bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validating Paired-end Read Alignments in Sequence Graphs
Authors: Jain Chirag , Zhang Haowen , Dilthey Alexander , Aluru Srinivas 
Published: June 2019

AbstractGraph based non-linear reference structures such as variation graphs and colored de Bruijn graphs enable incorporation of full genomic diversity within a population. However, transitioning from a simple string-based reference to graphs requires addressing many computational challenges, one of which concerns accurately mapping sequencing read sets to graphs. Paired-end Illumina sequencing is a commonly used sequencing platform in genomics, where the paired-end distance constraints allow disambiguation of repeats. Many recent works have explored provably good index-based and alignment-based strategies for mapping individual reads to graphs. However, validating distance constraints efficiently over graphs is not trivial, and existing sequence to graph mappers rely on heuristics. We introduce a mathematical formulation of the problem, and provide a new algorithm to solve it exactly. We take advantage of the high sparsity of reference graphs, and use sparse matrix-matrix multiplications (SpGEMM) to build an index which can be queried efficiently by a mapping algorithm for validating the distance constraints. Effectiveness of the algorithm is demonstrated using real reference graphs, including a human MHC variation graph, and a pan-genome de-Bruijn graph built using genomes of 20 B. anthracis strains. While the one-time indexing time can vary from a few minutes to a few hours using our algorithm, answering a million distance queries takes less than a second.2012 ACM Subject ClassificationMathematics of computing → Paths and connectivity problems; Applied computing → Computational genomics
High conservation priority of range-edge plant populations not matched by habitat protection or research effort
Authors: Caissy P. , Klemet-N’Guessan S. , Jackiw R. , Eckert C.G. , Hargreaves A. L. 
Published: June 2019

ABSTRACTHigh-latitude countries tend to contain the polar range-edge of many species that are nationally rare but globally common. This can focus national conservation efforts toward range-edge populations, whose conservation needs and value are disputed. Using plants in Canada as a case study, we ask whether national species-conservation rankings prioritize range-edge populations, and whether conservation priority is matched by habitat protection and research effort. We found that >75% of federally-protected plants only occur in Canada peripherally, at the northernmost 20% or less of their total range, and that the most imperilled taxa had the smallest percentage of their range in Canada (endangered plants: median=1.0%). Occurring peripherally in Canada was associated with higher threat even after accounting for range area, potentially because range-edge taxa experienced 85% higher human population densities in their Canadian range than non-peripheral taxa. High conservation priority was not matched by habitat protection, as more imperilled and more peripheral taxa had smaller fractions of their Canadian range in protected areas. Finally, peer-reviewed research on plants at-risk in Canada was low. Only 42% of plants considered at-risk in Canada had been studied in Canada, and only 11% of species with large distributions outside Canada had been studied in the context of their wider geographic range—information that is critical to establishing their relative conservation value. Our results illustrate that plant conservation in Canada is fundamentally linked to conserving range-edge populations, yet edge populations themselves are understudied, a research gap we must close to improve evidence-based conservation.
A hydrogen dependent geochemical analogue of primordial carbon and energy metabolism
Authors: Preiner Martina , Igarashi Kensuke , Muchowska Kamila B. , Yu Mingquan , Varma Sreejith J. , Kleinermanns Karl , Nobu Masaru K. , Kamagata Yoichi , Tüysüz Harun , Moran Joseph , Martin William F. 
Published: June 2019

AbstractHydrogen gas, H2, is generated in alkaline hydrothermal vents from reactions of iron containing minerals with water during a geological process called serpentinization. It has been a source of electrons and energy since there was liquid water on the early Earth, and it fuelled early anaerobic ecosystems in the Earth’s crust1–3. H2is the electron donor for the most ancient route of biological CO2fixation, the acetyl-CoA (or Wood-Ljungdahl) pathway, which unlike any other autotrophic pathway simultaneously supplies three key requirements for life: reduced carbon in the form of acetyl groups, electrons in the form of reduced ferredoxin, and ion gradients for energy conservation in the form of ATP4,5. The pathway is linear, not cyclic, it releases energy rather than requiring energy input, its enzymes are replete with primordial metal cofactors6,7, it traces to the last universal common ancestor8and abiotic, geochemical organic syntheses resembling segments of the pathway occur in hydrothermal vents today9,10. Laboratory simulations of the acetyl-CoA pathway’s reactions include the nonenzymatic synthesis of thioesters from CO and methylsulfide11, the synthesis of acetate12and pyruvate13from CO2using native iron or external electrochemical potentials14as the electron source. However, a full abiotic analogue of the acetyl-CoA pathway from H2and CO2as it occurs in life has not been reported to date. Here we show that three hydrothermal minerals — awaruite (Ni3Fe), magnetite (Fe3O4) and greigite (Fe3S4) — catalyse the fixation of CO2with H2at 100 °C under alkaline aqueous conditions. The product spectrum includes formate (100 mM), acetate (100 μM), pyruvate (10 μM), methanol (100 μM), and methane. With these simple catalysts, the overall exergonic reaction of the acetyl-CoA pathway is facile, shedding light on both the geochemical origin of microbial metabolism and on the nature of abiotic formate and methane synthesis in modern hydrothermal vents.
Calcium buffers and L-type calcium channels as modulators of cardiac subcellular alternans
Authors: Lai Yi Ming , Coombes Stephen , Thul Rüdiger 
Published: June 2019

AbstractIn cardiac myocytes, calcium cycling links the dynamics of the membrane potential to the activation of the contractile filaments. Perturbations of the calcium signalling toolkit have been demonstrated to disrupt this connection and lead to numerous pathologies including cardiac alternans. This rhythm disturbance is characterised by alternations in the membrane potential and the intracellular calcium concentration, which in turn can lead to sudden cardiac death. In the present computational study, we make further inroads into understanding this severe condition by investigating the impact of calcium buffers and L-type calcium channels on the formation of subcellular calcium alternans when calcium diffusion in the sarcoplasmic reticulum is strong. Through numerical simulations of a two dimensional network of calcium release units, we show that increasing calcium entry is proarrhythmogenic and that this is modulated by the calcium-dependent inactivation of the L-type calcium channel. We also find that while calcium buffers can exert a stabilising force and abolish subcellular Ca2+alternans, they can significantly shape the spatial patterning of subcellular calcium alternans. Taken together, our results demonstrate that subcellular calcium alternans can emerge via various routes and that calcium diffusion in the sarcoplasmic reticulum critically determines their spatial patterns.
Cerebral dopamine neurotrophic factor (CDNF) reduces myocardial ischemia/reperfusion injuries by the activation of PI3K-AKT via KDEL-receptor binding
Authors: Maciel Leonardo , de Oliveira Dahienne Ferreira , Mesquita Fernanda , da Silva Souza Hercules Antônio , Oliveira Leandro , Palhano Fernando L. , de Carvalho Antônio Carlos Campos , Matheus Nascimento José Hamilton , Foguel Debora 
Published: June 2019

AbstractCDNF (Cerebral Dopamine Neurotrophic Factor) belongs to a new family of NF, which presents several beneficial activities beyond the brain. Little is known about CDNF in the cardiac context. Herein we investigate CDNF effects in cardiomyocytes under endoplasmic reticulum (ER)-stress and in whole rat hearts subjected to ischemia/reperfusion (I/R). We showed that CDNF is secreted by cardiomyocytes stressed by thapsigargin and by isolated hearts subjected to I/R. CDNF protects human and mouse cardiomyocytes against ER-stress by restoring the calcium transient, and isolated heart against I/R injuries by reducing the infarct area and avoiding mitochondrial impairment. This protection is abrogated by wortmannin (PI3K-inhibitor) or by heptapeptides containing KDEL sequence, which block KDEL-receptor. These data suggest that CDNF induces cardioprotection via KDEL receptor binding and PI3K/AKT activation. This is the first study to propose CDNF as a cardiomyokine and to unravel the receptor and signaling pathway for this interesting family of NF.
Sequential Operations Revealed by Serendipitous Feature Selectivity in Frontal Eye Field
Authors: Lowe Kaleb A. , Schall Jeffrey D. 
Published: June 2019

ABSTRACTNeurons in macaque frontal eye field contribute to spatial but typically not feature selection during visual search. Using an innovative visual search task, we report a serendipitous discovery that some frontal eye field neurons can develop rapid selectivity for stimulus orientation that is used to guide gaze during a visual search task with pro-saccade and anti-saccade responses. This feature selectivity occurs simultaneously at multiple locations for all objects sharing that feature and coincides with when neurons select the singleton of a search array. This feature selectivity also reveals the distinct, subsequent operation of selecting the endpoint of the saccade in pro-saccade as well as anti-saccade trials. These results demonstrate that target selection preceding saccade preparation is composed of multiple operations. We conjecture that singleton selection indexes the allocation of attention, which can be divided, to conspicuous items. Consequently, endpoint selection indexes the focused allocation of attention to the endpoint of the saccade. These results demonstrate that saccade target selection is not a unitary process.SIGNIFICANCE STATEMENTFrontal eye field is well known to contribute to spatial selection for attention and eye movements. We discovered that some frontal eye field neurons can acquire selectivity for stimulus orientation when it guides visual search. The chronometry of neurons with and without feature selectivity reveal distinct operations accomplishing visual search.
Quantifying within-host diversity of H5N1 influenza viruses in humans and poultry in Cambodia
Authors: Moncla Louise H. , Bedford Trevor , Dussart Philippe , Horm Srey Viseth , Rith Sareth , Buchy Philippe , Karlsson Erik A , Li Lifeng , Liu Yongmei , Zhu Huachen , Guan Yi , Friedrich Thomas C. , Horwood Paul F. 
Published: June 2019

AbstractAvian influenza viruses (AIVs) periodically cross species barriers and infect humans. The likelihood that an AIV will evolve mammalian transmissibility depends on acquiring and selecting mutations during spillover, but data from natural infection is limited. We analyze deep sequencing data from infected humans and domestic ducks in Cambodia to examine how H5N1 viruses evolve during spillover. Overall, viral populations in both species are predominated by low-frequency (<10%) variation shaped by purifying selection and genetic drift, and half of the variants detected within-host are never detected on the H5N1 virus phylogeny. However, we do detect a subset of mutations linked to human receptor binding and replication (PB2 E627K, HA A150V, and HA Q238L) that arose in multiple, independent humans. PB2 E627K and HA A150V were also enriched along phylogenetic branches leading to human infections, suggesting that they are likely human-adaptive. Our data show that H5N1 viruses generate putative human-adapting mutations during natural spillover infection, many of which are detected at >5% frequency within-host. However, short infection times, genetic drift, and purifying selection likely restrict their ability to evolve extensively during a single infection. Applying evolutionary methods to sequence data, we reveal a detailed view of H5N1 virus adaptive potential, and develop a foundation for studying host-adaptation in other zoonotic viruses.Author summaryH5N1 avian influenza viruses can cross species barriers and cause severe disease in humans. H5N1 viruses currently cannot replicate and transmit efficiently among humans, but animal infection studies and modeling experiments have suggested that human adaptation may require only a few mutations. However, data from natural spillover infection has been limited, posing a challenge for risk assessment. Here, we analyze a unique dataset of deep sequence data from H5N1 virus-infected humans and domestic ducks in Cambodia. We find that well-known markers of human receptor binding and replication arise in multiple, independent humans. We also find that 3 mutations detected within-host are enriched along phylogenetic branches leading to human infections, suggesting that they are likely human-adapting. However, we also show that within-host evolution in both humans and ducks are shaped heavily by purifying selection and genetic drift, and that a large fraction of within-host variation is never detected on the H5N1 phylogeny. Taken together, our data show that H5N1 viruses do generate human-adapting mutations during natural infection. However, short infection times, purifying selection, and genetic drift may severely limit how much H5N1 viruses can evolve during the course of a single infection.
An individual interneuron participates in many kinds of inhibition and innervates much of the mouse visual thalamus
Authors: Morgan Josh L. , Lichtman Jeff W. 
Published: June 2019

SUMMARYOne way to assess a neuron’s function is to describe all its inputs and outputs. With this goal in mind, we used serial section electron microscopy to map 899 synaptic inputs and 623 outputs in one inhibitory interneuron in a large volume of the mouse visual thalamus. This neuron innervated 256 thalamocortical cells spread across functionally distinct subregions of the visual thalamus. All but one of its neurites were bifunctional, innervating thalamocortical and local interneurons while also receiving synapses from the retina. We observed a wide variety of local synaptic motifs. While this neuron innervated many cells weakly, with single en passant synapses, it also deployed specialized branches that climbed along other dendrites to form strong multi-synaptic connections with a subset of partners. This neuron’s diverse range of synaptic relationships allows it to participate in a mix of global and local processing but defies assigning it a single circuit function.
Corticotrophin-Releasing Hormone neurons of Barrington’s nucleus: Probabilistic, spinally-gated control of bladder pressure and micturition
Authors: Ito H. , Sales A.C. , Fry C.H. , Kanai A.J. , Drake M.J. , Pickering A.E. 
Published: June 2019

AbstractMicturition, the co-ordinated process of expulsion of urine from the bladder, requires precise control of bladder and urethral sphincter via parasympathetic, sympathetic and somatic motoneurons. In adult mammals this involves a spinobulbospinal control circuit incorporating Barrington’s nucleus in the pons (Barr). The largest Barr cell population is comprised of pontospinal glutamatergic neurons that express corticotrophin-releasing hormone. There is evidence that BarrCRH neurons can generate bladder contractions but it is unknown whether they act as a simple switch or a high-fidelity pre-parasympathetic motor drive and whether their activation can actually trigger voids. Combined opto- and chemo-genetic manipulations along with recordings in mice shows that BarrCRH neurons provide a probabilistic drive that generates co-ordinated voids or non-voiding contractions depending on the phase of the micturition cycle. These findings inform a new inferential model of micturition and emphasise the importance of the state of the spinal gating circuit in the generation of voiding.
A Consensus Framework Unifies Multi-Drug Synergy Metrics
Authors: Wooten David J. , Meyer Christian T. , Quaranta Vito , Lopez Carlos 
Published: June 2019

AbstractDrug combination discovery depends on reliable synergy metrics; however, no consensus exists on the appropriate synergy model to prioritize lead candidates. The fragmented state of the field confounds analysis, reproducibility, and clinical translation of combinations. Here we present a mass-action based formalism to accurately measure the synergy of drug combinations. In this work, we clarify the relationship between the dominant drug synergy principles and show how biases emerge due to intrinsic assumptions which hinder their broad applicability. We further present a mapping of commonly used frameworks onto a unified synergy landscape, which identifies fundamental issues impacting the interpretation of synergy in discovery efforts. Specifically, we infer how traditional metrics mask consequential synergistic interactions, and contain biases dependent on the Hill-slope and maximal effect of single-drugs. We show how these biases systematically impact the classification of synergy in large combination screens misleading discovery efforts. The proposed approach has potential to accelerate the translatability and reproducibility of drug-synergy studies, by bridging the gap between the curative potential of drug mixtures and the complexity in their study.
Insights into LIS1 function in cargo-adapter-mediated dynein activation in vivo
Authors: Qiu Rongde , Zhang Jun , Xiang Xin 
Published: June 2019

AbstractDeficiency of the LIS1 protein causes lissencephaly, a brain developmental disorder. Although LIS1 binds the microtubule motor cytoplasmic dynein and has been linked to dynein function in many experimental systems, its mechanism of action remains unclear. Here we revealed the function of LIS1 in cargo-adapter-mediated dynein activation in the model organism Aspergillus nidulans. Specifically, we found that overexpressed cargo adapter HookA (Hook in A. nidulans) missing its cargo-binding domain (ΔC-HookA) causes dynein and its regulator dynactin to relocate from the microtubule plus ends to the minus ends, and this dramatic relocation requires LIS1 and its binding protein NudE. Astonishingly, the requirement for LIS1 or NudE can be bypassed to a significant extent by specific mutations that open the auto-inhibited “phi-dynein” in which the motor domains of the dynein dimer are held close together. Our results suggest a novel mechanism of LIS1 action: it promotes the switch of dynein from the auto-inhibited state to an open state to facilitate dynein activation.SummaryThis study reveals the role of Lissencephaly 1 (LIS1) in cargo-adapter-mediated dynein activation. Furthermore, it discovers a novel mechanism of LIS1 action involving a switch of dynein from an auto-inhibited state to an active state.
Exploring the Relationship between Geomagnetic Activity and Human Heart Rate Variability
Authors: Mattoni Matthew , Ahn Sangtae , Fröhlich Carla , Fröhlich Flavio 
Published: June 2019

AbstractBoth geomagnetic and solar activity fluctuate over time and have been proposed to affect human physiology. One physiological measurement that has been previously investigated in this context, heart rate variability (HRV), has substantial health implications regarding the ability to adapt to stressors and has been shown to be altered in many cardiovascular and neurological disorders. Intriguingly, previous work found significant, strong correlations between HRV and geomagnetic/solar activity. In an attempt to replicate these findings, we simultaneously measured HRV from 20 healthy participants during a thirty-day period. In agreement with previous work, we found several significant correlations between HRV and geophysical time-series. However, after correction for autocorrelation, which is inherent in time-series, the only significant results were an increase in very low frequency during higher local geomagnetic activity and a geomagnetic anticipatory decrease in heart rate a day before higher global geomagnetic activity. Both correlations were very low. The loss of most significant effects after this correction suggests that previous findings may be a result of autocorrelation. A further note of caution is required since our and the previous studies in the field do not correct for multiple comparisons given the exploratory analysis strategy. We thus conclude that the effects of geomagnetic and solar activity are (if present) most likely of very small effect size and question the validity of the previous studies given the methodological concerns we have uncovered in our work.
Tensor decomposition-Based Unsupervised Feature Extraction Applied to Single-Cell Gene Expression Analysis
Authors: Taguchi Y-h. , Turki Turki 
Published: June 2019

ABSTRACTAlthough single cell RNA sequencing (scRNA-seq) technology is newly invented and promising one, because of lack of enough information that labels individual cells, it is hard to interpret the obtained gene expression of each cell. Because of this insufficient information available, unsupervised clustering, e.g., t-Distributed Stochastic Neighbor Embedding and Uniform Manifold Approximation and Projection, is usually employed to obtain low dimensional embedding that can help to understand cell-cell relationship. One possible drawback of this strategy is that the outcome is highly dependent upon genes selected for the usage of clustering. In order to fulfill this requirement, there are many methods that performed unsupervised gene selection. In this study, a tensor decomposition (TD) based unsupervised feature extraction (FE) was applied to the integration of two scRNA-seq expression profiles that measure human and mouse midbrain development. TD based unsupervised FE could not only select coincident genes between human and mouse, but also biologically reliable genes. Coincidence between two species as well as biological reliability of selected genes is increased compared with principal component analysis (PCA) based FE applied to the same data set in the previous study. Since PCA based unsupervised FE outperformed other three popular unsupervised gene selection methods, highly variable genes, bimodal genes and dpFeature, TD based unsupervised FE can do so as well. In addition to this, ten transcription factors (TFs) that might regulate selected genes and might contribute to midbrain development are identified. These ten TFs, BHLHE40, EGR1, GABPA, IRF3, PPARG, REST, RFX5, STAT3, TCF7L2, and ZBTB33, were previously reported to be related to brain functions and diseases. TD based unsupervised FE is a promising method to integrate two scRNA-seq profiles effectively.