bluuebunny/crossref_metadata_2025 huggingface dataset:
The Trials and Tribulations of Priors and Posteriors in Bayesian Timing of Divergence Analyses: the Age of Butterflies Revisited
Authors: Chazot Nicolas , Wahlberg Niklas , Victor Lucci Freitas André , Mitter Charles , Labandeira Conrad , Sohn Jae-Cheon , Sahoo Ranjit Kumar , Seraphim Noemy , De Jong Rienk , Heikkilä Maria
Published: February 2018

The need for robust estimates of times of divergence is essential for downstream analyses, yet assessing this robustness is still rare. We generated a time-calibrated genus-level phylogeny of butterflies (Papilionoidea), including 994 taxa, up to 10 gene fragments and an unprecedented set of 12 fossils and 10 host-plant node calibration points. We compared marginal priors and posterior distributions to assess the relative importance of the former on the latter. This approach revealed a strong influence of the set of priors on the root age but for most calibrated nodes posterior distributions shifted from the marginal prior, indicating significant information in the molecular dataset. We also tested the effects of changing assumptions for fossil calibration priors and the tree prior. Using a very conservative approach we estimated an origin of butterflies at 107.6 Ma, approximately equivalent to the Early Cretaceous–Late Cretaceous boundary, with a credibility interval ranging from 89.5 Ma (mid Late Cretaceous) to 129.5 Ma (mid Early Cretaceous). This estimate was robust to alternative analyses changing core assumptions. With 994 genera, this tree provides a comprehensive source of secondary calibrations for studies on butterflies.
Genome-wide transcriptome analysis identifies alternative splicing regulatory network and key splicing factors in mouse and human psoriasis
Authors: Li Jin , Yu Peng
Published: February 2018

Psoriasis is a chronic inflammatory disease that affects the skin, nails, and joints. For understanding the mechanism of psoriasis, though, alternative splicing analysis has received relatively little attention in the field. Here, we developed and applied several computational analysis methods to study psoriasis. Using psoriasis mouse and human datasets, our differential alternative splicing analyses detected hundreds of differential alternative splicing changes. Our analysis of conservation revealed many exon-skipping events conserved between mice and humans. In addition, our splicing signature comparison analysis using the psoriasis datasets and our curated splicing factor perturbation RNA-Seq database, SFMetaDB, identified nine candidate splicing factors that may be important in regulating splicing in the psoriasis mouse model dataset. Three of the nine splicing factors were confirmed upon analyzing the human data. Our computational methods have generated predictions for the potential role of splicing in psoriasis. Future experiments on the novel candidates predicted by our computational analysis are expected to provide a better understanding of the molecular mechanism of psoriasis and to pave the way for new therapeutic treatments.
Time efficient preparation methods for MRI brain scanning in awake young children and factors associated with success
Authors: Thieba Camilia , Frayne Ashleigh , Walton Matthew , Mah Alyssa , Benischek Alina , Dewey Deborah , Lebel Catherine
Published: February 2018

Objective

Young children are often unable to remain still for magnetic resonance imaging (MRI). Various preparation methods have been reported to avoid sedation or anesthesia, with mixed success rates and feasibility. Here we describe a time-efficient preparation method and factors associated with successful scanning in young chdilren.

We recruited 134 children aged 2.0–5.0 years for an MRI study. Some children completed a training session on a mock scanner, and all children received a 15–20 minute introduction to scanning procedures immediately before their scan. We compared success between children receiving mock scanner training or not, and evaluated demographic or cognitive factors that predicted success.

Results

97 children (72%) completed at least one sequence successfully; 64 children provided high-quality data for all 3 sequences. Cognitive scores were higher in successful children, but children who received mock scanner training were less likely to be successful. A case-controlled comparison of children matched on age, gender, and cognitive scores found no differences between children receiving training or not.

We present a quick method for preparing young children for awake MRI scans. Our data suggests limited advantages of mock scanner preparation for healthy young children, and that cognitive abilities may help predict success.
The H3K9 methyltransferase SETDB1 maintains female identity inDrosophilagerm cells by repressing expression of key spermatogenesis genes
Authors: Smolko Anne E. , Shapiro-Kulnane Laura , Salz Helen K.
Published: February 2018

The preservation of germ cell sexual identity is essential for gametogenesis. Here we show that H3K9me3-mediated gene silencing is integral to female fate maintenance inDrosophilagerm cells. Germ cell-specific loss of the H3K9me3 pathway members, the trimethyltransferase SETDB1, its binding partner WDE, and the H3K9 binding protein HP1a, cause the inappropriate expression of testis genes. SETDB1 is required for H3K9me3 accumulation on a select subset of the silenced testis genes. Interestingly, these SETDB1-dependent H3K9me3 domains are highly localized and do not spread into neighboring loci. Regional deposition is especially striking at thephf7locus, a key regulator of male germ cell sexual fate.phf7is primarily regulated by alternative promoter usage and transcription start site (TSS) selection. We find H3K9me3 accumulation is restricted to the silenced testis-specific TSS region in ovaries. Furthermore, its recruitment tophf7and repression of the testis-specific transcript is dependent on the female sex determination geneSxl. These findings demonstrate that female identity is secured by a pathway in whichSxlis the upstream female-specific regulator, SETDB1 is the required chromatin writer andphf7is one of the critical SETDB1 target genes. This function of SETDB1 is unrelated to its canonical role in piRNA biogenesis and silencing of transposable elements. Collectively our findings support a novel model in which female fate is preserved by deposition of H3K9me3 repressive marks on key spermatogenesis genes and suggest that this strategy for securing cell fate may be widespread.
GITAR: an Open Source Tool for Analysis and Visualization of Hi-C Data
Authors: Calandrelli Riccardo , Wu Qiuyang , Guan Jihong , Zhong Sheng
Published: February 2018

Interactions between chromatin segments play a large role in functional genomic assays and developments in genomic interaction detection methods have shown interacting topological domains within the genome. Among these methods, Hi-C plays a key role. Here, we present GITAR (Genome Interaction Tools and Resources), a software to perform a comprehensive Hi-C data analysis, including data preprocessing, normalization, visualization and topologically associated domains (TADs) analysis. GITAR is composed of two main modules: 1) HiCtool, a Python library to process and visualize Hi-C data, including TADs analysis and 2) Processed data library, a large collection of human and mouse datasets processed using HiCtool. HiCtool leads the user step-by-step through a pipeline which goes from the raw Hi-C data to the computation, visualization and optimized storage of intra-chromosomal contact matrices and topological domain coordinates. A large collection of standardized processed data allows to compare different datasets in a consistent way and it saves time of work to obtain data for visualization or additional analyses. GITAR enables users without any programming or bioinformatic expertise to work with Hi-C data and it is freely available for the public at http://genomegitar.org as an open source software.
Cold shock as a screen for genes involved in cold acclimatization in Neurospora crassa
Authors: Watters Michael K. , Manzanilla Victor , Howell Holly , Mehreteab Alexander , Rose Erik , Walters Nicole , Seitz Nicholas , Nava Jacob , Kekelik Sienna , Knuth Laura , Scivinsky Brianna
Published: February 2018

When subjected to rapid drops of temperature (cold shock), Neurospora responds with a dramatic, but temporary shift in its branching pattern. While the cold shock response has been described morphologically, it has yet to be examined genetically. This project aims to begin the genetic characterization of the cold shock response and the associated acclimatization to cold environments. We report here the results of a screen of mutants from the Neurospora knockout library for alterations in their morphological response to cold shock and thus, their ability to acclimatize to the cold. Three groups of knockouts were selected to be subject to this screen: genes previously suspected to be involved in hyphal development as well as knockouts resulting in morphological changes; transcription factors; and genes homologous to E. coli genes known to alter their expression in response to cold shock. Several strains were identified with altered responses. The genes impacted in these mutants are listed and discussed. A significant percentage (81%) of the knockouts of genes homologous to those previously identified in E. coli showed altered cold shock responses in Neurospora – suggesting that the response in these two organisms is largely shared in common.
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

The 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

The 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-print

We 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

In 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.
Defect-Facilitated Buckling in Supercoiled Double-Helix DNA
Authors: Brahmachari Sumitabha , Dittmore Andrew , Takagi Yasuharu , Neuman Keir C. , Marko John F.
Published: February 2018

We present a statistical-mechanical model for stretched twisted double-helix DNA, where thermal fluctuations are treated explicitly from a Hamiltonian without using any scaling hypotheses. Our model applied to defect-free supercoiled DNA describes coexistence of multiple plectoneme domains in long DNA molecules at physiological salt concentrations (≈ 0.1 M Na+) and stretching forces (≈ 1 pN). We find higher (lower) number of domains at lower (higher) ionic strengths and stretching forces, in accord with experimental observations. We use our model to study the effect of an immobile point defect on the DNA contour that allows a localized kink. The degree of the kink is controlled by the defect size, such that a larger defect further reduces the bending energy of the defect-facilitated kinked end loop. We find that a defect can spatially pin a plectoneme domain via nucleation of a kinked end loop, in accord with experiments and simulations. Our model explains previously-reported magnetic tweezer experiments [1] showing two buckling signatures: buckling and ‘rebuckling’ in supercoiled DNA with a base-unpaired region. Comparing with experiments, we find that under 1 pN force, a kinked end loop nucleated at a base-mismatched site reduces the bending energy by ≈ 0.7 kBT per unpaired base. Our model predicts coexistence of three states at the buckling and rebuckling transitions that warrants new experiments.
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

Describing 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

Brain 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

Myoelectric 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

Log 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

Conditioned 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

Transcription 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

The 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

Over 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

Motivation

Whole-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.

Results

We 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.

Availability

https://github.com/marbl/MashMap.

Contact

adam.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

Tissue-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.
Selection of appropriate metagenome taxonomic classifiers for ancient microbiome research
Authors: Velsko Irina M. , Frantz Laurent A. F. , Herbig Alexander , Larson Greger , Warinner Christina
Published: February 2018

Metagenomics enables the study of complex microbial communities from myriad sources, including the remains of oral and gut microbiota preserved in archaeological dental calculus and paleofeces, respectively. While accurate taxonomic assignment is essential to this process, DNA damage, characteristic to ancient samples (e.g. reduction in fragment size), may reduce the accuracy of read taxonomic assignment. Using a set of in silico-generated metagenomic datasets we investigated how the addition of ancient DNA (aDNA) damage patterns influences microbial taxonomic assignment by five widely-used profilers: QIIME/UCLUST, MetaPhlAn2, MIDAS, CLARK-S, and MALT (BLAST-X-mode). In silico-generated datasets were designed to mimic dental plaque, consisting of 40, 100, and 200 microbial species/strains, both with and without simulated aDNA damage patterns. Following taxonomic assignment, the profiles were evaluated for species presence/absence, relative abundance, alpha-diversity, beta-diversity, and specific taxonomic assignment biases. Unifrac metrics indicated that both MIDAS and MetaPhlAn2 provided the most accurate community structure reconstruction. QIIME/UCLUST, CLARK-S, and MALT had the highest number of inaccurate taxonomic assignments; however, filtering out species present at <0.1% abundance greatly increased the accuracy of CLARK-S and MALT. All programs except CLARK-S failed to detect some species from the input file that were in their databases. Ancient DNA damage resulted in minimal differences in species detection and relative abundance between simulated ancient and modern datasets for most programs. In conclusion, taxonomic profiling biases are program-specific rather than damage-dependent, and the choice of taxonomic classification program to use should be tailored to the research question.

Importance

Ancient biomolecules from oral and gut microbiome samples have been shown to preserve in the archaeological record. Studying ancient microbiome communities using metagenomic techniques offer a unique opportunity to reconstruct the evolutionary trajectories of microbial communities through time. DNA accumulates specific damage over time, which could potentially affect taxonomic classification and our ability to reconstruct community assemblages accurately. It is therefore necessary to assess whether ancient DNA (aDNA) damage patterns affect metagenomic taxonomic profiling. Here, we assessed biases in community structure, diversity, species detection, and relative abundance estimates by five popular metagenomic taxonomic classification programs using in silico-generated datasets with aDNA damage. Age-related damage patterns had minimal impact on the taxonomic profiles produced by each program, and biases were intrinsic to each program. Therefore, an appropriate classification program should be chosen that minimizes the biases related to the questions being addressed.
Automatic Cell Segmentation by Adaptive Thresholding (ACSAT) for large scale calcium imaging datasets
Authors: Shen Simon P. , Tseng Hua-an , Hansen Kyle R. , Wu Ruofan , Gritton Howard , Si Jennie , Han Xue
Published: February 2018

Advances in calcium imaging have made it possible to record from an increasingly larger number of neurons simultaneously. Neuroscientists can now routinely image hundreds to thousands of individual neurons. With the continued neurotechnology development effort, it is expected that millions of neurons could soon be simultaneously measured. An emerging technical challenge that parallels the advancement in imaging such a large number of individual neurons is the processing of correspondingly large datasets, an important step of which is the identification of individual neurons. Traditional methods rely mainly on manual or semi-manual inspection, which cannot be scaled to processing large datasets. To address this challenge, we have developed an automated cell segmentation method, which is referred to as Automated Cell Segmentation by Adaptive Thresholding (ACSAT). ACSAT includes an iterative procedure that automatically calculates global and local threshold values during each iteration based on image pixel intensities. As such, the algorithm is capable of handling morphological variations and dynamic changes in fluorescence intensities in different calcium imaging datasets. In addition, ACSAT computes adaptive threshold values based on a time-collapsed image that is representative of the image sequence, and thus ACSAT provides segmentation results at a fast speed. We tested the algorithm on wide-field calcium imaging datasets in the brain regions of hippocampus and striatum in mice. ACSAT achieved precision and recall rates of approximately 80% when compared to individual neurons that are verified by human inspection. Additionally, ACSAT successfully detected low-intensity neurons that were initially undetected by humans.

Significance

ACSAT automatically segments cells in large scale wide-field calcium imaging datasets. It is based on adaptive thresholding at both global and local levels, implemented in an iterative process to identify individual neurons in a time-collapsed image from an image sequence. It is therefore capable of handling variation in cell morphology and dynamic changes between different calcium imaging datasets at a fast speed. Based on tests performed on two datasets from mouse hippocampus and striatum, ACSAT performed comparable to human referees and was even able to detect low-intensity neurons that were initially undetected by human referees.
The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice
Authors: Tong Da-li , Chen Rui-guo , Lu Yu-lan , Li Wei-ke , Zhang Yue-fang , Lin Jun-kai , He Ling-jie , Dang Ting , Shan Shi-fang , Xu Xiao-Hong , Zhang Yi , Zhang Chen , Du Ya-Song , Zhou Wen-Hao , Wang Xiaoqun , Qiu Zilong
Published: February 2018

Accumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that Cntnap3-null mice exhibited deficits in social interaction, spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing the mechanistic insights for ASD.
Additional Essential Oils with High Activity against Stationary PhaseBorrelia burgdorferi
Authors: Feng Jie , Shi Wanliang , Miklossy Judith , Zhang Ying
Published: February 2018

Lyme disease is the most common vector borne-disease in the US. While the majority of the Lyme disease patients can be cured with 2-4 week antibiotic treatment, about 10-20% of patients continue to suffer from persisting symptoms. While the cause of this condition is unclear, persistent infection was proposed as one possibility. It has recently been shown thatB. burgdorferidevelops dormant persisters in stationary phase cultures that are not killed by the current Lyme antibiotics, and there is interest to identify novel drug candidates that more effectively kill such forms. We previously evaluated 34 essential oils and identified some highly active candidates with excellent activity against biofilm and stationary phaseB. burgdorferi.Here we screened another 35 essential oils and found 10 essential oils (garlic, allspice, cumin, palmarosa, myrrh, hedycheim, amyris, thyme white, litsea cubeba, lemon eucalyptus) and the active component of cinnamon bark cinnamaldehyde (CA) at a low concentration of 0.1% to have high activity against stationary phaseB. burgdorferi.At a very low 0.05% concentration, garlic, allspice, palmarosa and CA still exhibited strong activity against the stationary phaseB. burgdorferi. CA also showed strong activity against replicatingB. burgdorferi, with a MIC of 0.02% (or 0.2 μg/mL). In subculture studies, the top 5 hits garlic, allspice, myrrh, hedycheim, and litsea cubeba completely eradicated allB. burgdorferistationary phase cells at 0.1%, while palmarosa, lemon eucalyptus, amyris, cumin, and thyme white failed to do so as shown by visible spirochetal growth after 21-day subculture. At 0.05% concentration, only garlic essential oil and CA sterilized theB. burgdorferistationary phase culture as shown by no regrowth during subculture, while allspice, myrrh, hedycheim and litsea cubeba all had visible growth during subculture. Future studies are needed to determine if these highly active essential oils could eradicate persistentB. burgdorferiinfection in vivo.
First Efficient Transfection in Choanoflagellates using Cell-Penetrating Peptides
Authors: Li Ruibao , Neundorf Ines , Nitsche Frank
Published: February 2018

Only recently, based on phylogenetic studies choanoflagellates have been confirmed to form the sister group to metazoan. The mechanisms and genes behind the step from single to multicellular organisation and as a consequence the evolution of metazoan multicellularity could not be verified yet, as no reliable and efficient method for transfection of choanoflagellates was available. Here we present cell-penetrating peptides (CPPs) as an alternative to conventional transfection methods. In a series of experiments with the choanoflagellate Diaphanoeca grandis we proof for the first time that the use of CPPs is a reliable and highly efficient method for the transfection of choanoflagellates. We were able to silence the silicon transporter gene (SIT) by siRNA, and hence, to suppress the lorica (characteristic siliceous basket) formation. High gene silencing efficiency was determined and measured by light microscope and RT-qPCR. In addition, only low cytotoxic effects of CPP were detected. Our new method allows the reliable and efficient transfection of choanoflagellates, finally enabling us to verify the function of genes, thought to be involved in cell adhesion or cell signaling by silencing them via siRNA. This is a step stone for the research on the origin of multicellularity in metazoans.
Vasohibin1, a new IRES trans-acting factor for induction of (lymph)angiogenic factors in early hypoxia
Authors: Hantelys Fransky , Godet Anne-Claire , David Florian , Tatin Florence , Renaud-Gabardos Edith , Pujol Françoise , Diallo Leila , Ader Isabelle , Ligat Laetitia , Henras Anthony K. , Sato Yasufumi , Parini Angelo , Lacazette Eric , Garmy-Susini Barbara , Prats Anne-Catherine
Published: February 2018

Hypoxia, a major inducer of angiogenesis, is known to trigger major changes of gene expression at the transcriptional level. Furthermore, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 cardiomyocytes: most genes are not induced at the transcriptome-, but at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) able to activate FGF1 and VEGFD IRESs in hypoxia while it inhibits several IRESs in normoxia. Thus this new ITAF may have opposite effects on IRES activities. These data suggest a generalized process of IRES-dependent translational induction of (lymph)angiogenic growth factors expression in early hypoxia, whose pathophysiological relevance is to trigger formation of new functional vessels in ischemic heart. VASH1 is not always required, indicating that the IRESome composition is variable, thus allowing subgroups of IRESs to be activated under the control of different ITAFs.
Evolutionary pathways for the generation of new self-incompatibility haplotypes in a non-self recognition system
Authors: Bod’bvá Katarína , Priklopil Tadeas , Field David L. , Barton Nicholas H. , Pickup Melinda
Published: February 2018

Self-incompatibility (SI) is a genetically based recognition system that functions to prevent self-fertilization and mating among related plants. An enduring puzzle in SI is how the high diversity observed in nature arises and is maintained. Based on the underlying recognition mechanism, SI can be classified into two main groups: self- and non-self recognition. Most work has focused on diversification within self-recognition systems despite expected differences between the two groups in the evolutionary pathways and outcomes of diversification. Here, we use a deterministic population genetic model and stochastic simulations to investigate how novel S-haplotypes evolve in a gametophytic non-self recognition (SRNase/S Locus F-box (SLF)) SI system. For this model the pathways for diversification involve either the maintenance or breakdown of SI and can vary in the order of mutations of the female (SRNase) and male (SLF) components. We show analytically that diversification can occur with high inbreeding depression and self-pollination, but this varies with evolutionary pathway and level of completeness (which determines the number of potential mating partners in the population), and in general is more likely for lower haplotype number. The conditions for diversification are broader in stochastic simulations of finite population size. However, the number of haplotypes observed under high inbreeding and moderate to high self-pollination is less than that commonly observed in nature. Diversification was observed through pathways that maintain SI as well as through self-compatible intermediates. Yet the lifespan of diversified haplotypes was sensitive to their level of completeness. By examining diversification in a non-self recognition SI system, this model extends our understanding of the evolution and maintenance of haplotype diversity observed in a recognition system common in flowering plants.