoxia-induced protein aggregation if they are fasted (removed from their food source) prior to experiencing hypoxia. Furthermore, we show that the insulin receptor is required for this protection. The insulin receptor is responsible for detecting insulin, a hormone that is released after feeding. Worms with a nonfunctional version of the insulin receptor displayed hypoxia-induced protein aggregation despite being fasted before the hypoxic exposure. Our results highlight a new role for the insulin signaling pathway in coordinating the effects of both hypoxia and nutritional state on protein aggregation.
The expression tractability of a biological trait
Authors: Liu Li , Wang Jianguo , Yang Jianrong , He Xionglei 
Published: March 2018

AbstractUnderstanding how gene expression is translated to phenotype is central to modern molecular biology, but the success is contingent on the intrinsic tractability of the specific traits under examination. However, an a priori estimate of trait tractability from the perspective of gene expression is unavailable. Motivated by the concept of entropy in a thermodynamic system, we here propose such an estimate (ST) by gauging the number (N) of different expression states that underlie the same trait abnormality, with large ST corresponding to large N. By analyzing over 200 yeast morphological traits we show that ST is constrained by natural selection, which builds co-regulated gene modules to minimize the total number of possible expression states. We further show that ST is a good measure of the titer of recurrent patterns of an expression-trait relationship, predicting the extent to which the trait could be deterministically understood with gene expression data.
An expression atlas of chemosensory ionotropic glutamate receptors identifies a molecular basis of carbonation detection
Authors: Sánchez-Alcañiz Juan Antonio , Silbering Ana Florencia , Croset Vincent , Zappia Giovanna , Sivasubramaniam Anantha Krishna , Abuin Liliane , Sahai Saumya Yashmohini , Auer Thomas O. , Cruchet Steeve , Neagu-Maier G. Larisa , Sprecher Simon G. , Yapici Nilay , Benton Richard 
Published: March 2018

AbstractTaste perception is thought to involve the encoding of appetitive and aversive chemical cues in food through a limited number of sensory pathways. Through expression analysis of the complete repertoire ofDrosophilaIonotropic Receptors (IRs), a sensory subfamily of ionotropic glutamate receptors, we reveal that the majority of IRs is expressed in diverse peripheral neuron populations across gustatory organs in both larvae and adults, implying numerous roles in taste-evoked behaviours. We characteriseIr56d, which labels two anatomically-distinct classes of neurons in the proboscis: one represents a subset of sugar- and fatty acid-sensing neurons, while the other responds to carbonated solutions and fatty acids. Mutational analysis shows that IR56d, together with the broadly-expressed co-receptors IR25a and IR76b, is essential for physiological activation by carbonation and fatty acids, but not sucrose. We further demonstrate that carbonation is behaviourally attractive to flies (in an IR56d-dependent manner), but in a distinct way to other appetitive stimuli. Our work provides a valuable toolkit for investigating the taste functions of IRs, defines a molecular basis of carbonation sensing, and illustrates how the gustatory system uses combinatorial expression of sensory receptors in distinct neuron types to coordinate behaviour.
Bub1 is not required for the checkpoint response to unattached kinetochores in diploid human cells
Authors: Currie Cerys E. , Mora-Santos Mar , Smith Chris , McAinsh Andrew D. , Millar Jonathan B.A. 
Published: March 2018

AbstractError-free chromosome segregation during mitosis depends on a functional spindle assembly checkpoint (SAC). The SAC is a multi-component signaling system that is recruited to incorrectly attached kinetochores to catalyze the formation of a soluble inhibitor, known as the mitotic checkpoint complex (MCC), which binds and inhibits the anaphase promoting complex [1]. We have previously proposed that two separable pathways, composed of KNL1-Bub3-Bub1 (KBB) and Rod-Zwilch-Zw10 (RZZ), recruit Mad1-Mad2 complexes to human kinetochores to activate the SAC [2]. We refer to this as the dual pathway model. Although Bub1 is absolutely required for MCC formation in yeast (which lack RZZ), there is conflicting evidence as to whether this is also the case in human cells based on siRNA studies [2–5]. Here we report, using genome editing, that Bub1 is not strictly required for the SAC response to unattached kinetochores in human diploid hTERT-RPE1 cells, consistent with the dual pathway model.
Alzheimer’s environmental and genetic risk scores are differentially associated with ‘g’ and δ
Authors: Andrews Shea J. , McFall G. Peggy , Dixon Roger A. , Cherbuin Nicolas , Eramudugolla Ranmalee , Anstey Kaarin J 
Published: March 2018

AbstractIntroductionWe investigated the association of the Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI) and an AD genetic risk score (GRS) with cognitive performance.MethodsThe ANU-ADRI (composed of 11 risk factors for AD) and GRS (composed of 25 AD risk loci) were computed in 1,061 community-dwelling older adults. Participants were assessed on 11 cognitive tests and activities of daily living. Structural equation modelling was used to evaluate the association of the ANU-ADRI and GRS with: 1) general cognitive ability (g) 2) dementia related variance in cognitive performance (δ) and 3) verbal ability, episodic memory, executive function and processing speed.ResultsA worse ANU-ADRI score was associated with poorer performance in ‘g’, δ, and each cognitive domain. A worse GRS was associated with poorer performance in δ and episodic memory.DiscussionThe ANU-ADRI was broadly associated with worse cognitive performance, validating its further use in early dementia risk assessment.HighlightsAn environmental/lifestyle dementia risk index is broadly associated with cognitive performanceAn Alzheimer’s genetic risk score is associated with dementia severity and episodic memoryThe environmental risk index is more strongly associated with dementia severity than genetic riskResearch in ContextSystematic ReviewThe authors reviewed the literature using online databases (e.g. PubMed). Previous research has highlighted the need for dementia risk assessment tools to be evaluated on outcomes prior to dementia onset, such as cognitive performance. The relevant citations have been appropriately cited.InterpretationThe Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI) was more broadly associated with cognitive performance than Alzheimer’s genetic risk. For the ANU-ADRI, stronger effects were observed for dementia-related variance in cognitive task performance that for variance in general cognitive function. This suggests that ANU-ADRI is more specifically associated with dementia-related processes and further validates its use in early risk assessment for dementia.Future DirectionsAccordingly, future studies should seek to evaluate the association of the ANU-ADRI and genetic risk with AD biomarkers and longitudinal cognitive performance to evaluate differential trajectories in ‘g’ and δ.
Anti-CRISPR phages cooperate to overcome CRISPR-Cas immunity
Authors: Landsberger Mariann , Gandon Sylvain , Meaden Sean , Chabas Hélène , Buckling Angus , Westra Edze R. , Houte Stineke van 
Published: March 2018

SummarySome phages encode anti-CRISPR (acr) genes, which antagonize bacterial CRISPR-Cas immune systems by binding components of its machinery, but it is less clear how deployment of these acr genes impacts phage replication and epidemiology. Here we demonstrate that bacteria with CRISPR-Cas resistance are still partially immune to Acr-encoding phage. As a consequence, Acr-phages often need to cooperate in order to overcome CRISPR resistance, with a first phage taking down the host CRISPR-Cas immune system to allow a second Acr- phage to successfully replicate. This cooperation leads to epidemiological tipping points in which the initial density of Acr-phage tips the balance from phage extinction to a phage epidemic. Furthermore, both higher levels of CRISPR-Cas immunity and weaker Acr activities shift the tipping points towards higher phage densities. Collectively these data help to understand how interactions between phage-encoded immune suppressors and the CRISPR systems they target shape bacteria-phage population dynamics.HighlightsBacteria with CRISPR immunity remain partially resistant to Acr-phageSequentially infecting Acr phages cooperate to overcome CRISPR resistanceAcr-phage epidemiology depends on the initial phage densityCRISPR resistant bacteria can drive Acr phages extincteTOC blurbSome phages encode Acr proteins that block bacterial CRISPR-Cas immune systems. Although CRISPR-Cas can clear the first infection, this Acr-phage still suppresses the host immune system, which can be exploited by other Acr-phages. This is critical for Acr-phage amplification, but this “cooperation” only works beyond a critical Acr-phage density threshold.
Improvement of the memory function of a mutual repression network in a stochastic environment by negative autoregulation
Authors: Hasan A B M Shamim Ul , Kurata Hiroyuki , Pechmann Sebastian 
Published: March 2018

AbstractBackgroundCellular memory is a ubiquitous function of biological systems. By generating a sustained response to a transient inductive stimulus, often due to bistability, memory is central to the robust control of many important biological processes. However, our understanding of the origins of cellular memory remains incomplete. Stochastic fluctuations that are inherent to most biological systems have been shown to hamper memory function. Yet, how stochasticity changes the behavior of genetic circuits is generally not clear from a deterministic analysis of the network alone. Here, we apply deterministic rate equations, stochastic simulations, and theoretical analyses of Fokker-Planck equations to investigate how intrinsic noise affects the memory function in a mutual repression network.ResultsWe find that the addition of negative autoregulation improves the persistence of memory in a small gene regulatory network by reducing stochastic fluctuations. Our theoretical analyses reveal that this improved memory function stems from an increased stability of the steady states of the system. Moreover, we show how the tuning of critical network parameters can further enhance memory.ConclusionsOur work illuminates the power of stochastic and theoretical approaches to understanding biological circuits, and the importance of considering stochasticity to designing synthetic circuits with memory function.
Presurgical language fMRI: Current technical practices in epilepsy surgical planning
Authors: Benjamin Christopher F. A. , Dhingra Isha , Li Alexa X , Blumenfeld Hal , Alkawadri Rafeed , Bickel Stephan , Helmstaedter Christoph , Meletti Stefano , Bronen Richard A. , Warfield Simon K. , Peters Jurriaan M. , Reutens David , Połczyńska Monika M. , Hirsch Lawrence J. , Spencer Dennis D. 
Published: March 2018

AbstractLittle is known about how language functional MRI (fMRI) is executed in clinical practice in spite of its widespread use. Here we comprehensively documented its execution in surgical planning in epilepsy. A questionnaire focusing on cognitive design, imaging acquisition, analysis and interpretation and practical considerations was developed. Individuals responsible for collecting, analyzing, and interpreting clinical language fMRI data at 63 epilepsy surgical programs responded. The central finding was of marked heterogeneity in all aspects of fMRI. Most programs use multiple tasks, with a fifth routinely using 2, 3, 4 or 5 tasks with a modal run duration of five minutes. Variants of over fifteen protocols are in routine use with forms of noun-verb generation, verbal fluency, and semantic decision-making used most often. Nearly all aspects of data acquisition and analysis vary markedly. Neither of the two best-validated protocols were used by more than 10% of respondents. Preprocessing steps are broadly consistent across sites, language-related blood flow is most often identified using general linear modeling (76% of respondents), and statistical thresholding typically varies by patient (79%). The software SPM is most often used. fMRI programs inconsistently include input from experts with all required skills (imaging, cognitive assessment, MR physics, statistical analysis, brain-behavior relationships). These data highlight marked gaps between the evidence supporting fMRI and its clinical application. Teams performing language fMRI may benefit from evaluating practice with reference to the best-validated protocols to date and ensuring individuals trained in all aspects of fMRI are involved to optimize patient care.
Bacteriophage cooperation suppresses CRISPR-Cas3 and Cas9 immunity
Authors: Borges Adair L. , Zhang Jenny Y. , Rollins MaryClare F. , Osuna Beatriz A. , Wiedenheft Blake , Bondy-Denomy Joseph 
Published: March 2018

SUMMARY>Bacteria utilize CRISPR-Cas adaptive immune systems for protection from bacteriophages (phages), and some phages produce anti-CRISPR (Acr) proteins that inhibit immune function. Despite thorough mechanistic and structural information for some Acr proteins, how they are deployed and utilized by a phage during infection is unknown. Here, we show that Acr production does not guarantee phage replication, but instead, infections fail when phage population numbers fall below a critical threshold. Failing infections can be rescued by related phages that act as Acr donors, demonstrating that infections succeed if a sufficient Acr dose is contributed to a single cell by multiple phage genomes. The production of Acr proteins by phage genomes that fail to replicate leave the cell immunosuppressed, which predisposes the cell for successful infection by other phages in the population. This “cooperative” phage mechanism for CRISPR-Cas inhibition demonstrates inter-virus cooperation that may also manifest in other host-parasite interactions.