bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive functions and jugular venous reflux in severe mitral regurgitation
Authors: Sung Shih-Hsien , Lee Ching-Wei , Wang Pei-Ning , Lee Hsiang-Ying , Chen Chen-Huan , Chung Chih-Ping 
Published: November 2018

AbstractCardiac diseases with elevated central venous pressure have higher frequency of jugular venous reflux (JVR), which is associated with decreased cerebral blood flow and white matter hyperintensities. Whether patients with severe mitral-regurgitation (SMR) have poorer cognitive functions and whether JVR is involved were determined. Patients with SMR and age/sex-matched controls were prospectively recruited. Neuropsychological tests such as global cognitive (Mini-Mental State Examination, MMSE), verbal memory, executive, and visuospatial domains were performed. Cardiac parameters by cardiac catheterisation and echocardiography, and the frequency of JVR by colour-coded duplex ultrasonography were obtained. Forty patients with SMR and 40 controls (71.1±12.2, 38–89 years; 75% men) were included. Compared with the controls, patients with SMR had lower scores in all neuropsychological tests but only MMSE and visuospatial test scores were statistically significant after adjusting for age, sex, and educational level. We further adjusted for cardiovascular risk factors; the significance remained in the visuospatial test but diminished in MMSE. Multivariate linear regression analyses adjusted for age, sex, and educational level showed that JVR combined with high right-atrial-pressure (RAP > 50th-percentile, 12 mmHg) was significantly associated with poorer performances in both MMSE [right JVR: B coefficient(95% confidence interval, p)=-2.83(−5.46–0.20, 0.036); left JVR: −2.77(−5.52–0.02, 0.048)] and visuospatial test [right JVR: −4.52(−8.89–0.16, 0.043); left JVR: −4.56(−8.81–0.30, 0.037)], with significances that remained after further adjusting for cardiovascular risk factors. Our results suggest that retrogradely-transmitted venous pressure might be involved in the mechanisms mediating the relationship between cardiac diseases and brain functions.
Phasic norepinephrine is a neural interrupt signal for unexpected events in rapidly unfolding sensory sequences – evidence from pupillometry
Authors: Zhao Sijia , Chait Maria , Dick Fred , Dayan Peter , Furukawa Shigeto , Liao Hsin-I 
Published: November 2018

SummaryThe ability to track the statistics of our surroundings is a key computational challenge. A prominent theory (Dayan & Yu, 2006) proposes that the brain monitors for ‘unexpected uncertainty’ – events which deviate substantially from model predictions, indicating model failure. Norepinephrine (NE) is thought to play a key role in this process by serving as an interrupt signal, initiating model-resetting. However, evidence is from paradigms where participants actively monitored stimulus statistics. To determine whether NE routinely reports the statistical structure of our surroundings, even when not behaviourally relevant, we used rapid tone-pip sequences that contained perceptually salient pattern-changes associated with abrupt structural violations vs. emergence of regular structure. Phasic pupil dilations (PDR) were monitored to assess NE. We reveal a remarkable specificity: When not behaviourally relevant, only abrupt structural violations evoked a PDR. The results demonstrate that NE tracks ‘unexpected uncertainty’ on rapid time scales relevant to sensory signals.
Widespread conservation of chromatin accessibility patterns and transcription factor binding in human and chimpanzee induced pluripotent stem cells
Authors: Romero Irene Gallego , Gopalakrishnan Shyam , Gilad Yoav 
Published: November 2018

AbstractChanges in gene regulation have been shown to contribute to phenotypic differences between closely related species, most notably in primates. It is likely that a subset of inter-species regulatory differences can be explained by changes in chromatin accessibility and transcription factor binding, yet there is a paucity of comparative data sets with which to investigate this. Using ATAC-seq, we profiled genome-wide chromatin accessibility in a matched set of 6 human and 6 chimpanzee (Pan troglodytes, our closest living relative) induced pluripotent stem cells from which we have previously collected gene expression data. We examined chromatin accessibility patterns near 20,745 orthologous transcriptions start sites and used a footprinting algorithm to predict transcription factor binding activity in each species. We found that the majority of chromatin accessibility patterns and transcription factor activity are conserved between these two closely related species. Interestingly, interspecies divergence in chromatin accessibility and transcription factor binding in pluripotent cells appear to contribute not to differences in the pluripotent state, but to downstream developmental processes. Put together, our findings suggest that the pluripotent state is extremely stable and potentially subject to stronger evolutionary constraint than other somatic tissues.
Metastable regimes and tipping points of biochemical networks with potential applications in precision medicine
Authors: Samal Satya Swarup , Krishnan Jeyashree , Esfahani Ali Hadizadeh , Lüders Christoph , Weber Andreas , Radulescu Ovidiu 
Published: November 2018

AbstractThe concept of attractor of dynamic biochemical networks has been used to explain cell types and cell alterations in health and disease. We have recently proposed an extension of the notion of attractor to take into account metastable regimes, deﬁned as long lived dynamical states of the network. These regimes correspond to slow dynamics on low dimensional invariant manifolds of the biochemical networks. Methods based on tropical geometry allow to compute the metastable regimes and represent them as polyhedra in the space of logarithms of the species concentrations. We are looking for sensitive parameters and tipping points of the networks by analyzing how these polyhedra depend on the model parameters. Using the coupled MAPK and PI3K/Akt signaling networks as an example, we test the idea that large changes of the metastable states can be associated to cancer disease speciﬁc alterations of the network. In particular, we show that for model parameters representing protein concentrations, the protein differential level between tumors of different types is reasonably reﬂected in the sensitivity scores, with sensitive parameters corresponding to differential proteins.
The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype
Authors: Hari Priya , Millar Fraser R. , Tarrats Nuria , Birch Jodie , Rink Curtis J. , Fernández-Duran Irene , Muir Morwenna , Finch Andrew J. , Brunton Valerie G. , Passos João F. , Morton Jennifer P. , Boulter Luke , Acosta Juan Carlos 
Published: November 2018

ABSTRACTCellular senescence is a stress response program characterised by a robust cell cycle arrest and the induction of a pro-inflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that during oncogene-induced senescence (OIS), the Toll-like receptor TLR2 and its partner TLR10 are key mediators of senescence in vitro and in murine models. TLR2 promotes cell cycle arrest by regulating the tumour suppressors p53-p21CIP1, p16INK4a and p15INK4b, and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAA) that, in turn, function as the damage associated molecular patterns (DAMPs) signalling through TLR2 in OIS. Finally, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAA expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.
Melatonin attenuates mitochondrial and metabolic dysfunction caused by leptin deficiency
Authors: Potes Yaiza , Díaz-Luis Andrea , Bermejo-Millo Juan C , Pérez-Martínez Zulema , de Luxán-Delgado Beatriz , Rubio-González Adrian , Menéndez-Valle Ivan , Gutiérrez-Rodríguez José , Solano Juan J , Caballero Beatriz , Vega-Naredo Ignacio , Coto-Montes Ana 
Published: November 2018

AbstractLeptin, as a nutritional inhibitor by repressing food intake, is critical compromised in the major common forms of obesity. Skeletal muscle is the main effector tissue for energy expenditure modifications by the effect of endocrine axes, such as leptin signaling. Our study has been carried out using skeletal muscle from leptin-deficient animal model, in order to ascertain the importance of this hormone in eating disorders. Here we report that leptin-deficiency stimulates an uncontrolled oxidative phosphorylation metabolism, resulting in an excess of energy production that culminates in mitochondrial dysfunction. Thus, different nutrient sensing pathways are perturbed, loosing proteostasis and promoting lipid anabolism, that induces myofiber degeneration and drives oxidative type I fiber conversion. Melatonin treatment plays a significant role in regulating energy homeostasis and fuel utilization. This study reveals melatonin to be a decisive mitochondrial function-fate regulator, with implications for resembling physiological energy requirements and targeting glycolytic type II fibers recovery.
A computationally efficient Bayesian Seemingly Unrelated Regressions model for high-dimensional Quantitative Trait Loci discovery
Authors: Bottolo L. , Banterle M. , Richardson S. , Ala-Korpela M. , Järvelin M-R. , Lewin A. 
Published: November 2018

AbstractMotivationOur work is motivated by the search for metabolite Quantitative Trait Loci (QTL) in a cohort of more than 5,000 people. There are 158 metabolites measured by NMR spectroscopy measured in the 31-year follow-up of the Northern Finland Birth Cohort 1966 (NFBC66). These metabolites, as with many multivariate phenotypes produced by high-throughput biomarker technology, exhibit strong correlation structures. Existing approaches for combining such data with genetic variants for multivariate QTL analysis generally ignore phenotypic correlations or make restrictive assumptions about the associations between phenotypes and genetic loci.ResultsWe present a computationally efficient Bayesian Seemingly Unrelated Regressions (SUR) model for high-dimensional data, with cell-sparse variable selection and sparse graphical structure for covariance selection. Cell-sparsity allows different phenotype responses to be associated with different genetic predictors and the graphical structure is used to represent the conditional dependencies between phenotype variables. To achieve feasible computation of the large model space, we exploit a factorisation of the covariance matrix. Applying the model to the NFBC66 data with 9,000 directly-genotyped Single Nucleotide Polymorphisms, we are able to simultaneously estimate genotype-phenotype associations and the residual dependence structure amongst the metabolites at the same time.Availability and implementationThe R packageBayesSURwith full documentation is available athttps://cran.r-project.org/web/packages/BayesSUR/Contactalex.lewin@lshtm.ac.uk
Filamentous aggregates are fragmented by the proteasome holoenzyme
Authors: Cliffe Rachel , Sang Jason C , Kundel Franziska , Finley Daniel , Klenerman David , Ye Yu 
Published: November 2018

AbstractFilamentous aggregates (fibrils) are regarded as the final stage in the assembly of amyloidogenic proteins and are formed in many neurodegenerative diseases. Accumulation of aggregates occurs as a result of an imbalance between their formation and removal. Although there have been numerous studies of the aggregation process in vitro, far fewer studies of aggregate disassembly and degradation are available. Here we use single-aggregate imaging to show that large fibrils assembled from full-length tau are substrates of the 26S proteasome holoenzyme, which fragments them into small aggregates. TEM further revealed that these small aggregate species had no distinct structure. The intact proteasome holoenzyme is required to effectively target fibrils. Interestingly, while degradation of monomeric tau was not inhibited by ATPγS, fibril fragmentation was predominantly dependent on the ATPase activity of the proteasome. The proteasome holoenzyme was also found to target fibrils assembled from α-synuclein (αS), suggesting that its fibril fragmenting function may be a general mechanism. The fragmented species produced by the proteasome showed significant toxicity to human cell lines compared to intact fibrils. Together, our results indicate that the proteasome holoenzyme possesses a novel fragmentation function that disassembles large fibrils into smaller and more cytotoxic species.
Negative mood induction effects on problem solving task in women with eating disorders: a multi-method examination
Authors: French Melanie N. , Eneva Kalina , Arlt Jean M. , Yiu Angelina , Chen Eunice Y. 
Published: November 2018

AbstractEating disorders (EDs) are a serious public health concern, affecting about 5.2% of American women. The effects of negative affect on problem-solving and its psychophysiological correlates are poorly understood in this population. This study examined respiratory sinus arrhythmia (RSA) and skin conductance responses of 102 women with EDs (Binge eating disorder [BED]: n = 57, Anorexia nervosa: n = 13, Bulimia nervosa [BN]: n = 32) and 24 healthy controls (HCs) at baseline, and then during: a negative mood induction task, an adapted Means Ends Problem-Solving (MEPS) task and recovery. The MEPS Task included four interpersonal scenarios: 1) binge-eating when sad, 2) job dissatisfaction, 3) feeling rejected by friends, and 4) jealousy in a relationship. ED groups reported more negative and less positive emotions than HCs. After a negative mood induction, women with BED provided significantly less effective problem-solving strategies compared to HCs and women with BN for the binge-eating MEPS scenario. Relative to baseline and the negative mood induction, all participants exhibited significantly higher skin conductance response and skin conductance levels throughout the MEPS scenarios and recovery. BED showed significantly lower RSA levels than individuals with BN and HCs throughout the protocol. The multimethod findings suggest individuals with BED are likely to solve problems by binge-eating when in a negative affective state.
A case study on the detailed reproducibility of a human cell atlas project
Authors: Hua Kui , Zhang Xuegong 
Published: November 2018

AbstractReproducibility is a defining feature of a scientific discovery. Reproducibility can be at different levels for different types of study. The purpose of the Human Cell Atlas (HCA) project is to build maps of molecular signatures of all human cell types and states to serve as references for future discoveries. Constructing such a complex reference atlas must involve the assembly and aggregation of data from multiple labs, probably generated with different technologies. It has much higher requirements on reproducibility than individual research projects. To add another layer of complexity, the bioinformatics procedures involved for single-cell data have high flexibility and diversity. There are many factors in the processing and analysis of single-cell RNA-seq data that can shape the final results in different ways. To study what levels of reproducibility can be reached in current practices, we conducted a detailed reproduction study for a well-documented recent publication on the atlas of human blood dendritic cells as an example to break down the bioinformatics steps and factors that are crucial for the reproducibility at different levels. We found that the major scientific discovery can be well reproduced after some efforts, but there are also some differences in some details that may cause uncertainty in the future reference. This study provides a detailed case observation on the on-going discussions of the type of standards the HCA community should take when releasing data and publications to guarantee the reproducibility and reliability of the future atlas.
Transformation of event representations along middle temporal gyrus
Authors: Leshinskaya Anna , Thompson-Schill Sharon L. 
Published: November 2018

ABSTRACTWhen learning about events through visual experience, one must not only identify which events are visually similar, but also retrieve those events’ associates—which may be visually dissimilar—and recognize when different events have similar predictive relations. How are these demands balanced? To address this question, we taught participants the predictive structures among four events, which appeared in four different sequences, each cued by a distinct object. In each, one event (‘cause’) was predictably followed by another (‘effect’). Sequences in the same relational category had similar predictive structure, while across categories, the effect and cause events were reversed. Using fMRI data, we measuredassociative coding, indicated by correlated responses between effect and cause events;perceptual coding, indicated by correlated responses to visually similar events; andrelational category coding, indicated by correlated responses to objects in the same relational category. All three models characterized responses within right middle temporal gyrus (MTG), but in different ways: perceptual and associative coding diverged along the posterior to anterior axis, while relational categories emerged anteriorly in tandem with associative coding. Thus, along the posterior-anterior axis of MTG, the representation of the visual attributes of events is transformed to a representation of both specific and generalizable relational attributes.
Direct binding of Cdt2 to PCNA is important for targeting the CRL4Cdt2 E3 ligase activity to Cdt1
Authors: Hayashi Akiyo , Giakoumakis Nickolaos Nikiforos , Heidebrecht Tatjana , Ishii Takashi , Panagopoulos Andreas , Caillat Christophe , Takahara Michiyo , Hibbert Richard G. , Suenaga Naohiro , Stadnik-Spiewak Magda , Takahashi Tatsuro , Shiomi Yasushi , Taraviras Stavros , von Castelmur Eleonore , Lygerou Zoi , Perrakis Anastassis , Nishitani Hideo 
Published: November 2018

AbstractThe CRL4Cdt2 ubiquitin ligase complex is an essential regulator of cell-cycle progression and genome stability, ubiquitinating substrates such as p21, Set8 and Cdt1, via a display of substrate degrons on PCNA. Here, we examine the hierarchy of the ligase and substrate recruitment kinetics onto PCNA at sites of DNA replication. We demonstrate that the C-terminal end of Cdt2 bears a PCNA interaction protein motif (PIP box, Cdt2PIP), which is necessary and sufficient for binding of Cdt2 to PCNA. Cdt2PIP binds PCNA directly with high affinity, two orders of magnitude tighter than the PIP box of Cdt1. X-ray crystallographic structures of PCNA bound to Cdt2PIP and Cdt1PIP show that the peptides occupy all three binding sites of the trimeric PCNA ring. Mutating Cdt2PIP weakens the interaction with PCNA, rendering CRL4Cdt2 less effective in Cdt1 ubiquitination and leading to defects in Cdt1 degradation. The molecular mechanism we present suggests a new paradigm for bringing substrates to the CRL4-type ligase, where the substrate receptor and substrates bind to a common multivalent docking platform to enable subsequent ubiquitination.Summary blurbThe C-terminal end of Cdt2 contains a PIP-box for binding to PCNA to promote CRL4Cdt2 function, creating a new paradigm, where the substrate receptor and substrates bind to a common multivalent docking platform for ubiquitination.
Reorganization of budding yeast cytoplasm upon energy depletion
Authors: Marini Guendalina , Nüske Elisabeth , Leng Weihua , Alberti Simon , Pigino Gaia 
Published: November 2018

AbstractYeast cells, when exposed to stress, can enter a protective state in which cell division, growth and metabolism are downregulated. They remain viable in this state until nutrients become available again. How cells enter this protective survival state and what happens at a cellular and subcellular level is largely unknown. In this study, we used electron tomography to investigate the stress-induced ultrastructural changes in the cytoplasm of yeast cells. After ATP depletion, we observed a significant cytosolic compaction and an extensive cytoplasmic reorganization, as well as the emergence of distinct membrane-bound and membrane-less organelles. By using correlative light and electron microscopy (CLEM), we further demonstrate that one of these membrane-less organelles is generated by the reversible polymerization into large bundles of filaments of the eukaryotic translation initiation factor 2B (eIF2B), an essential enzyme in the initiation of protein synthesis. The changes we observe are part of a stress-induced survival strategy, allowing yeast cells to save energy, protect proteins from degradation, and inhibit protein functionality by forming assemblies of said proteins.
Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer’s disease
Authors: Konki Mikko , Malonzo Maia , Karlsson Ida K. , Lindgren Noora , Ghimire Bishwa , Smolander Johannes , Scheinin Noora M. , Ollikainen Miina , Laiho Asta , Elo Laura L. , Lönnberg Tapio , Röyttä Matias , Pedersen Nancy L. , Kaprio Jaakko , Lähdesmäki Harri , Rinne Juha , Lund Riikka J. 
Published: November 2018

ABSTRACTAlzheimer’s disease (AD) results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. As life style factors largely modulate the disease risk, we hypothesised that the disease associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs. Reduced Representation Bisulfite Sequencing, single cell RNA-sequencing and gene array data were utilised to examine DNA methylation signatures and associated gene expression changes in blood and hippocampus, and targeted bisulfite sequencing in cross cohort validation. Our results reveal that discordant twin pairs have disease associated differences in their peripheral blood epigenomes. A subset of affected genes, e.g.ADARB2contain differentially methylated sites also in anterior hippocampus. The DNA methylation differences seem to influence gene expression in brain rather than in blood cells. The affected genes are associated with neuronal functions and pathologies. These DNA methylation signatures are valuable disease marker candidates and may provide insights into the molecular mechanisms of pathogenesis.