bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ca2+-induced mitochondrial ROS regulate the early embryonic cell cycle
Authors: Han Yue , Ishibashi Shoko , Iglesias-Gonzalez Javier , Chen Yaoyao , Love Nick R. , Amaya Enrique 
Published: December 2017

SUMMARYWhile it has long been appreciated that reactive oxygen species (ROS) can act as second messengers in both homeostastic and stress response signaling pathways, potential roles for ROS during early vertebrate development have remained largely unexplored. Here we show that fertilization inXenopusembryos triggers a rapid increase in ROS levels, which oscillates with each cell division. Furthermore, we show that the fertilization induced Ca2+wave is both necessary and sufficient to induce ROS production in activated or fertilized eggs. Using chemical inhibitors, we identified mitochondria as the major source of fertilization induced ROS production. Inhibition of mitochondrial ROS production in early embryos results in cell cycle arrest, in part, via ROS dependent regulation of Cdc25C activity. This study reveals for the first time, a role for oscillating ROS levels in the regulation of the early cell cycle inXenopusembryos.HighlightsROS, including hydrogen peroxide, are produced after fertilization inXenopusCa2+signaling after fertilization induces ROS production in mitochondriaMitochondria are the major source of oscillating ROS levelsROS regulate Cdc25C activity and the early cell cycle
Asymmetrical localization of Nup107-160 subcomplex components within the nuclear pore complex in fission yeast
Authors: Asakawa Haruhiko , Kojidani Tomoko , Yang Hui-Ju , Ohtsuki Chizuru , Osakada Hiroko , Matsuda Atsushi , Iwamoto Masaaki , Chikashige Yuji , Nagao Koji , Obuse Chikashi , Hiraoka Yasushi , Haraguchi Tokuko 
Published: December 2017

AbstractThe nuclear pore complex (NPC) forms a gateway for nucleocytoplasmic transport. The outer ring protein complex of the NPC (the Nup107-160 subcomplex in humans) is a key component for building the NPC. Nup107-160 subcomplexes are believed to be symmetrically localized on the nuclear and cytoplasmic sides of the NPC. However, in S. pombe immunoelectron and fluorescence microscopic analyses revealed that the homologous components of the human Nup107-160 subcomplex had an asymmetrical localization: constituent proteins spNup132 and spNup107 were present only on the nuclear side (designated the spNup132 subcomplex), while spNup131, spNup120, spNup85, spNup96, spNup37, spEly5 and spSeh1 were localized only on the cytoplasmic side (designated the spNup120 subcomplex), suggesting the complex was split into two pieces at the interface between spNup96 and spNup107. This contrasts with the symmetrical localization reported in other organisms. Fusion of spNup96 (cytoplasmic localization) with spNup107 (nuclear localization) caused cytoplasmic relocalization of spNup107. In this strain, half of the spNup132 proteins, which interact with spNup107, changed their localization to the cytoplasmic side of the NPC, leading to defects in mitotic and meiotic progression similar to an spNup132 deletion strain. These observations suggest the asymmetrical localization of the outer ring spNup132 and spNup120 subcomplexes of the NPC is necessary for normal cell cycle progression in fission yeast.Author summaryThe nuclear pore complexes (NPCs) form gateways to transport intracellular molecules between the nucleus and the cytoplasm across the nuclear envelope. The Nup107-160 subcomplex, that forms nuclear and cytoplasmic outer rings, is a key complex responsible for building the NPC by symmetrical localization on the nuclear and cytoplasmic sides of the nuclear pore. This structural characteristic was found in various organisms including humans and budding yeasts, and therefore believed to be common among “all” eukaryotes. However, in this paper, we revealed an asymmetrical localization of the homologous components of the human Nup107-160 subcomplex in fission yeast by immunoelectron and fluorescence microscopic analyses: in this organism, the Nup107-160 subcomplex is split into two pieces, and each of the split pieces is differentially distributed to the nuclear and cytoplasmic side of the NPC: one piece is only in the nuclear side while the other piece is only in the cytoplasmic side. This contrasts with the symmetrical localization reported in other organisms. In addition, we confirmed that the asymmetrical configuration of the outer ring structure is necessary for cell cycle progression in fission yeast. This study provides notions of diverse structures and functions of NPCs evolved in eukaryotes.
Value generalization in human avoidance learning
Authors: Norbury Agnes , Robbins Trevor W. , Seymour Ben 
Published: December 2017

SummaryGeneralization during aversive decision-making allows us to avoid a broad range of potential threats following experience with a limited set of exemplars. However, over-generalization, resulting in excessive and inappropriate avoidance, has been implicated in a variety of psychological disorders. Here, we use reinforcement learning modelling to dissect out different contributions to the generalization of instrumental avoidance in two groups of human volunteers (N=26,N=482). We found that generalization of avoidance could be parsed into perceptual and value-based processes, and further, that value-based generalization could be subdivided into that relating to aversive and neutral feedback - with corresponding circuits including primary sensory cortex, anterior insula, and ventromedial prefrontal cortex, respectively. Further, generalization from aversive, but not neutral, feedback was associated with self-reported anxiety and intrusive thoughts. These results reveal a set of distinct mechanisms that mediate generalization in avoidance learning, and show how specific individual differences within them can yield anxiety.
Neural circuits for long-range color filling-in
Authors: Gerardin Peggy , Abbatecola Clément , Devinck Frédéric , Kennedy Henry , Dojat Michel , Knoblauch Kenneth 
Published: December 2017

AbstractSurface color appearance depends on both local surface chromaticity and global context. How are these inter-dependencies supported by cortical networks? Combining functional imaging and psychophysics, we examined if color from long-range filling-in engages distinct pathways from responses caused by a field of uniform chromaticity. We find that color from filling-in is best classified and best correlated with appearance by two dorsal areas, V3A and V3B/KO. In contrast, a field of uniform chromaticity is best classified by ventral areas hV4 and LO. Dynamic causal modeling revealed feedback modulation from area V3A to areas V1 and LO for filling-in, contrasting with feedback from LO modulating areas V1 and V3A for a matched uniform chromaticity. These results indicate a dorsal stream role in color filling-in via feedback modulation of area V1 coupled with a cross-stream modulation of ventral areas suggesting that local and contextual influences on color appearance engage distinct neural networks.
On the motion of spikes: a model of multifractality as observed in the neuronal activity of the human basal ganglia
Authors: Andres Daniela Sabrina 
Published: December 2017

AbstractNeuronal signals are usually characterized in terms of their discharge rate. However, this description is inadequate to account for the complex temporal organization of spike trains. In particular multifractality is a hallmark of the neuronal activity of the human, parkinsonian basal ganglia, which is not accounted for in most models. Here I develop a new conceptualization of neuronal activity, enabling the analysis of spike trains in terms of a velocity field. Firstly, I show that structure functions of increasing order can be used to recover the multifractal spectrum of spike trains obtained from the globus pallidus interna (GPi) of patients with Parkinson’s disease. Further, I propose a neural field model to study the observed multifractality. The model describes the motion of spikes in terms of a velocity field, including a diffusive term to consider the physical properties of the electric field that is associated to neuronal activity. As the model is perturbed with colored noise, the following is observed: 1. multifractality is present for a wide range of diffusion coefficients; and 2. multifractal temporal properties are mirrored into space. These results predict that passive electric properties of neuronal activity are far more relevant to the human brain than what has been usually considered.
Circulating selenium and prostate cancer risk: a Mendelian randomization analysis
Authors: Yarmolinsky James , Bonilla Carolina , Haycock Philip C , Langdon Ryan JQ , Lotta Luca A , Langenberg Claudia , Relton Caroline L , Lewis Sarah J , Evans David M ,   the PRACTICAL consortium, Smith George Davey , Martin Richard M 
Published: December 2017

AbstractIn the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 μg/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian randomization analysis uses genetic variants to proxy modifiable risk factors and can strengthen causal inference in observational studies. We constructed a genetic risk score comprising eleven single-nucleotide polymorphisms robustly (P<5x10−8) associated with circulating selenium in genome-wide association studies. In a Mendelian randomization analysis of 72,729 men in the PRACTICAL Consortium (44,825 cases, 27,904 controls), 114 μg/L higher genetically-elevated circulating selenium was not associated with prostate cancer (OR: 1.01; 95% CI: 0.89-1.13). Concordant with findings from SELECT, selenium was weakly associated with advanced (including high-grade) prostate cancer (OR: 1.21; 95% CI: 0.98-1.49) and type 2 diabetes (OR: 1.18; 95% CI: 0.97-1.43; in a type 2 diabetes GWAS meta-analysis with up to 49,266 cases, 249,906 controls). Mendelian randomization mirrored the outcome of selenium supplementation in SELECT and may offer an approach for the prioritization of interventions for follow-up in large-scale randomized controlled trials.
Transcriptome-wide association studies accounting for colocalization using Egger regression
Authors: Barfield Richard , Feng Helian , Gusev Alexander , Wu Lang , Zheng Wei , Pasaniuc Bogdan , Kraft Peter 
Published: December 2017

AbstractIntegrating genome-wide association (GWAS) and expression quantitative trait locus (eQTL) data into transcriptome-wide association studies (TWAS) based on predicted expression can boost power to detect novel disease loci or pinpoint the susceptibility gene at a known disease locus. However, it is often the case that multiple eQTL genes colocalize at disease loci, making the identification of the true susceptibility gene challenging, due to confounding through linkage disequilibrium (LD). To distinguish between true susceptibility genes (where the genetic effect on phenotype is mediated through expression) and colocalization due to LD, we examine an extension of the Mendelian Randomization Egger regression method that allows for LD while only requiring summary association data for both GWAS and eQTL. We derive the standard TWAS approach in the context of Mendelian Randomization and show in simulations that the standard TWAS does not control Type I error for causal gene identification when eQTLs have pleiotropic or LD-confounded effects on disease. In contrast, LD Aware MR-Egger regression can control Type I error in this case while attaining similar power as other methods in situations where these provide valid tests. However, when the direct effects of genetic variants on traits are correlated with the eQTL associations, all of the methods we examined including LD Aware MR-Egger regression can have inflated Type I error. We illustrate these methods by integrating gene expression within a recent large-scale breast cancer GWAS to provide guidance on susceptibility gene identification.
RetSynth: Solving all optimal retrosynthesis solutions using dynamically constrained integer linear programming
Authors: Whitmore Leanne S. , Pinar Ali , George Anthe , Hudson Corey M. 
Published: December 2017

AbstractMotivationNaive determination of all the optimal pathways to production of a target chemical on an arbitrarily defined chassis organism is computationally intractable. Methods like linear integer programming can provide a singular solution to this problem, but fail to provide all optimal pathways.ResultsHere we present RetSynth, an algorithm for determining all optimal biological retrosynthesis solutions, given a starting biological chassis and target chemical. By dynamically scaling constraints, additional pathway search scales relative to the number of fully independent branches in the optimal pathways, and not relative to the number of reactions in the database or size of the metabolic network. This feature allows all optimal pathways to be determined for a very large number of chemicals and for a large corpus of potential chassis organisms.AvailabilityThis algorithm is distributed as part of the RetSynth software package, under a BSD 2-clause license at https://www.github.com/sandialabs/RetSynth/
Acute myeloid/T-lymphoblastic leukemia (AMTL): A distinct category of acute leukemias with common pathogenesis in need of improved therapy
Authors: Gutierrez Alejandro , Kentsis Alex 
Published: December 2017

AbstractAdvances in the immunophenotypic and cytogenetic classification of acute leukemias have led to improved clinical outcomes for a substantial fraction of patients. However, resistance to chemotherapy remains a major barrier to cure for patients with specific subsets of acute myeloid and lymphoblastic leukemias. Here, we propose that a molecularly distinct subtype of acute leukemia with shared myeloid and T-cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukemia (AMTL), and has been divided between 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-cell lymphoid lineages. This new diagnostic group is supported by the i) shared hematopoietic ontogeny in which myeloid differentiation potential is specifically retained during early T-cell lymphoid development, ii) recognition of cases of AML with hallmarks of T-cell development such as clonal rearrangements of the T-cell receptor genes, and iii) identification of common gene mutations in subsets of AML and T-ALL cases. This proposed diagnostic entity overlaps with early T-cell precursor (ETP) T-ALL and T-cell/myeloid mixed phenotype acute leukemias (MPAL), and also includes a subset of leukemias currently classified as AML with hallmarks of T-lymphoblastic development. AMTLs express variable levels of both T-cell and myeloid-specific markers, such as CD3 and myeloperoxidase, and additionally have shared gene mutations including WT1, PHF6, RUNX1 and BCL11B. The proposed classification of AMTL as a distinct entity should enable prospective diagnosis and development of improved therapies for patients whose treatment is inadequate with current approaches.
Computational Design of Asymmetric Three-dimensional RNA Structures and Machines
Authors: Yesselman Joseph D. , Eiler Daniel , Carlson Erik D. , Ooms Alexandra N. , Kladwang Wipapat , Shi Xuesong , Costantino David A. , Herschlag Daniel , Jewett Michael C. , Kieft Jeffrey S. , Das Rhiju 
Published: December 2017

AbstractThe emerging field of RNA nanotechnology seeks to create nanoscale 3D machines by repurposing natural RNA modules, but successes have been limited to symmetric assemblies of single repeating motifs. We present RNAMake, a suite that automates design of RNA molecules with complex 3D folds. We first challenged RNAMake with the paradigmatic problem of aligning a tetraloop and sequence-distal receptor, previously only solved via symmetry. Single-nucleotide-resolution chemical mapping, native gel electrophoresis, and solution x-ray scattering confirmed that 11 of the 16 ‘miniTTR’ designs successfully achieved clothespin-like folds. A 2.55 Å diffraction-resolution crystal structure of one design verified formation of the target asymmetric nanostructure, with large sections achieving near-atomic accuracy (< 2.0 Å). Finally, RNAMake designed asymmetric segments to tether the 16S and 23S rRNAs together into a synthetic singlestranded ribosome that remains uncleaved by ribonucleases and supports life in Escherichia coli, a challenge previously requiring several rounds of trial-and-error.
Migration alters oscillatory dynamics and promotes survival in connected bacterial populations
Authors: Gokhale Shreyas , Conwill Arolyn , Ranjan Tanvi , Gore Jeff 
Published: December 2017

AbstractMigration influences population dynamics on networks, thereby playing a vital role in scenarios ranging from species extinction to epidemic propagation. While low migration rates prevent local populations from becoming extinct, high migration rates enhance the risk of global extinction by synchronizing the dynamics of connected populations. Here, we investigate this trade-off using two mutualistic strains of E. coli that exhibit population oscillations when co-cultured. In experiments, as well as in simulations using a mechanistic model, we observe that high migration rates lead to in-phase synchronization whereas intermediate migration rates perturb the oscillations and change their period. Further, our simulations predict, and experiments show, that connected populations subjected to more challenging antibiotic concentrations have the highest probability of survival at intermediate migration rates. Finally, we identify altered population dynamics, rather than recolonization, as the primary cause of extended survival.
Evidence against tetrapod-wide digit identities and for a limited frame shift in bird wings
Authors: Stewart Thomas A. , Liang Cong , Cotney Justin L. , Noonan James P. , Sanger Thomas J. , Wagner Günter P. 
Published: December 2017

SummaryIn crown group tetrapods, individual digits are homologized in relation to a pentadactyl ground plan. However, testing hypotheses of digit homology is challenging because it is unclear whether digits develop with distinct and conserved gene regulatory states. Here we show dramatic evolutionary dynamism in the gene expression profiles of digits, challenging the notion that five digit identities are conserved across amniotes. Transcriptomics of developing limbs shows diversity in the patterns of genetic differentiation of digits, although the anterior-most digit of the pentadactyl limb has a unique, conserved expression profile. Further, we identify a core set of transcription factors that are differentially expressed among the digits of amniote limbs; their spatial expression domains, however, vary between species. In light of these results, we reevaluate the frame shift hypothesis of avian wing evolution and conclude that only the identity of the anterior-most digit has shifted position, suggesting a 1,3,4 digit identity in the bird wing.
Aging in a relativistic biological space-time
Authors: Maestrini D. , Abler D. , Adhikarla V. , Armenian S. , Branciamore S. , Carlesso N. , Kuo Y-H. , Marcucci G. , Sahoo P. , Rockne R. 
Published: December 2017

AbstractHere we present a theoretical and mathematical perspective on the process of aging. We extend the concepts of physical space and time to an abstract, mathematically-defined space, which we associate with a concept of “biological space-time” in which biological clocks operate. We hypothesize that biological dynamics, represented as trajectories in biological space-time, may be used to model and study different rates of biological aging. As a consequence of this hypothesis, we show how the dilation or contraction of time resulting from accelerated or decelerated biological dynamics may be used to study precipitous or protracted aging. We show specific examples of how these principles may be used to model different rates of aging, with an emphasis on cancer in aging. We discuss the implications of this theory, including novel concepts that may improve our interpretation of biological aging.
Characterizing the effects of sex, APOE ɛ4, and literacy on mid-life cognitive trajectories: Application of Information-Theoretic model-averaging and multi-model inference techniques to the Wisconsin Registry for Alzheimer’s Prevention Study
Authors: Koscik Rebecca L. , Norton Derek L. , Allison Samantha L. , Jonaitis Erin M. , Clark Lindsay R. , Mueller Kimberly D. , Hermann Bruce P. , Engelman Corinne D. , Gleason Carey E. , Sager Mark A. , Chappell Richard J. , Johnson Sterling C. 
Published: December 2017

ObjectiveIn this paper we apply Information-Theoretic (IT) model averaging to characterize a set of complex interactions in a longitudinal study on cognitive decline. Prior research has identified numerous genetic (including sex), education, health and lifestyle factors that predict cognitive decline. Traditional model selection approaches (e.g., backward or stepwise selection) attempt to find models that best fit the observed data; these techniques risk interpretations that only the selected predictors are important. In reality, several models may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates); inference from traditional model selection approaches can lead to overly confident conclusions.MethodHere we use longitudinal cognitive data from ~1550 late-middle aged adults the Wisconsin Registry for Alzheimer’s Prevention study to examine the effects of sex, Apolipoprotein E (APOE) ɛ4 allele (non-modifiable factors), and literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a model set with combinations of interactions among sex, APOE, literacy, and age.ResultsFor a list-learning test, model-averaged results showed better performance for women vs men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less of an effect on cognitive performance in this age range (~40-70).ConclusionsThese results illustrate the utility of the IT approach and point to literacy as a potential modifier of decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work.
Distinct descending motor cortex pathways and their roles in movement
Authors: Economo Michael N. , Viswanathan Sarada , Tasic Bosiljka , Bas Erhan , Winnubst Johan , Menon Vilas , Graybuck Lucas T. , Nguyen Thuc Nghi , Wang Lihua , Gerfen Charles R. , Chandrashekar Jayaram , Zeng Hongkui , Looger Loren L. , Svoboda Karel 
Published: December 2017

ABSTRACTActivity in motor cortex predicts specific movements, seconds before they are initiated. This preparatory activity has been observed in L5 descending ‘pyramidal tract’ (PT) neurons. A key question is how preparatory activity can be maintained without causing movement, and how preparatory activity is eventually converted to a motor command to trigger appropriate movements. We used single cell transcriptional profiling and axonal reconstructions to identify two types of PT neuron. Both types share projections to multiple targets in the basal ganglia and brainstem. One type projects to thalamic regions that connect back to motor cortex. In a delayed-response task, these neurons produced early preparatory activity that persisted until the movement. The second type projects to motor centers in the medulla and produced late preparatory activity and motor commands. These results indicate that two motor cortex output neurons are specialized for distinct roles in motor control.