bluuebunny/crossref_metadata_2025_split huggingface dataset:
Choices in Vaccine Trial Design for Epidemics of Emerging Infections
Authors: Kahn Rebecca , Rid Annette , Smith Peter G , Eyal Nir , Lipsitch Marc 
Published: February 2018

AbstractThe 2014–2016 Ebola epidemic highlighted the lack of consensus on the design of trials for investigational vaccine products in an emergency setting. With the advent of the ring vaccination strategy, it also underscored that the range of design options is evolving according to scientific need and creativity. Ideally, principles and protocols will be drawn up in advance, facilitating expediency and trust, for rapid deployment early in an epidemic. Here, we attempt a summary of the scientific, ethical and feasibility considerations relevant to different trial designs. We focus on four elements of design choices which, in our view, are most fundamental to designing an experimental vaccine trial and for which the most distinctive issues arise in the setting of an emerging infectious disease for which no proven vaccines exist: 1) randomization unit, 2) trial population, 3) comparator intervention and 4) trial implementation. Likewise, we focus on three of several ethical considerations in clinical research, namely the trial’s social and scientific value, its risk-benefit profile and its participant selection. A catalogue of possible designs to guide trial design choices is offered, along with a systematic evaluation of the benefits and drawbacks of each in given contexts.
Estimation of age-specific susceptibility to influenza in the Netherlands and its relation to loss of CD8+ T-cell memory
Authors: van Dorp Christiaan H. , Woolthuis Rutger G. , Yu Jeffrey H. C. , de Boer Rob J. , van Boven Michiel 
Published: February 2018

AbstractThe magnitude of influenza epidemics is largely determined by the number of susceptible individuals at the start of the influenza season. Susceptibility, in turn, is influenced by antigenic drift. The evolution of influenza’s B-cell epitopes has been charted thoroughly, and only recently evidence for T-cell driven evolution is accumulating. We investigate the relation between susceptibility to influenza, and antigenic drift at CD8+ T-cell epitopes over a 45-year timespan. We estimate age-specific susceptibility with data reported by general practitioners, using a disease-transmission model in a Bayesian framework. We find large variation in susceptibility, both between seasons and age classes. Although it is often assumed that antigenic drift drives the variation in susceptibility, we do not find evidence for a relation between drift and susceptibility in our data. This suggests that other factors determining the variation in susceptibility play a dominating role, or that complex influenza-infection histories obscure any direct effects.Preface to this bioRχiv pre-printWe are currently in the process of making this manuscript ready for re-submission, and are resolving some issues brought forward by our referees. Most importantly, we aim to better incorporate the co-circulation of the various influenza A and B subtypes during the different seasons, both in the estimation of susceptibility and antigenic drift.
Robustness of STDP to spike timing jitter
Authors: Cui Yihui , Prokin Ilya , Mendes Alexandre , Berry Hugues , Venance Laurent 
Published: February 2018

ABSTRACTIn Hebbian plasticity, neural circuits adjust their synaptic weights depending on patterned firing of action potential on either side of the synapse. Spike-timing-dependent plasticity (STDP) is an experimental implementation of Hebb’s postulate that relies on the precise order and the millisecond timing of the paired activities in pre- and postsynaptic neurons. In recent years, STDP has attracted considerable attention in computational and experimental neurosciences. However, canonical STDP is assessed with deterministic (constant) spike timings and time intervals between successive pairings, thus exhibiting a regularity that strongly differs from the biological variability. Hence, the emergence of STDP from noisy neural activity patterns as expected in in vivo-like firing remains unresolved. Here, we used noisy STDP stimulations where the spike timing and/or the interval between successive pairings were jittered. We explored with a combination of experimental neurophysiology and mathematical modeling, the impact of jittering on three distinct forms of STDP at corticostriatal synapses: NMDAR-mediated tLTP, endocannabinoid-mediated tLTD and endocannabinoid-mediated tLTP. As the main result, we found a differential sensitivity to jittered spike timing: NMDAR-tLTP was highly fragile whereas endocannabinoid-plasticity (tLTD and tLTP) appeared more resistant. Moreover, when the frequency or the number of pairings was increased, NMDAR-tLTP became more robust and could be expressed despite strong jittering of the spike timing. Taken together, our results identify endocannabinoid-mediated plasticity as a robust form of STDP while the sensitivity to jitter of NMDAR-tLTP varies with activity frequency. This provides new insights into the mechanisms at play during the different phases of learning and memory and the emergence of Hebbian plasticity in in vivo-like firing.
What drives interaction strengths in complex food webs? A test with feeding rates of a generalist stream predator
Authors: Preston Daniel L. , Henderson Jeremy S. , Falke Landon P. , Segui Leah M. , Layden Tamara J. , Novak Mark 
Published: February 2018

AbstractDescribing the mechanisms that drive variation in species interaction strengths is central to understanding, predicting, and managing community dynamics. Multiple factors have been linked to trophic interaction strength variation, including species densities, species traits, and abiotic factors. Yet most empirical tests of the relative roles of multiple mechanisms that drive variation have been limited to simplified experiments that may diverge from the dynamics of natural food webs. Here, we used a field-based observational approach to quantify the roles of prey density, predator density, predator-prey body-mass ratios, prey identity, and abiotic factors in driving variation in feeding rates of reticulate sculpin (Cottus perplexus). We combined data on over 6,000 predator-prey observations with prey identification time functions to estimate 289 prey-specific feeding rates at nine stream sites in Oregon. Feeding rates on 57 prey types showed an approximately log-normal distribution, with few strong and many weak interactions. Model selection indicated that prey density, followed by prey identity, were the two most important predictors of prey-specific sculpin feeding rates. Feeding rates showed a positive, accelerating relationship with prey density that was inconsistent with predator saturation predicted by current functional response models. Feeding rates also exhibited four orders-of-magnitude in variation across prey taxonomic orders, with the lowest feeding rates observed on prey with significant anti-predator defenses. Body-mass ratios were the third most important predictor variable, showing a hump-shaped relationship with the highest feeding rates at intermediate ratios. Sculpin density was negatively correlated with feeding rates, consistent with the presence of intraspecific predator interference. Our results highlight how multiple co-occurring drivers shape trophic interactions in nature and underscore ways in which simplified experiments or reliance on scaling laws alone may lead to biased inferences about the structure and dynamics of species-rich food webs.
Neurocognitive Aging and Brain Signal Complexity
Authors: McIntosh Anthony Randal 
Published: February 2018

SummaryBrain organization can be appreciated across multiple spatial and temporal scales, where each scale affects the other in the emergent functions that we appreciate as cognition. As a complex adaptive system, the interplay of these scales in the brain represents the information that ultimately supports what we think and do. The dynamics of these multiscale operations can be quantified with measures of complexity, which are sensitive to the balance between information that is coded in local cell populations and that captured in the network interactions between populations. This local vs. global balance has its foundation in the structural connectivity of the brain, which is then realized through the dynamics of cell populations and their ensuing interactions with other populations. Considering brain function and cognition in this way enables a different perspective on the changes in cognitive function in aging.Our initial work examined changes in brain signal complexity from childhood to adulthood. Across two independent studies, we observed an overall increase in signal complexity with maturation, which also correlated with more stable and accurate cognitive performance. There was some suggestion that the maximal change occurs in medial posterior cortical areas, which have been considered “network hubs” of the brain. In extending to study to healthy aging, we observed a scale dependent change in brain complexity across three independent studies. Healthy aging brings a shift in local/global balance, where more information is coded in local dynamics and less in global interactions. This balance is associated with better cognitive performance, and interestingly in a more active lifestyle. It also seems that the lack of this shift in local/global balance is predictive of worse cognitive performance and potentially predictive of additional decline indicative of dementia.
Audible Feedback Improves Internal Model Strength and Performance of Myoelectric Prosthesis Control
Authors: Shehata Ahmed W. , Scheme Erik J. , Sensinger Jonathon W. 
Published: February 2018

AbstractMyoelectric prosthetic devices are commonly used to help upper limb amputees perform activities of daily living, however amputees still lack the sensory feedback required to facilitate reliable and precise control. Augmented feedback may play an important role in affecting both short-term performance, through real-time regulation, and long-term performance, through the development of stronger internal models. In this work, we investigate the potential tradeoff between controllers that enable better short-term performance and those that provide sufficient feedback to develop a strong internal model. We hypothesize that augmented feedback may be used to mitigate this tradeoff, ultimately improving both short and long-term control. We used psychometric measures to assess the internal model developed while using a filtered myoelectric controller with augmented audio feedback, imitating classification-based control but with augmented regression-based feedback. In addition, we evaluated the short-term performance using a multi degree-of-freedom constrained-time target acquisition task. Results obtained from 24 able-bodied subjects show that an augmented feedback control strategy using audio cues enables the development of a stronger internal model than the filtered control with filtered feedback, and significantly better path efficiency than both raw and filtered control strategies. These results suggest that the use of augmented feedback control strategies may improve both short-term and long-term performance.
Log D Analysis Using Dynamic Approach
Authors: Paul Ganesh Kumar , Alluvada Prashanth , Alemayehu Esayas , Shahul Hameed M.S. , Alemayehu Wasihun , Kwa Timothy , Krishnamoorthy Janarthanan 
Published: February 2018

ABSTRACTLog D is one of the important parameters used in Lipinski’s rule to assess the druggability of a molecule in pharmaceutical formulations. It represents the logarithm (log10) of the distribution coefficient (D) of a molecule. The distribution coefficient is defined as the ratio of the concentration of the sum of ionized and unionized species of a molecule distributed between a hydrophobic organic phase and an aqueous buffer phase. Since the pH affects the ionic state of a molecule, log D value (which is dependent on the concentrations of the ionized species) also becomes dependent on pH. In this work, the conventional algebraic method is compared with a more generalized ‘dynamic’ approach to model the distribution coefficient of amphoteric, diamino-monoprotic molecule and monoprotic acid in the presence of salt or co-solvent. Recently reported experimental log D data of amphoteric molecules such as nalidixic acid, mebendazole, benazepril and telmisartan, were analyzed using both these approaches to show their equivalence.GRAPHICAL ABSTRACT
Forty-Eight Hour Conditioning Produces a Robust Long Lasting Flavor Preference in Rats
Authors: Kimbrough Adam , Houpt Thomas A. 
Published: February 2018

AbstractConditioned flavor preference (CFP) learning is a form of associative learning in ingestive behavior. CFP Learning can be rapid and produces preferences of varying strengths that can be exceptionally persistent. We sought to establish a method to produce a robust long-lasting CFP in rats. Rats were given 48-h access (conditioning) to a CS+ flavor (grape or cherry 0.05% Kool-Aid, counterbalanced) mixed with 8% glucose and 0.05% saccharin. In order to determine the strength of conditioning rats were given 14 consecutive days of 24-h access to CS+ and CS- flavors mixed only with 0.05% Kool-Aid and 0.05% saccharin (extinction), then further tested 34 days after the last extinction test (48 days post conditioning) for 2 consecutive days with the CS+ and CS-. We found that not only did the learned CFP fail to extinguish over 14 days of testing, but it also persisted for at least 48 days after conditioning. These data provide a method to produce a robust, long lasting and persistent CFP for use in future ingestive behavior research.
Defective RNA Polymerase III is negatively regulated by the SUMO-Ubiquitin-Cdc48 Pathway
Authors: Wang Zheng , Wu Catherine , Aslanian Aaron , Yates John R. , Hunter Tony 
Published: February 2018

ABSTRACTTranscription by RNA polymerase III (Pol III) is an essential cellular process, and mutations in Pol III can cause neurodegenerative disease in humans. However, in contrast to Pol II transcription, which has been extensively studied, the knowledge of how Pol III is regulated is very limited. We report here that in budding yeast,Saccharomyces cerevisiae, Pol III is negatively regulated by theSmallUbiquitin-likeMOdifier (SUMO), an essential post-translational modification pathway. Besides sumoylation, Pol III is also targeted by ubiquitylation and the Cdc48/p97 segregase, the three of which likely act in a sequential manner and eventually lead to proteasomal degradation of Pol III subunits, thereby repressing Pol III transcription. This study not only uncovered a regulatory mechanism for Pol III, but also suggests that the SUMO and ubiquitin modification pathways and the Cdc48/p97 segregase can be potential therapeutic targets for Pol III-related human diseases.
Conceptual content in images triggers rapid shifts of covert attention
Authors: Wyble Brad , Hess Michael , Callahan-Flintoft Chloe , Folk Charles 
Published: February 2018

AbstractThe visual system can use conceptual information to search for targets even in the absence of clear featural signifiers1, and visual saccades are often directed at target objects defined by conceptual content2. These abilities are a core component of our facility with the visual world. Here, we evaluate whether contingent mechanisms of visual attention, known to trigger in response to target features such as motion, color or luminance3, are also triggered by visual patterns that match conceptually specified categories. These pre-registered experiments provide convergent behavioral and electrophysiological support that covert spatial attention is rapidly triggered by natural image exemplars from superordinate conceptually described target sets such as dinner food or four-legged animal, even when each target was viewed only once. In the behavioral experiment when two targets were presented with onsets separated by only 167ms, subjects reported the second target more often when it was in the same spatial location as the first. In the EEG experiment, images elicited clear N2pc and P3 components only when they matched the conceptually specified target set. The latency of the N2pc peaked at roughly 250ms, which is comparable to that commonly found in other N2pc studies for simpler stimulus types. These results suggest that vision quickly decodes conceptual information from natural images and selectively deploys spatial attention to locations containing information that matches current search goals.
Two Novel Forms of ERG Oscillation inDrosophila: Age and Activity Dependence
Authors: Ueda Atsushi , Woods Scott , McElree Ian , O’Harrow Tristan C.D.G. , Inman Casey , Thenuwara Savantha , Aftab Muhammad , Iyengar Atulya 
Published: February 2018

AbstractOver an animal’s lifespan, neuronal circuits and systems often decline in an inherently heterogeneous fashion. To compare the age-dependent progression of changes in visual behavior with alterations in retinal physiology, we examined phototaxis and electroretinograms (ERGs) in a wild-typeD. melanogasterstrain(Canton-S)across their lifespan. In aged flies (beyond 50% median lifespan), we found a marked decline in phototaxis, while motor coordination was less disrupted, as indicated by relatively stronger negative geotaxis. These aged flies displayed substantially reduced ERG transient amplitudes while the receptor potentials (RP) remained largely intact. Using a repetitive light flash protocol, we serendipitously discovered two forms of activity-dependent oscillation in the ERG waveforms of young flies: “light-off’ and “light-on” oscillations. After repeated 500 ms light flashes, light-off oscillations appeared during the ERG off-transients (frequency: 50-120 Hz, amplitude: ~1 mV). Light-on oscillations (100-200 Hz, ~0.3 mV) were induced by a series of 50 ms flashes, and were evident during the ERG on-transients. Both forms of oscillation were observed in other strains ofD. melanogaster(Oregon-R, Berlin), additionalDrosophilaspecies(funerbris, euronotus, hydei, americana), and were evoked by a variety of light sources. Both light-off and light-on oscillations were distinct from previously described ERG oscillations in visual mutants, such asrosA, in terms of location within the waveform and frequency. However, withinrosAmutants, light-off oscillations, but not light-on oscillations could be recruited by the repetitive light flash protocol. Importantly though, we found that both forms of oscillation were rarely observed in aged flies. Although the physiological bases of these oscillations remain to be elucidated, they may provide important clues to age-related changes in neuronal excitability and synaptic transmission.
A Fast Adaptive Algorithm for Computing Whole-Genome Homology Maps
Authors: Jain Chirag , Koren Sergey , Dilthey Alexander , Phillippy Adam M. , Aluru Srinivas 
Published: February 2018

AbstractMotivationWhole-genome alignment is an important problem in genomics for comparing different species, mapping draft assemblies to reference genomes, and identifying repeats. However, for large plant and animal genomes, this task remains compute and memory intensive.ResultsWe introduce an approximate algorithm for computing local alignment boundaries between long DNA sequences. Given a minimum alignment length and an identity threshold, our algorithm computes the desired alignment boundaries and identity estimates using kmer-based statistics, and maintains sufficient probabilistic guarantees on the output sensitivity. Further, to prioritize higher scoring alignment intervals, we develop a plane-sweep based filtering technique which is theoretically optimal and practically efficient. Implementation of these ideas resulted in a fast and accurate assembly-to-genome and genome-to-genome mapper. As a result, we were able to map an error-corrected whole-genome NA12878 human assembly to the hg38 human reference genome in about one minute total execution time and < 4 GB memory using 8 CPU threads, achieving significant performance improvement over competing methods. Recall accuracy of computed alignment boundaries was consistently found to be > 97% on multiple datasets. Finally, we performed a sensitive self-alignment of the human genome to compute all duplications of length ≥ 1 Kbp and ≥ 90% identity. The reported output achieves good recall and covers 5% more bases than the current UCSC genome browser's segmental duplication annotation.Availabilityhttps://github.com/marbl/MashMap.Contactadam.phillippy@nih.gov, aluru@cc.gatech.edu
Gene Coregulation and Coexpression in the Aryl Hydrocarbon Receptor-mediated Transcriptional Regulatory Network in the Mouse Liver
Authors: Josyula Navya , Andersen Melvin E. , Kaminski Norbert , Dere Edward , Zacharewski Timothy R. , Bhattacharya Sudin 
Published: February 2018

AbstractTissue-specific network models of chemical-induced gene perturbation can improve our mechanistic understanding of the intracellular events leading to adverse health effects resulting from chemical exposure. The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor (TF) that activates a battery of genes and produces a variety of species-specific adverse effects in response to the potent and persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here we assemble a global map of the AHR gene regulatory network in TCDD-treated mouse liver from a combination of previously published gene expression and genome-wide TF binding data sets. Using Kohonen selforganizing maps and subspace clustering, we show that genes co-regulated by common upstream TFs in the AHR network exhibit a pattern of co-expression. Specifically, directly-bound, indirectly-bound and non-genomic AHR target genes exhibit distinct patterns of gene expression, with the directly bound targets generally associated with highest median expression. Further, among the directly bound AHR target genes, the expression level increases with the number of AHR binding sites in the proximal promoter regions. Finally, we show that co-regulated genes in the AHR network activate distinct groups of downstream biological processes, with AHR-bound target genes enriched for metabolic processes and enrichment of immune responses among AHR-unbound target genes, likely reflecting infiltration of immune cells into the mouse liver upon TCDD treatment. This work describes an approach to the reconstruction and analysis of transcriptional regulatory cascades underlying cellular stress response using bioinformatic and statistical tools.