bluuebunny/crossref_metadata_2025_split huggingface dataset:
How sample heterogeneity can obscure the signal of microbial interactions
Authors: Armitage David W. , Jones Stuart E. 
Published: January 2019

ABSTRACTMicrobial community data are commonly subjected to computational tools such as correlation networks, null models, and dynamic models, with the goal of identifying the ecological processes structuring microbial communities. Researchers applying these methods assume that the signs and magnitudes of species interactions and vital rates can be reliably parsed from observational data on species’ (relative) abundances. However, we contend that this assumption is violated when sample units contain any underlying spatial structure. Here, we show how three phenomena — Simpson’s paradox, context-dependence, and nonlinear averaging — can lead to erroneous conclusions about population parameters and species interactions when samples contain heterogeneous mixtures of populations or communities. At the root of this issue is the fundamental mismatch between the spatial scales of species interactions (micrometres) and those of typical microbial community samples (millimetres to centimetres). These issues can be overcome by measuring and accounting for spatial heterogeneity at very small scales, which will lead to more reliable inference of the ecological mechanisms structuring natural microbial communities.
The behavioral phenotype of early life adversity: a 3-level meta-analysis of preclinical studies
Authors: Bonapersona V , Kentrop J , Van Lissa CJ , van der Veen R , Joëls M , Sarabdjitsingh RA 
Published: January 2019

1AbstractBackgroundAltered cognitive performance has been suggested as an intermediate phenotype mediating the effects of early life adversity (ELA) on later-life development of mental disorders, e.g. depression. Whereas most human studies are limited to correlational conclusions, rodent studies can prospectively investigate how ELA alters cognitive performance in a number of domains. Despite the vast volume of reports, no consensus has yet been reached on thei)behavioral domains being affected by ELA andii)the extent of these effects.MethodsTo test how ELA (here: aberrant maternal care) affects specific behavioral domains, we used a 3-level mixed-effect meta-analysis, a flexible model that accounts for the dependency of observations. We thoroughly explored heterogeneity with MetaForest, a machine-learning data-driven analysis never applied before in preclinical literature. We validated the robustness of our findings with substantial sensitivity analyses and bias assessments.ResultsOur results, based on >400 independent experiments, yielded >700 comparisons, involving ~8600 animals. Especially in males, ELA promotes memory formation during stressful learning but impairs non-stressful learning. Furthermore, ELA increases anxiety and decreases social behavior. The ELA phenotype was strongest wheni)combined with other negative experiences (“hits”);ii)in rats;iii)in ELA models of ~10days duration.ConclusionProspective and well-controlled animal studies demonstrate that ELA durably and differentially impacts distinct behavioral domains. All data is now easily accessible with MaBapp (https://osf.io/ra947/), which allows researchers to run tailor-made meta-analyses on the topic, thereby revealing the optimal choice of experimental protocols and study power.
Genes lost during the transition from land to water in cetaceans highlight genomic changes involved in aquatic adaptations
Authors: Huelsmann Matthias , Hecker Nikolai , Springer Mark S. , Gatesy John , Sharma Virag , Hiller Michael 
Published: January 2019

AbstractThe transition from land to water in whales and dolphins (cetaceans) was accompanied by remarkable anatomical, physiological and behavioral adaptations. To better understand the genomic changes that occurred during this transition, we systematically screened for protein-coding genes that were inactivated in the ancestral cetacean lineage. We discovered genes whose loss is likely beneficial for cetaceans by reducing the risk of thrombus formation during diving (F12,KLKB1), improving the fidelity of oxidative DNA damage repair (POLM), and protecting from oxidative stress-induced lung inflammation (MAP3K19). Additional gene losses may reflect other diving-related adaptations, such as enhanced vasoconstriction during the diving response (mediated bySLC6A18) and altered pulmonary surfactant composition (SEC14L3), while loss ofSLC4A9relates to a reduced need for saliva in aquatic environments. Finally, the complete loss of melatonin synthesis and receptor genes (AANAT,ASMT,MTNR1A/B) may have been a precondition for the evolution of unihemispheric sleep. Our findings suggest that some genes lost in the ancestral cetacean lineage may have been involved in adapting to a fully-aquatic lifestyle.
Identification of the Calmodulin-dependent NAD+kinase sustaining the elicitor-induced oxidative burst in plants
Authors: Dell’ Aglio Elisa , Giustini Cécile , Kraut Alexandra , Couté Yohann , Mazars Christian , Matringe Michel , Finazzi Giovanni , Curien Gilles 
Published: January 2019

AbstractNADP(H) is an essential cofactor ofmultiple metabolic processes in all living organisms. While NADP+ production in plants has long been known to involve a Calmodulin (CaM)/Ca2+-dependent NAD+kinase, the nature of the enzyme catalyzing this activity has remained enigmatic, as well as its role in plant physiology. Here, we identify an Arabidopsis P-loop ATPase (Atlg04280) with a bacterial type II zeta toxin domain, that catalyzes NADP+production upon binding of CaM/Ca2+to a domain located in its N-terminal region. The encoded protein (NADKc-1) is associated with the mitochondria and amplifies the elicitor-induced oxidative burst in Arabidopsis leaves representing the missing link between calcium signalling and metabolism in the response to pathogen elicitor. By analysis of various plants and algae, we show that NADKc is well conserved in the plant lineage and present in basal plants. Our data allows proposing that the CaM-dependent NAD kinase activity is only found in photosynthetic species carrying NADKc-1 related proteins, which would represent the only proteins harboring CaM-dependent NAD kinase activity in plants and algae.
Phosgene Inhalation Causes Hemolysis and Acute Lung Injury
Authors: Aggarwal Saurabh , Jilling Tamas , Doran Stephen , Ahmad Israr , Eagen Jeannette E. , Gu Stephen , Gillespie Mark , Albert Carolyn J. , Ford David , Oh Joo-Yeun , Patel Rakesh P. , Matalon Sadis 
Published: January 2019

AbstractPhosgene (Carbonyl Chloride, COCl2) remains an important chemical intermediate in many industrial processes such as combustion of chlorinated hydrocarbons and synthesis of solvents (degreasers, cleaners). It is a sweet smelling gas, and therefore does not prompt escape by the victim upon exposure. Supplemental oxygen and ventilation are the only available management strategies. This study was aimed to delineate the pathogenesis and identify novel biomarkers of acute lung injury post exposure to COCl2gas. Adult male and female C57BL/6 mice (20-25 g), exposed to COCl2gas (10 or 20ppm) for 10 minutes in environmental chambers, had a dose dependent reduction in PaO2and an increase in PaCO2, 1 day post exposure. However, mortality increased only in mice exposed to 20ppm of COCl2for 10 minutes. Correspondingly, these mice (20ppm) also had severe acute lung injury as indicated by an increase in lung wet to dry weight ratio, extravasation of plasma proteins and neutrophils into the bronchoalveolar lavage fluid, and an increase in total lung resistance. The increase in acute lung injury parameters in COCl2(20ppm, 10min) exposed mice correlated with simultaneous increase in oxidation of red blood cells (RBC) membrane, RBC fragility, and plasma levels of cell-free heme. In addition, these mice had decreased plasmalogen (plasmenylethanolamine) and elevated levels of their breakdown product, polyunsaturated lysophosphatidylethanolamine, in the circulation suggesting damage to cellular plasma membranes. This study highlights the importance of free heme in the pathogenesis of COCl2 lung injury and identifies plasma membrane breakdown product as potential biomarkers of COCl2toxicity.
Computational modeling reveals frequency modulation of calcium-cAMP/PKA pathway in dendritic spines
Authors: Ohadi D. , Schmitt D. L. , Calabrese B. , Halpain S. , Zhang J. , Rangamani P. 
Published: January 2019

AbstractDendritic spines are the primary excitatory postsynaptic sites that act as subcompartments of signaling. Ca2+is often the first and most rapid signal in spines. Downstream of calcium, the cAMP/PKA pathway plays a critical role in the regulation of spine formation, morphological modifications, and ultimately, learning and memory. While the dynamics of calcium are reasonably well-studied, calcium-induced cAMP/PKA dynamics, particularly with respect to frequency modulation, are not fully explored. In this study, we present a well-mixed model for the dynamics of calcium-induced cAMP/PKA dynamics in dendritic spines. The model is constrained using experimental observations in the literature. Further, we measured the calcium oscillation frequency in dendritic spines of cultured hippocampal CA1 neurons and used these dynamics as model inputs. Our model predicts that the various steps in this pathway act as frequency modulators for calcium and the high frequency of calcium input is filtered by AC1 and PDEs in this pathway such that cAMP/PKA only responds to lower frequencies. This prediction has important implications for noise filtering and long-timescale signal transduction in dendritic spines. A companion manuscript presents a three-dimensional spatial model for the same pathway.Statement of SignificancecAMP/PKA activity triggered by calcium is an essential biochemical pathway for synaptic plasticity, regulating spine structure, and long-term potentiation. In the current study, we predicted that for a given calcium input, AC1, and PDE1 kinetics reflect both the high and the low frequencies with different amplitudes and cAMP/PKA acts as a leaky integrator of calcium because of frequency attenuation by the intermediary steps. These findings have implications for cAMP/PKA signaling in dendritic spines in particular and neuronal signal transduction in general.
Chromosome dynamics in bacteria: triggering replication at opposite location and segregation in opposite direction
Authors: Meléndez Ady B. , Menikpurage Inoka P. , Mera Paola E. 
Published: January 2019

ABSTRACTThe accurate onset of chromosome replication and segregation are fundamental for the survival of the cell. In bacteria, regulation of chromosome replication lies primarily at the initiation step. The bacterial replication initiator DnaA recognizes the origin of replication (ori) and opens this double stranded site allowing for the assembly of the DNA replication machinery. Following the onset of replication initiation, the partitioning protein ParA triggers the onset of chromosome segregation by direct interactions with ParB-bound to the centromere. The subcellular organization oforiand centromere are maintained after the completion of each cell cycle. It remains unclear what triggers the onset of these key chromosome regulators DnaA and ParA. One potential scenario is that the microenvironment of where the onset of replication and segregation take place hosts the regulators that trigger the activity of DnaA and ParA. In order to address this, we analyzed whether the activity of DnaA and ParA are restricted to only one site within the cell. In non-dividing cells of the alpha proteobacteriumCaulobacter crescentus,oriand centromere are found near the stalked pole. To test DnaA’s ability to initiate replication away from the stalked pole, we engineered a strain where movement oforiwas induced in the absence of chromosome replication. Our data show that DnaA can initiate replication of the chromosome independently of the subcellular localization ofori. Furthermore, we discovered that the partitioning protein ParA was functional and could segregate the replicated centromere in the opposite direction from the new pole toward the stalked pole. We showed that the organization of the ParA gradient can be completely reconstructed in the opposite orientation by rearranging the location of the centromere. Our data reveal the high flexibility of the machineries that trigger the onset of chromosome replication and segregation in bacteria. Our work also provides insights into the coordination between replication and segregation with the cellular organization of specific chromosomal loci.
Cerebellar disruption impairs working memory during evidence accumulation
Authors: Deverett Ben , Kislin Mikhail , Tank David W. , Wang Samuel S.-H. 
Published: January 2019

AbstractTo select actions based on sensory evidence, animals must create and manipulate representations of stimulus information in memory. We found that during accumulation of somatosensory evidence, optogenetic manipulation of cerebellar Purkinje cells reduced the accuracy of subsequent memory-guided decisions and caused mice to downweight prior information. Behavioral deficits were consistent with the addition of noise and leak to the evidence accumulation process, suggesting the cerebellum can influence the maintenance of working memory contents.
A multimodal approach to identify clinically relevant parameters to monitor disease progression in a preclinical model of neuropediatric disease
Authors: Johnson Tyler B. , Brudvig Jon J. , Lehtimäki Kimmo K. , Cain Jacob T. , White Katherine A. , Bragge Timo , Rytkönen Jussi , Huhtala Tuulia , Timm Derek , Vihma Maria , Puoliväli Jukka T. , Nurmi Antti , Weimer Jill M. 
Published: January 2019

AbstractWhile research has accelerated the development of new treatments for pediatric neurodegenerative disorders, the ability to demonstrate the long-term efficacy of these therapies has been hindered by the lack of convincing, noninvasive methods for tracking disease progression both in animal models and in human clinical trials. Here, we unveil a new translational platform for tracking disease progression in an animal model of a pediatric neurodegenerative disorder, CLN6-Batten disease. Instead of looking at a handful of parameters or a single “needle in a haystack”, we embrace the idea that disease progression, in mice and patients alike, is a diverse phenomenon best characterized by a combination of relevant biomarkers. Thus, we employed a multi-modal quantitative approach where 144 parameters were longitudinally monitored to allow for individual variability. We use a range of noninvasive neuroimaging modalities and kinematic gait analysis, all methods that parallel those commonly used in the clinic, followed by a powerful statistical platform to identify key progressive anatomical and metabolic changes that correlate strongly with the progression of pathological and behavioral deficits. This innovative, highly sensitive platform can be used as a powerful tool for preclinical studies on neurodegenerative diseases, and provides proof-of-principle for use as a potentially translatable tool for clinicians in the future.One Sentence SummaryPrincipal component analysis identifies a set of clinically relevant parameters able to measure progression of Batten disease in a mouse model.
Age-dependent characterization of the carotid and cerebral artery morphologies in a transgenic mouse model of sickle cell anemia using ultrasound and microcomputed tomography
Authors: Rivera Christian P. , Li Li , Cai Shuangyi , Pei Nui , McAlear George E. , Bollavaram Keval , Aryio Oluwasanmi V. , Omojola Victor O. , Song Hannah , Tan Wenchang , Huo Yunlong , Platt Manu O. 
Published: January 2019

AbstractChildren with sickle cell anemia have elevated stroke risks as well as other arterial complications, but morphological changes to large arteries are not well defined, and the focus has been on the microcirculation where deoxygenation promotes sickling of red blood cells. The goal of this study was to define morphological changes in carotid and cerebral arteries in the Townes transgenic sickle cell mouse model, and to specifically determine anatomical measurement differences in mice homozygous for β-globin S mutation (SS) compared to heterozygous (AS) littermate controls. We used a combination of live imaging with ultrasound and microcomputed tomography (micro-CT) imaging of corrosion casted vessels to quantify arterial dimensions and changes in mice 4, 12, and 24 weeks of age with or without sickle cell anemia. 12 week SS mice had significantly larger common carotid artery diameters than AS mice, and significantly larger diameters in the extracranial and intracranial portions of the internal carotid artery (ICA), determined by ultrasound and micro-CT, respectively. There were also side specific differences between the left and right vessels. There was significant narrowing along ICA length in 12-and 24-week SS mice, decreasing by as much as 70%, such that there was no difference in size between the anterior and middle cerebral arteries, where the ICA terminates, by genotype. Significant narrowing along the length was also measured in the anterior cerebral arteries of 12-and 24-week SS mice, but not AS. Collectively, these findings indicate that sickle cell anemia causes increased arterial dimensions in 12-and 24-week aged mice. We also provide these measurements for the common carotid, internal carotid, anterior cerebral, and middle cerebral arteries for left and right sides, for AS and SS genotypes as a reference for other investigators using in silico modeling of arterial complications caused by aging with sickle cell anemia.
Superadditive and subadditive dynamics are not inherent to the types of interacting threat
Authors: Haller-Bull V , Bode M 
Published: January 2019

AbstractSpecies and ecosystems usually face more than one threat. The damage caused by these multiple threats can accumulate nonlinearly: either subadditively, when the joint damage of combined threats is less than the damages of both threats individually added together, or superadditively, when the joint damage is greater than the two individual damages added together. These additivity dynamics are commonly attributed to the nature of the threatening processes, but conflicting empirical observations challenge this assumption. Here, we use a theoretical model to demonstrate that the additivity of threats can change with different magnitudes of threat impacts (effect of a threat on the population parameter, like growth rate). We use a harvested single-species population model to integrate the effects of multiple threats on equilibrium abundance. Our results reveal that threats do not always display consistent additive behavior, even in simple systems. Instead, their additivity depends on the magnitudes of the impacts of two threats, and the population parameter that is impacted by each threat. In our model specifically, when multiple threats have a low impact on the growth rate of a population, they display superadditive dynamics. In contrast, threats that impact the species’ carrying capacity are always additive or subadditive. These dynamics can be understood by reference to the curvature of the relationship between a given population parameter (e.g., growth) and equilibrium population size. Our results suggest that management actions can achieve amplified benefits if they target low-amplitude threats that affect the growth rate, since these will be in a superadditive phase. More generally, our results suggest that cumulative impact theory should focus more than previously on the magnitude of the impact on the population parameter, and should be cautious about attributing additive dynamics to particular threat combinations.
Image-derived Models of Cell Organization Changes During Differentiation of PC12 Cells
Authors: Ruan Xiongtao , Johnson Gregory R. , Bierschenk Iris , Nitschke Roland , Boerries Melanie , Busch Hauke , Murphy Robert F. 
Published: January 2019

AbstractCellular differentiation is a complex process requiring the coordination of many cellular components. PC12 cells are a popular model system to study changes driving and accompanying neuronal differentiation. While significant attention has been paid to changes in transcriptional regulation and protein signaling, much less is known about the changes in cell organization that accompany PC12 differentiation. Fluorescence microscopy can provide extensive information about this, although photobleaching and phototoxicity frequently limit the ability to continuously observe changes in single cells over the many days that differentiation occurs. Here we describe a generative model of differentiation-associated changes in cell and nuclear shape and their relationship to mitochondrial distribution constructed from images of different cells at discrete time points. We show that our spherical harmonic-based model can accurately represent cell and nuclear shapes by measuring reconstruction errors. We then learn a regression model that relates cell and nuclear shape and mitochondrial distribution and observe that the predictive accuracy generally increases during differentiation. Most importantly, we propose a method, based on cell matching and linear interpolation in the shape space, to model the dynamics of cell differentiation using only static images. Without any prior knowledge, the method produces a realistic shape evolution process.Author SummaryCellular differentiation is an important process that is challenging to study due to the number of organizational changes it includes and the different time scales over which it occurs. Fluorescent microscopy is widely used to study cell dynamics and differentiation, but photobleaching and phototoxicity often make it infeasible to continuously observe a single cell undergoing differentiation for several days. In this work, we described a method to model aspects of the dynamics of PC12 cell differentiation without continuous imaging. We constructed accurate representations of cell and nuclear shapes and quantified the relationships between shapes and mitochondrial distributions. We used these to construct a generative model and combined it with a matching process to infer likely sequences of the changes in single cells undergoing differentiation.