bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing concentration-dependent neural dynamics of 4-aminopyridine-induced epileptiform activity
Authors: Myers Timothy L , González Oscar C , Stein Jacob B , Bazhenov Maxim 
Published: January 2018

AbstractEpilepsy remains one of the most common neurological disorders. In patients, it is characterized by unprovoked, spontaneous, and recurring seizures or ictal events. Typically, inter-ictal events or large bouts of population level activity can be measured between seizures and are generally asymptomatic. Decades of research has focused on understanding the mechanisms leading to the development of seizure-like activity using various proconvulsive pharmacological agents, including 4-aimnopyridine (4AP). However, the lack of consistency in the concentrations used for studying 4AP-induced epileptiform activity in animal models may give rise to differences in the results and interpretation thereof. Indeed, the range of 4AP concentration in both in vivo and in vitro studies varies from 3μM to 40mM. Here, we explored the effects of various 4AP concentrations on the development and characteristics of hippocampal epileptiform activity in acute mouse brain slices of either sex. Using multielectrode array recordings, we show that 4AP induces hippocampal epileptiform activity for broad range of concentrations. The frequency component and the spatio-temporal patterns of the epileptiform activity revealed a dose-dependent response. Finally, in the presence of 4AP, reduction of KCC2 co-transporter activity by KCC2 antagonist VU0240551 prevented the manifestation of the frequency component differences between different concentrations of 4AP. Overall, the study predicts that different concentrations of 4AP can result in the different mechanisms behind hippocampal epileptiform activity, of which some are dependent on the KCC2 co-transporter function.
Guiding Vaccine Efficacy Trial Design During Public Health Emergencies: An interactive web-based decision support tool
Authors: Bellan Steven E. , Eggo Rosalind M , Gsell Pierre-Stéphane , Kucharski Adam J , Dean Natalie E , Donohue Richard , Zook Matt , Odhiambo Frank , Longini Ira , Brisson Marc , Mahon Barbara E , Henao-Restrepo Ana Maria 
Published: January 2018

AbstractThe design and execution of rigorous, fast, and ethical vaccine efficacy trials can be challenging during epidemics of emerging pathogens, such as the 2014-2016 Ebola virus and 2015-2016 Zika virus epidemics. Response to an urgent public health crisis requires accelerated research even as emerging epidemics themselves change rapidly and are inherently less well understood than well-established diseases. As part of the World Health Organization Research and Development Blueprint, we designed a web-based interactive decision support system (InterVax-Tool) to help diverse stakeholders navigate the epidemiological, logistical, and ethical decisions involved in designing a vaccine efficacy trial during a public health emergency. In contrast to existing literature on trial design, InterVax-Tool offers high-level visual and interactive assistance through a set of four decision trees, guiding users through selection of 1) the Primary Endpoint, (2) the Target Population, (3) Randomization, and (4) the Comparator. Guidance is provided on how each of fourteen key considerations–grouped as Epidemiological, Vaccine-related, Infrastructural, or Sociocultural–should be used to inform each decision in the trial design process. The tool is not intended to provide a black box decision framework for identifying an optimal trial design, but rather to facilitate transparent, collaborative and comprehensive discussion of the relevant decisions, while recording the decision process. The tool can also assist capacity building by providing a cross-disciplinary picture of trial design using concepts from epidemiology, study design, vaccinology, biostatistics, mathematical modeling and clinical research ethics. Here, we describe the goals and features of InterVax-Tool as well as its application to the design of a Zika vaccine efficacy trial.One Sentence SummaryAn interactive web-based decision support tool was developed to assist in the design of vaccine efficacy trials during emerging outbreaks.
Unsupervised clustering of temporal patterns in high-dimensional neuronal ensembles using a novel dissimilarity measure
Authors: Grossberger Lukas , Battaglia Francesco P. , Vinck Martin 
Published: January 2018

AbstractTemporally ordered multi-neuron patterns likely encode information in the brain. We introduce an unsupervised method, SPOTDisClust (Spike Pattern Optimal Transport Dissimilarity Clustering), for their detection from high-dimensional neural ensembles. SPOTDisClust measures similarity between two ensemble spike patterns by determining the minimum transport cost of transforming their corresponding normalized cross-correlation matrices into each other (SPOTDis). Then, it performs density-based clustering based on the resulting inter-pattern dissimilarity matrix. SPOTDisClust does not require binning and can detect complex patterns (beyond sequential activation) even when high levels of out-of-pattern “noise” spiking are present. Our method handles efficiently the additional information from increasingly large neuronal ensembles and can detect a number of patterns that far exceeds the number of recorded neurons. In an application to neural ensemble data from macaque monkey V1 cortex, SPOTDisClust can identify different moving stimulus directions on the sole basis of temporal spiking patterns.Author summaryThe brain encodes information by ensembles of neurons, and recent technological developments allow researchers to simultaneously record from over thousands of neurons. Neurons exhibit spontaneous activity patterns, which are constrained by experience and development, limiting the portion of state space that is effectively visited. Patterns of spontaneous activity may contribute to shaping the synaptic connectivity matrix and contribute to memory consolidation, and synaptic plasticity formation depends crucially on the temporal spiking order among neurons. Hence, the unsupervised detection of spike sequences is a sine qua non for understanding how spontaneous activity contributes to memory formation. Yet, sequence detection presents major methodological challenges like the sparsity and stochasticity of neuronal output, and its high dimensionality. We propose a dissimilarity measure between neuronal patterns based on optimal transport theory, determining their similarity from the pairwise cross-correlation matrix, which can be taken as a proxy of the “trace” that is left on the synaptic matrix. We then perform unsupervised clustering and visualization of patterns using density clustering on the dissimilarity matrix and low-dimensional embedding techniques. This method does not require binning of spike times, is robust to noise, jitter and rate fluctuations, and can detect more patterns than the number of neurons.
The Folding Pathway of an Ig Domain is Conserved On and Off the Ribosome
Authors: Tian Pengfei , Steward Annette , Kudva Renuka , Su Ting , Shilling Patrick J. , Nickson Adrian A. , Hollins Jeffrey J. , Beckmann Roland , Heijne Gunnar von , Clarke Jane , Best Robert B. 
Published: January 2018

AbstractProteins that fold cotranslationally may do so in a restricted configurational space, due to the volume occupied by the ribosome. How does this environment, coupled with the close proximity of the ribosome, affect the folding pathway of a protein? Previous studies have shown that the cotranslational folding process for many proteins, including small, single domains, is directly affected by the ribosome. Here, we investigate the cotranslational folding of an all-b immunoglobulin domain, titin I27. Using an arrest peptide-based assay and structural studies by cryo-EM, we show that I27 folds in the mouth of the ribosome exit tunnel. Simulations that use a kinetic model for the force-dependence of escape from arrest, accurately predict the fraction of folded protein as a function of length. We used these simulations to probe the folding pathway on and off the ribosome. Our simulations - which also reproduce experiments on mutant forms of I27 - show that I27 folds, while still sequestered in the mouth of the ribosome exit tunnel, by essentially the same pathway as free I27, with only subtle shifts of critical contacts from the C to the N terminus.Significance StatementMost proteins need to fold into a specific three-dimensional structure in order to function. The mechanism by which isolated proteins fold has been thoroughly studied by experiment and theory. However, in the cell proteins do not fold in isolation, but are synthesized as linear chains by the ribosome during translation. It is therefore natural to ask at which point during synthesis proteins fold, and whether this differs from the folding of isolated protein molecules. By studying folding of a well characterized protein domain, titin I27, stalled at different points during translation, we show that it already folds in the mouth of the ribosome exit tunnel, and that the mechanism is almost identical to that of the isolated protein.
Natural variation in stomata size contributes to the local adaptation of water-use efficiency in Arabidopsis thaliana
Authors: Dittberner H. , Korte A. , Mettler-Altmann T. , Weber A.P.M. , Monroe G. , de Meaux J. 
Published: January 2018

AbstractStomata control gas exchanges between the plant and the atmosphere. How natural variation in stomata size and density contributes to resolve trade-offs between carbon uptake and water-loss in response to local climatic variation is not yet understood. We developed an automated confocal microscopy approach to characterize natural genetic variation in stomatal patterning in 330 fully-sequenced Arabidopsis thaliana accessions collected throughout the European range of the species. We compared this to variation in water-use efficiency, measured as carbon isotope discrimination (δ13C). We detect substantial genetic variation for stomata size and density segregating within Arabidopsis thaliana. A positive correlation between stomata size and δ13C further suggests that this variation has consequences on water-use efficiency. Genome-wide association analyses indicate a complex genetic architecture underlying not only variation in stomata patterning but also to its co-variation with carbon uptake parameters. Yet, we report two novel QTL affecting δ13C independently of stomata patterning. This suggests that, in A. thaliana, both morphological and physiological variants contribute to genetic variance in water-use efficiency. Patterns of regional differentiation and co-variation with climatic parameters indicate that natural selection has contributed to shape some of this variation, especially in Southern Sweden, where water availability is more limited in spring relative to summer. These conditions are expected to favor the evolution of drought avoidance mechanisms over drought escape strategies.
Chromosome evolution at the origin of the ancestral vertebrate genome
Authors: Sacerdot Christine , Louis Alexandra , Bon Céline , Roest Crollius Hugues 
Published: January 2018

ABSTRACTAbout 450 million years ago, a marine chordate was subject to two successive whole genome duplications (WGDs) before becoming the common ancestor of vertebrates and diversifying into the more than 60,000 species found today. Here, we reconstruct in details the evolution of chromosomes of this early vertebrate along successive steps of the two WGD. We first compared 61 extant animal genomes to build a highly contiguous order of genes in a 326 million years old ancestral Amniota genome. In this genome, we established a well-supported list of duplicated genes originating from the WGDs to link chromosomes in tetrads, a telltale signature of these events. This enabled us to reconstruct a scenario where a pre-vertebrate genome composed of 17 chromosomes duplicated into 34 chromosomes, and was subject to 7 chromosome fusions before duplicating again into 54 chromosomes. After the separation of Agnatha (jawless fish) and Gnathostomata, four more fusions took place to form the ancestral Euteleostomi genome of 50 chromosomes. These results firmly establish the occurrence of the two WGD, resolving in particular the ambiguity raised by the analysis of the lamprey genetic map. In addition, we provide insight into the origin of homologous micro-chromosomes found in the chicken and the gar genomes. This work provides a foundation for studying the evolution of vertebrate chromosomes from the standpoint of a common ancestor, and particularly the pattern of duplicate gene retention and loss that resulted in the gene composition of extant genomes.
Analysis of heat-induced protein aggregation in human mitochondria
Authors: Wilkening Anne , Rüb Cornelia , Sylvester Marc , Voos Wolfgang 
Published: January 2018

AbstractAs proteins in mammalian cells exhibit optimal stability at natural temperatures, small temperature variations may cause unfolding and subsequent non-specific aggregation. As this process leads to a loss of function of the affected polypeptides as well as to further cytotoxic stress, aggregate formation has been recognized as a major pathogenic factor in human diseases. In this study we determined the impact of physiological heat stress on mammalian mitochondria on a proteomic level. The overall solubility of endogenous mitochondrial proteins was only marginally affected by a treatment at elevated temperatures. However, we identified a small subset of polypeptides that exhibited an exceptionally high sensitivity to heat stress. The mitochondrial translation elongation factor Tu (Tufm), a protein essential for organellar protein biosynthesis, was highly aggregation-prone and lost its solubility already under mild heat stress conditions. In parallel, mitochondrial translation as well as the import of cytosolic proteins was defective in heat stressed mitochondria. Both types of nascent polypeptides, derived from translation as well as from import exhibited a strong heat-induced aggregation tendency. We propose a model that a quick and specific inactivation of elongation factors may prevent an accumulation of misfolded nascent polypeptides and thereby attenuate proteotoxicity under stress.
Reliability of Whole-Exome Sequencing for Assessing Intratumor Genetic Heterogeneity
Authors: Shi Weiwei , Ng Charlotte K. Y. , Lim Raymond S. , Jiang Tingting , Kumar Sushant , Li Xiaotong , Wali Vikram B. , Piscuoglio Salvatore , Gerstein Mark B. , Chagpar Anees B. , Weigelt Britta , Pusztai Lajos , Reis-Filho Jorge S. , Hatzis Christos 
Published: January 2018

SUMMARYMulti-region sequencing is used to detect intratumor genetic heterogeneity (ITGH) in tumors. To assess whether genuine ITGH can be distinguished from sequencing artifacts, we whole-exome sequenced (WES) three anatomically distinct regions of the same tumor with technical replicates to estimate technical noise. Somatic variants were detected with three different WES pipelines and subsequently validated by high-depth amplicon sequencing. The cancer-only pipeline was unreliable, with about 69% of the identified somatic variants being false positive. Even with matched normal DNA where 82% of the somatic variants were detected reliably, only 36%-78% were found consistently in technical replicate pairs. Overall 34%-80% of the discordant somatic variants, which could be interpreted as ITGH, were found to constitute technical noise. Excluding mutations affecting low mappability regions or occurring in certain mutational contexts was found to reduce artifacts, yet detection of subclonal mutations by WES in the absence of orthogonal validation remains unreliable.
Natural Secretory Immunoglobulins Enhance Norovirus Infection
Authors: Turula Holly , Bragazzi-Cunha Juliana , Ramakrishnan Sadeesh , Wilke Carol , Gonzalez-Hernandez Mariam , Pry Alexandra , Fava Julianne , Svoboda Sophia , Shah Yatrik , Corthesy Blaise , Moore Bethany , Wobus Christiane E. 
Published: January 2018

AbstractSecretory immunoglobulins (SIg) are a first line of mucosal defense by the host. They are secreted into the gut lumen via the polymeric immunoglobulin receptor (pIgR) where they bind to antigen and are transported back across the FAE via M cells. Noroviruses are highly prevalent, enteric pathogens that cause significant morbidity, mortality and economic losses worldwide. Murine norovirus (MNV) exploits microfold (M) cells to cross the lymphoid follicle-associated epithelium (FAE) and infect the underlying population of immune cells. However, whether natural, innate SIg can protect against norovirus infection remains unknown. To investigate the role of natural SIg during murine norovirus pathogenesis, we used pIgR-deficient animals, which lack SIg in the intestinal lumen. Contrary to other enteric pathogens, acute MNV replication was significantly reduced in the gastrointestinal tract of pIgR-deficient animals compared to controls, despite increased numbers of dendritic cells, macrophages, and B cells in the Peyer’s patch, established MNV target cell types. Also, natural SIg did not alter MNV FAE binding or FAE crossing into the lymphoid follicle. Instead, further analysis revealed enhanced baseline levels of the antiviral molecules interferon gamma (IFNɣ) and inducible nitric oxide synthase (iNOS) in the small intestine of naive pIgR-deficient animals compared to controls. Removing the microbiota equalized IFNɣ and iNOS transcript levels as well as MNV viral loads in germ-free pIgR KO mice compared to germ-free controls. These data are consistent with a model whereby SIg sensing reduces pro-inflammatory, antiviral molecules, which facilitates intestinal homeostasis but thereby promotes MNV infection. In conclusion, these findings demonstrate that natural SIg are not protective during norovirus infection in mice and represent another example of indirect modulation of enteric virus pathogenesis by the microbiota.
Vagus Nerve Stimulation Promotes Gastric Emptying by Increasing Pyloric Opening Measured with Magnetic Resonance Imaging
Authors: Lu Kun-Han , Cao Jiayue , Oleson Steven , Ward Matthew P , Powley Terry L , Liu Zhongming 
Published: January 2018

AbstractBackgroundVagus nerve stimulation (VNS) is an emerging electroceutical therapy for remedying gastric disorders that are poorly managed by pharmacological treatments and/or dietary changes. Such therapy seems promising since the vagovagal neurocircuitry controlling the enteric nervous system strongly influences gastric functions.MethodsHere, the modulatory effects of left cervical VNS on gastric emptying in rats was quantified using a 1) feeding protocol in which the animal voluntarily consumed a post-fast, gadolinium-labeled meal and 2) newly developed, robust, sensitive and non-invasive imaging strategy to measure antral motility, pyloric activity and gastric emptying based on contrast-enhanced magnetic resonance imaging (MRI) and computer-assisted image processing pipelines.Key ResultsVNS significantly accelerated gastric emptying (control vs. VNS: 24.9±3.5% vs. 40.7±3.9% of meal emptied per 4hrs, p<0.05). This effect resulted from a greater relaxation of the pyloric sphincter (control vs. VNS: 1.4±0.2 vs. 2.5±0.5 mm2cross-sectional area of lumen, p<0.05), without notable changes in antral contraction amplitude (control vs. VNS: 30.6±3.0% vs. 32.5±3.0% occlusion), peristaltic velocity (control vs. VNS: 0.67±0.03 vs. 0.67±0.03 mm/s), or frequency (control vs. VNS: 6.3±0.1 vs. 6.4±0.2 cpm). The degree to which VNS relaxed the pylorus positively correlated with gastric emptying rate (r = 0.5465, p<0.01).Conclusions & InferencesThe MRI protocol employed in this study is expected to enable advanced preclinical studies to understand stomach pathophysiology and its therapeutics. Results from this study suggest an electroceutical treatment approach for gastric emptying disorders using cervical VNS to control the degree of pyloric sphincter relaxation.Key PointsVagus nerve stimulation is emerging as a new electroceutical therapy for treating gastric disorders. However, its underlying mechanism(s) and therapeutic effect(s) remain incompletely understood.Vagus nerve stimulation significantly accelerated gastric emptying by promoting the relaxation of the pyloric sphincter.MRI offers high spatial and temporal resolution to non-invasively characterize gastric motility and physiology in preclinical animal models.
Genetically encoded ratiometric indicators for potassium ion
Authors: Shen Yi , Wu Sheng-Yi , Rancic Vladimir , Qian Yong , Miyashita Shin-Ichiro , Ballanyi Klaus , Campbell Robert E. , Dong Min 
Published: January 2018

AbstractPotassium ion (K+) homeostasis and dynamics play critical roles in regulating various biological activities, and the ability to monitor K+spatial-temporal dynamics is critical to understanding these biological functions. Here we report the design and characterization of a Förster resonance energy transfer (FRET)-based genetically encoded K+indicator, KIRIN1, constructed by inserting a bacterial cytosolic K+binding protein (Kbp) between a fluorescent protein (FP) FRET pair, mCerulean3 and cp173Venus. Binding of K+induces a conformational change in Kbp, resulting in an increase in FRET efficiency. KIRIN1 was able to detect K+at physiologically relevant concentrationsin vitroand is highly selective toward K+over Na+. We further demonstrated that KIRIN1 allowed real-time imaging of pharmacologically induced depletion of cytosolic K+in live cells, and KIRIN1 also enabled optical tracing of K+efflux and reuptake in neurons upon glutamate stimulation in cultured primary neurons. These results demonstrate that KIRIN1 is a valuable tool to detect K+in vitroand in live cells.
The gender difference in leadership effectiveness and its Sino-US comparison
Authors: Yan Shimei , Wu Yike , Zhang Gang 
Published: January 2018

PurposeThere are mainly two viewpoints on women’s leadership effectiveness compared with that of men – the questioning view and the admiring view, two points of view that are not in agreement. Based on that, this study aims to find the gender difference in leadership effectiveness.Design/methodology/approachThis study uses carefully matched male and female presidents (223 pairs) of Chinese listed companies and male and female chief executive officers (141 pairs) of American listed companies as samples. Analysis of variance was conducted to analyze the indicator data of the leadership effectiveness.FindingsThe findings show that women’s leadership effectiveness is not significantly inferior to that of men, and that women’s leadership effectiveness compared to that of men in the Chinese cultural context is not inferior to that in the American cultural context. The findings do not support the questioning view of women’s leadership effectiveness.Originality/valueThis study first uses the carefully matched (female/male leaders) data of Chinese listed companies and American listed companies as samples to find which viewpoint (the questioning view and the admiring view) is supported or is not supported.