bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of the HIF pathway: Differential regulation by chemical hypoxia and oxygen glucose deprivation
Authors: Novak Alicia E. , Jones Susan M. , Elliott J. Paul 
Published: January 2019

AbstractThe Hypoxia Inducible Factor (HIF) proteins are the master regulators in the cellular response to varying oxygen levels, including hypoxia. The HIF complex is stabilized and accumulates when oxygen levels drop through inhibition of a degradative enzyme. An active HIF complex can act as a transcriptional regulator of hundreds of genes. In turn, these genes determine the response of the cell by inducing pathways which can promote survival, or result in cell death. However, little is known about the regulation of the transcriptional process. We were interested in learning more about the time dependence of transcriptional activation in order to target those pathways which could enhance cell survival after ischemia. Using mouse hippocampal organotypic cultures (HOTCs), we compared oxygen-glucose deprivation with the hypoxia mimetic cobalt, which inhibits the oxygen dependent prolyl hydroylase and blocks degradation of the HIF proteins. We demonstrated that two of the most studied HIF target genes (VEGF, EPO) as well as HIF structural genes show complex time and dose-dependent expression patterns in response to the two different insults. Understanding of these molecular responses is crucial for the development of future treatments to enhance recovery from hypoxia and stroke.
Microbial networks in SPRING - Semi-parametric rank-based correlation and partial correlation estimation for quantitative microbiome data
Authors: Yoon Grace , Gaynanova Irina , Müller Christian L. 
Published: January 2019

AbstractHigh-throughput microbial sequencing techniques, such as targeted amplicon-based and metagenomic profiling, provide low-cost genomic survey data of microbial communities in their natural environment, ranging from marine ecosystems to host-associated habitats. While standard microbiome profiling data can provide sparserelativeabundances of operational taxonomic units or genes, recent advances in experimental protocols give a more quantitative picture of microbial communities by pairing sequencing-based techniques with orthogonal measurements of microbial cell counts from the same sample. These tandem measurements provide absolute microbial count data albeit with a large excess of zeros due to limited sequencing depth. In this contribution we consider the fundamental statistical problem of estimating correlations and partial correlations from such quantitative microbiome data. To this end, we propose a semi-parametric rank-based approach to correlation estimation that can naturally deal with the excess zeros in the data. Combining this estimator with sparse graphical modeling techniques leads to theSemi-ParametricRank-based approach forINference inGraphical model (SPRING). SPRING enables inference of statistical microbial association networks from quantitative microbiome data which can serve as high-level statistical summary of the underlying microbial ecosystem and can provide testable hypotheses for functional species-species interactions. Due to the absence of verified microbial associations we also introduce a novel quantitative microbiome data generation mechanism which mimics empirical marginal distributions of measured count data while simultaneously allowing user-specified dependencies among the variables. SPRING shows superior network recovery performance on a wide range of realistic benchmark problems with varying network topologies and is robust to misspecifications of the total cell count estimate. To highlight SPRING’s broad applicability we infer taxon-taxon associations from the American Gut Project data and genus-genus associations from a recent quantitative gut microbiome dataset. We believe that, as quantitative microbiome profiling data will become increasingly available, the semi-parametric estimators for correlation and partial correlation estimation introduced here provide an important tool for reliable statistical analysis of quantitative microbiome data.
MaXLinker: proteome-wide cross-link identifications with high specificity and sensitivity
Authors: Yugandhar Kumar , Wang Ting-Yi , Leung Alden King-Yung , Lanz Michael Charles , Motorykin Ievgen , Liang Jin , Shayhidin Elnur Elyar , Smolka Marcus Bustamante , Zhang Sheng , Yu Haiyuan 
Published: January 2019

ABSTRACTProtein-protein interactions play a vital role in nearly all cellular functions. Hence, understanding their interaction patterns and three-dimensional structural conformations can provide crucial insights about various biological processes and underlying molecular mechanisms for many disease phenotypes. Cross-linking mass spectrometry has the unique capability to detect protein-protein interactions at a large scale along with spatial constraints between interaction partners. However, the current cross-link search algorithms follow an “MS2-centric” approach and, as a result, suffer from a high rate of mis-identified cross-links (~15%). We address this urgent problem, by designing a novel “MS3-centric” approach for cross-link identification and implemented it as a search engine called MaXLinker. MaXLinker significantly outperforms the current state of the art search engine with up to 18-fold lower false positive rate. Additionally, MaXLinker results in up to 31% more cross-links, demonstrating its superior sensitivity and specificity. Moreover, we performed proteome-wide cross-linking mass spectrometry using K562 cells. Employing MaXLinker, we unveiled the most comprehensive set of 9,319 unique cross-links at 1% false discovery rate, comprising 8,051 intraprotein and 1,268 interprotein cross-links. Finally, we experimentally validated the quality of a large number of novel interactions identified in our study, providing a conclusive evidence for MaXLinker’s robust performance.
Posttraumatic Stress Disorder and the Social Brain: Affect-Related Disruption of the Default and Mirror Networks
Authors: Tan Kevin M. , Burklund Lisa J. , Craske Michelle G. , Lieberman Matthew D. 
Published: January 2019

AbstractBackgroundSocial impairments, specifically in mentalizing and emotion recognition, are common and debilitating symptoms of posttraumatic stress disorder (PTSD). Despite this, little is known about the neural underpinnings of these impairments, as there have been no published neuroimaging investigations of social inference in PTSD.MethodsTrauma-exposed veterans with and without PTSD (N = 20 each) performed the Why/How social inference task during functional magnetic resonance imaging (fMRI). The PTSD group had two fMRI sessions, between which they underwent affect labeling training. We probed the primary networks of the “social brain”—the default mode network (DMN) and mirror neuron system (MNS)—by examining neural activity evoked by mentalizing and action identification prompts, which were paired with emotional and non-emotional targets.ResultsHyperactivation to emotional stimuli differentiated PTSD patients from controls, correlated with symptom severity, and predicted training outcomes. Critically, these effects were generally non-significant for non-emotional stimuli. PTSD-related effects were widely distributed throughout DMN and MNS. Effects were strongest in regions associated with the dorsal attention, ventral attention, and frontoparietal control networks. Unexpectedly, effects were non-significant in core affect regions.ConclusionsThe array of social cognitive processes subserved by DMN and MNS may be inordinately selective for emotional stimuli in PTSD. This selectivity may be tightly linked with attentional processes, as effects were strongest in attention-related regions. Putatively, we propose an attentional account of social inference dysfunction in PTSD, in which affective attentional biases drive widespread affect-selectivity throughout the social brain. This account aligns with numerous findings of affect-biased attentional processing in PTSD.
Characterization of a thaumarchaeal symbiont that drives incomplete nitrification in the tropical spongeIanthella basta
Authors: Moeller Florian U. , Webster Nicole S. , Herbold Craig W. , Behnam Faris , Domman Daryl , Albertsen Mads , Mooshammer Maria , Markert Stephanie , Turaev Dmitrij , Becher Dörte , Rattei Thomas , Schweder Thomas , Richter Andreas , Watzka Margarete , Nielsen Per Halkjaer , Wagner Michael 
Published: January 2019

SummaryMarine sponges represent one of the few eukaryotic groups that frequently harbor symbiotic members of theThaumarchaeota, which are important chemoautotrophic ammonia-oxidizers in many environments. However, in most studies, direct demonstration of ammonia-oxidation by these archaea within sponges is lacking, and little is known about sponge-specific adaptations of ammonia-oxidizing archaea (AOA). Here, we characterized the thaumarchaeal symbiont of the marine spongeIanthella bastausing metaproteogenomics, fluorescencein situhybridization, qPCR and isotope-based functional assays. “CandidatusNitrosospongia bastadiensis” is only distantly related to cultured AOA. It is an abundant symbiont that is solely responsible for nitrite formation from ammonia inI. bastathat surprisingly does not harbor nitrite-oxidizing microbes. Furthermore, this AOA is equipped with an expanded set of extracellular subtilisin-like proteases, a metalloprotease unique among archaea, as well as a putative branched-chain amino acid ABC transporter. This repertoire is strongly indicative of a mixotrophic lifestyle and is (with slight variations) also found in other sponge-associated, but not in free-living AOA. We predict that this feature as well as an expanded and unique set of secreted serpins (protease inhibitors), a unique array of eukaryotic-like proteins, and a DNA-phosporothioation system, represent important adaptations of AOA to life within these ancient filter-feeding animals.Originality-Significance StatementMany marine sponges harbor symbiotic members of theThaumarchaeota, but there is generally only indirect evidence available about their functional role within these filter-feeding animals. Furthermore, the specific adaptations of thaumarchaeal symbionts to their sponge hosts are incompletely understood. In this study, we thoroughly characterized a thaumarchaeal symbiont residing in the reef spongeIanthella bastaand demonstrate by using a combination of molecular tools and isotope techniques, that it is the only ammonia-oxidizer in its host. In contrast to other sponges,I. bastadoes not contain nitrite-oxidizing microbes and thus excretes considerable amounts of nitrite. Furthermore, using metagenomics and metaproteomics we reveal important adaptations of this symbiont, that represents a new genus within theThaumarchaeota, and conclude that it most likely lives as a mixotroph in its sponge host.
What do I do now? Intolerance of uncertainty is associated with discrete patterns of anticipatory physiological responding to different uncertain contexts
Authors: Morriss Jayne 
Published: January 2019

AbstractHeightened physiological responses to uncertainty are a common hallmark of anxiety disorders. Many separate studies have examined the relationship between individual differences in intolerance of uncertainty (IU) and physiological responses to uncertainty during different contexts. Despite this, little is known about the extent to which physiological responses during different uncertain contexts covary within individuals based on IU. Anticipatory physiological responses to uncertainty were assessed in three different contexts (associative threat learning, basic threat uncertainty, decision-making) within the same sample (n = 45). During these tasks, behavioural responses (i.e. reaction times, choices), skin conductance and corrugator supercilli activity were recorded. In addition, self-reported IU and trait anxiety were measured. IU made different contributions to the physiological measures during each task. IU was found to modulate both skin conductance and corrugator supercilii activity for the associative threat learning and decision-making contexts. However, trait anxiety was found to modulate corrugator supercilii activity during the basic threat uncertainty context. Ultimately, this research helps us further tease apart the role of IU in different uncertain contexts, which will be relevant for future IU-related models of psychopathology.
Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation
Authors: Zerbi Valerio , Floriou-Servou Amalia , Markicevic Marija , Vermeiren Yannick , Sturman Oliver , Privitera Mattia , von Ziegler Lukas , Ferrari Kim David , Weber Bruno , De Deyn Peter Paul , Wenderoth Nici , Bohacek Johannes 
Published: January 2019

AbstractThe locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain, regulates many fundamental brain functions, and is implicated in several neuropsychiatric diseases. Although selective manipulation of the LC is not possible in humans, studies have suggested that strong LC activation might shift network connectivity to favor salience processing. To test this hypothesis, we use a mouse model to study the impact of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term “chemo-connectomics”. LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. We reveal a direct correlation between functional connectivity changes and transcript levels of alpha-1, alpha-2, and beta-1 adrenoceptors across the brain, and a positive correlation between NE turnover and functional connectivity within select brain regions. These results represent the first brain-wide functional connectivity mapping in response to LC activation, and demonstrate a causal link between receptor expression, brain states and functionally connected large-scale networks at rest. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection.
Maternal age alters offspring lifespan, fitness, and lifespan extension under caloric restriction
Authors: Bock Martha J. , Jarvis George C. , Corey Emily L. , Stone Emily E. , Gribble Kristin E. 
Published: January 2019

ABSTRACTMaternal age has a negative effect on offspring lifespan in a range of taxa and is hypothesized to influence the evolution of aging. However, the mechanisms of maternal age effects are unknown, and it remains unclear if maternal age alters offspring response to therapeutic interventions to aging. Here, we evaluate maternal age effects on offspring lifespan, reproduction, and the response to caloric restriction, and investigate maternal investment as a source of maternal age effects using the rotifer,Brachionus manjavacas, an aquatic invertebrate. We found that offspring lifespan and fecundity decline with increasing maternal age. Caloric restriction increases lifespan in all offspring, but the magnitude of lifespan extension is greater in the offspring from older mothers. The trade-off between reproduction and lifespan extension under low food conditions expected by life history theory is observed in young-mother offspring, but not in old-mother offspring. Age-related changes in maternal resource allocation to reproduction do not drive changes in offspring fitness or plasticity under caloric restriction inB. manjavacas. Our results suggest that the declines in reproduction in old-mother offspring negate the evolutionary fitness benefits of lifespan extension under caloric restriction.
Anhedonia following mild traumatic brain injury in rats: A behavioral economic analysis of positive and negative reinforcement
Authors: Avcu Pelin , Fortress Ashley M. , Fragale Jennifer E. , Spiegler Kevin M. , Pang Kevin C.H. 
Published: January 2019

AbstractPsychiatric disorders affect nearly 50% of individuals who have experienced a traumatic brain injury (TBI). Anhedonia is a major symptom of numerous psychiatric disorders and is a diagnostic criterion for depression. Recently, anhedonia has been divided into consummatory, motivational and decisional components, all of which may be affected differently in disease. Although anhedonia is typically assessed using positive reinforcement, the importance of stress in psychopathology suggests the study of negative reinforcement (removal or avoidance of aversive events) may be equally important. The present study investigated positive and negative reinforcement following a rat model of mild TBI (mTBI) using lateral fluid percussion. Hedonic value of and motivation for reinforcement was determined by behavioral economic analyses. Following mTBI, the hedonic value of avoiding foot shock was reduced. In contrast, the hedonic value of escaping foot shock or obtaining a sucrose pellet was not altered by mTBI. Moreover, neither motivation to avoid or escape foot shock nor motivation to acquire sucrose was modified by mTBI. Our results suggest that individuals experiencing mTBI may experience more stress because of poor proactive control of stress resulting from reduced hedonic value of avoiding aversive events.
Subcortical Anatomy of the Default Mode Network: a functional and structural connectivity study
Authors: Alves Pedro Nascimento , Foulon Chris , Karolis Vyacheslav , Bzdok Danilo , Margulies Daniel S. , Volle Emmanuelle , de Schotten Michel Thiebaut 
Published: January 2019

AbstractMost existing research into the default-mode network (DMN) has taken a corticocentric approach. Despite the resemblance of the DMN with the unitary model of the limbic system, the anatomy and contribution of subcortical structures to the network may be underappreciated due to methods limitation. Here, we propose a new and more comprehensive neuroanatomical model of the DMN including the basal forebrain and anterior and mediodorsal thalamic nuclei and cholinergic nuclei. This has been achieved by considering functional territories during interindividual brain alignment. Additionally, tractography of diffusion-weighted imaging was employed to explore the structural connectivity of the DMN and revealed that the thalamus and basal forebrain had high importance in term of values of node degree and centrality in the network. The contribution of these neurochemically diverse brain nuclei reconciles previous neuroimaging with neuropathological findings in diseased brain and offers the potential for identifying a conserved homologue of the DMN in other mammalian species.
High-affinity free ubiquitin sensors as quantitative probes of ubiquitin homeostasis and deubiquitination
Authors: Choi Yun-Seok , Bollinger Sarah A. , Prada Luisa F. , Scavone Francesco , Yao Tingting , Cohen Robert E. 
Published: January 2019

AbstractUbiquitin (Ub) conjugation is an essential post-translational modification that affects nearly all proteins in eukaryotes. The functions and mechanisms of ubiquitination are areas of extensive and ongoing study, and yet the dynamics and regulation of even free (i.e., unconjugated) Ub are poorly understood. A major impediment has been the lack of simple and robust techniques to quantify Ub levels in cells and to monitor Ub release from conjugates. Here we describe the development of avidity-based fluorescent sensors that address this need. The sensors bind specifically to free Ub, have Kd values down to 60 pM, and, in concert with a newly developed workflow, allow us to distinguish and quantify the pools of free, protein-conjugated, and thioesterified forms of Ub from cell lysates. Alternatively, free Ub in fixed cells can be visualized microscopically by staining with a sensor. Real-time assays using the sensors afford unprecedented flexibility and precision to measure deubiquitination of virtually any (poly)Ub conjugate.
Tanycyte-independent control of hypothalamic leptin signaling
Authors: Yoo Sooyeon , Cha David , Kim Dong Won , Hoang Thanh V. , Blackshaw Seth 
Published: January 2019

AbstractLeptin is secreted by adipocytes to regulate appetite and body weight. Recent studies have reported that tanycytes actively transport circulating leptin across the brain barrier into the hypothalamus, and are required for normal levels of hypothalamic leptin signaling. However, direct evidence for leptin receptor (LepR) expression is lacking, and the effect of tanycyte-specific deletion of LepR has not been investigated. In this study, we analyze the expression and function of the tanycytic LepR in mice. Using single-molecule fluorescent in situ hybridization (smfISH), RT-qPCR, single-cell RNA sequencing (scRNA-Seq), and selective deletion of the LepR in tanycytes, we are unable to detect expression of LepR in the tanycytes. Tanycyte-specific deletion of LepR likewise did not affect leptin-induced pSTAT3 expression in hypothalamic neurons, regardless of whether leptin was delivered by intraperitoneal or intracerebroventricular injection. Finally, we use activity-regulated scRNA-Seq (act-Seq) to comprehensively profile leptin-induced changes in gene expression in all cell types in mediobasal hypothalamus. Clear evidence for leptin signaling is only seen in endothelial cells and subsets of neurons, although virtually all cell types show leptin-induced changes in gene expression. We thus conclude that LepR expression in tanycytes is either absent or undetectably low, that tanycytes do not directly regulate hypothalamic leptin signaling through a LepR-dependent mechanism, and that leptin regulates gene expression in diverse hypothalamic cell types through both direct and indirect mechanisms.
Cytokinetic furrowing and abscission dynamics during brain development revealed by live imaging
Authors: McNeely Katrina C. , Little Jessica Neville , Dwyer Noelle D. 
Published: January 2019

SummaryMcNeely et al. quantitatively analyze polarized cytokinetic furrow ingression and abscission in mouse neuroepithelium by live imaging. The findings show important differences from HeLa cells, and suggest abscission timing and midbody release may be developmentally regulated, to influence daughter cell fate during brain growth.AbstractWhile mechanisms of cytokinesis have been identified in single cell models, the spatial and temporal regulation in developing tissues is less understood. Here we compare cytokinetic furrowing and abscission in mouse neuroepithelial stem cells (NESCs) at different developmental stages and in a cytokinesis mutant, including imaging abscission dynamics in a polarized epithelium for the first time. We find that asymmetric furrows of NESCs ingress at a constant but slow rate, and form the midbody at the apical membrane. Usually, bilateral abscission on each midbody flank releases the midbody remnant extracellularly. Interestingly, midbody remnants are more associated with early proliferative divisions. Unexpectedly, in the microcephalicKif20bmutant, abscission is accelerated and occurs when the midbody is wider. The daughter cells of mutant NESCs show increased cell cycle exit that is p53-independent. We suggest that abscission mechanisms are developmentally regulated. These results provide significant insight into adaptations of a fundamental cell biological process required for proper brain growth.