bluuebunny/crossref_metadata_2025_split huggingface dataset:
The trauma center is too late: Major limb trauma without a pre-hospital tourniquet has increased death from hemorrhagic shock
Authors: Scerbo Michelle H. , Holcomb John B. , Taub Ethan , Gates Keith , Love Joseph D. , Wade Charles E. , Cotton Bryan A. 
Published: August 2017

BACKGROUND
To date, no civilian studies have demonstrated that pre-hospital (PH) tourniquets improve survival. We hypothesized that late, trauma center (TC) tourniquet use would increase death from hemorrhagic shock compared to early (PH) placement.

METHODS
All patients arriving to a Level 1, urban TC between October 2008 and January 2016 with a tourniquet placed before (T-PH) or after arrival to the TC (T-TC) were evaluated. Cases were assigned the following designations: indicated (absolute indication [vascular injury requiring repair/ligation, operation within 2 hours for extremity injury, or traumatic amputation] or relative indication [major musculoskeletal/soft tissue injury requiring operation 2–8 hours after arrival, documented large blood loss]) or non-indicated. Outcomes were death from hemorrhagic shock, physiology upon arrival to the TC, and massive transfusion requirements. After univariate analysis, logistic regression was carried out to assess independent predictors of death from hemorrhagic shock.

RESULTS
A total of 306 patients received 326 tourniquets for injuries to 157 upper and 147 lower extremities. Two hundred eighty-one (92%) had an indication for placement. Seventy percent of patients had a blunt mechanism of injury. T-TC patients arrived with a lower systolic blood pressure (SBP, 101 [86, 123] vs. 125 [100, 145] mm Hg, p < 0.001), received more transfusions in the first hour of arrival (55% vs. 34%, p = 0.02), and had a greater mortality from hemorrhagic shock (14% vs. 3.0%, p = 0.01). When controlling for year of admission, mechanism of injury and shock upon arrival (SBP ≤90 mm Hg or HR ≥120 bpm or base deficit ≤ 4) indicated T-TC had a 4.5-fold increased odds of death compared to T-PH (OR 4.5, 95% CI 1.23–16.4, p = 0.02).

CONCLUSIONS
Waiting until TC arrival to control hemorrhage with a tourniquet was associated with worsened blood pressure and increased transfusion within the first hour of arrival. In routine civilian trauma patients, delaying to T-TC was associated with 4.5-fold increased odds of mortality from hemorrhagic shock.

LEVEL OF EVIDENCE
Level IV.
Disabling Central Paroxysmal Positioning Upbeat Nystagmus and Vertigo Associated With the Presence of Anti–Glutamic Acid Decarboxylase Antibodies
Authors: Martins Ana I. , Carvalho João N. , Amorim Ana M. , Geraldo Argemiro , Eggenberger Eric , Lemos João 
Published: August 2017

Abstract:
An immune attack by anti–glutamic acid decarboxylase (GAD) antibodies is believed to cause a deficiency in gamma-aminobutyric acid–mediated neurotransmission in the cerebellum. This, in turn, leads to several eye movement disorders, including spontaneous downbeat (DBN) and periodic alternating nystagmus. We describe a 68-year-old diabetic woman with disabling paroxysmal positioning upbeat nystagmus (UBN) exclusively in the supine position, associated with asymptomatic spontaneous DBN, alternating skew deviation and hyperactive vestibulo-ocular reflex responses on head impulse testing, in whom high titers of anti-GAD antibodies were detected. After treatment with intravenous immunoglobulin, a complete resolution of positioning UBN and spontaneous DBN occurred, along with a decrease in anti-GAD antibody titers. Positioning UBN in this case may reflect a transient disinhibition of the central vestibular pathways carrying posterior semicircular canal signals, due to lack of normal inhibitory input from the cerebellar nodulus/uvula. Immunoglobulin restored cerebellar inhibitory output, possibly by improving gamma-aminobutyric acid neurotransmission.
Live imaging of heart tube development in mouse reveals alternating phases of cardiac differentiation and morphogenesis
Authors: Ivanovitch Kenzo , Temiño Susana , Torres Miguel 
Published: August 2017

ABSTRACTDuring vertebrate heart development two progenitor populations, first and second heart fields (FHF, SHF), sequentially contribute to longitudinal subdivisions of the heart tube (HT), with the FHF contributing the left ventricle and part of the atria, and the SHF the rest of the heart. Here we study the dynamics of cardiac differentiation and morphogenesis by tracking individual cells in live analysis of mouse embryos. We report that during an initial phase, FHF precursors differentiate rapidly to form a cardiac crescent, while limited morphogenesis takes place. In a second phase, no differentiation occurs while extensive morphogenesis, including splanchnic mesoderm sliding over the endoderm, results in HT formation. In a third phase, cardiac precursor differentiation resumes and contributes to SHF-derived regions and the dorsal closure of the HT. These results reveal tissue-level coordination between morphogenesis and differentiation during HT formation and provide a new framework to understand heart development.
ASPEN: A methodology for reconstructing protein evolution with improved accuracy using ensemble models
Authors: Sloutsky Roman , Naegle Kristen M. 
Published: August 2017

AbstractEvolutionary reconstruction algorithms produce models of the evolutionary history of proteins: the order of duplications and speciations that led to extant homologous proteins observed across species. Although they are regularly used to gain insight into protein function, these models are estimates of an unknowable truth according to the underlying assumptions inherent in each algorithm, its objective function, and the input sequences supplied for reconstruction. In practice, the generated models are highly sensitive to the sequence inputs. In this work, we asked whether we could identify stronger phylogenetic signal by capitalizing on the variance introduced by perturbing the input to evolutionary reconstruction to explore a rich space of possible models that could explain protein evolution. We subsampled from available protein orthologs, “same” proteins across multiple extant species, and produced an ensemble of topologies representing the duplication history which produced related proteins (paralogs) for simulated protein families and in a real protein family – the LacI transcription factor family. We found that two very important phenomena arise from this approach. First, the reproducibility of an all-sequence, single-alignment reconstruction, measured by comparing topologies inferred from 90% subsamples, directly correlates with the accuracy of that single-alignment reconstruction, producing a measurable value for something that has been traditionally unknowable. Second, if we take a large ensemble of trees inferred from 50% subsamples and cast the ensemble into a form that represents the distribution of pairwise leaf distances observed across the ensemble, then trees that capture the most frequently observed relationships are also the most accurate. We propose a new methodology, ASPEN, a meta-algorithm that finds and ranks the trees that are most consistent with observations across the ensemble. Top-ranked ASPEN trees are significantly more accurate than the single-alignment tree produced from all available sequences. Importantly, our findings suggest that the true tree is currently inaccessible for most real protein families. Instead, applications that rely on evolutionary models should integrate across many trees that are equally likely to represent the true evolutionary history of a protein family.
Both DNA Polymerases δ and ε Contact Active and Stalled Replication Forks differently
Authors: Yu Chuanhe , Gan Haiyun , Zhang Zhiguo 
Published: August 2017

AbstractThree DNA polymerases (Pol α, Pol δ, and Pol ε) are responsible for eukaryotic genome duplication. When DNA replication stress is encountered, DNA synthesis stalls until the stress is ameliorated. However, it is not known whether there is a difference in the association of each polymerase with active and stalled replication forks. Here, we show that each DNA polymerase has distinct patterns of association with active and stalled replication forks. Pol α is enriched at extending Okazaki fragments of active and stalled forks. In contrast, although Pol δ contacts the nascent lagging strands of active and stalled forks, it binds to only the matured (and not elongating) Okazaki fragments of stalled forks. Pol ε has a greater contact with the nascent ssDNA of leading strand on active forks compared with stalled forks. We propose that the configuration of DNA polymerases at stalled forks facilitate resumption of DNA synthesis after stress removal.
Heterosis is a systemic property emerging from nonlinear genotype-phenotype relationships: evidence fromin vitrogenetics and computer simulations
Authors: Fiévet Julie B. , Nidelet Thibault , Dillmann Christine , de Vienne Dominique 
Published: August 2017

AbstractHeterosis, the superiority of hybrids over their parents for quantitative traits, represents a crucial issue in plant and animal breeding. Heterosis has given rise to countless genetic, genomic and molecular studies, but has rarely been investigated from the point of view of systems biology. We hypothesized that heterosis is an emergent property of living systems resulting from frequent concave relationships between genotypic variables and phenotypes, or between different phenotypic levels. We chose the enzyme-flux relationship as a model of the concave genotype-phenotype (GP) relationship, and showed that heterosis can be easily created in the laboratory. First, we reconstitutedin vitrothe upper part of glycolysis. We simulated genetic variability of enzyme activity by varying enzyme concentrations in test tubes. Mixing the content of “parental” tubes resulted in “hybrids”, whose fluxes were compared to the parental fluxes. Frequent heterotic fluxes were observed, under conditions that were determined analytically and confirmed by computer simulation. Second, to test this model in a more realistic situation, we modeled the glycolysis/fermentation network in yeast by considering one input flux, glucose, and two output fluxes, glycerol and acetaldehyde. We simulated genetic variability by randomly drawing parental enzyme concentrations under various conditions, and computed the parental and hybrid fluxes using a system of differential equations. Again we found that a majority of hybrids exhibited positive heterosis for metabolic fluxes. Cases of negative heterosis were due to local convexity between certain enzyme concentrations and fluxes. In both approaches, heterosis was maximized when the parents were phenotypically closeandwhen the distributions of parental enzyme concentrations were contrasted and constrained. These conclusions are not restricted to metabolic systems: they only depend on the concavity of the GP relationship, which is commonly observed at various levels of the phenotypic hierarchy, and could account for the pervasiveness of heterosis.
The Validity of the Coalescent Approximation for Large Samples
Authors: Melfi Andrew , Viswanath Divakar 
Published: August 2017

AbstractThe Kingman coalescent, widely used in genetics, is known to be a good approximation when the sample size is small relative to the population size. In this article, we investigate how large the sample size can get without violating the coalescent approximation. If the haploid population size is 2N, we prove that for samples of sizeN1/3−ϵ,ϵ> 0, coalescence under the Wright-Fisher (WF) model converges in probability to the Kingman coalescent in the limit of largeN. For samples of sizeN2/5−ϵor smaller, the WF coalescent converges to a mixture of the Kingman coalescent and what we call the mod-2 coalescent. For samples of sizeN1/2or larger, triple collisions in the WF genealogy of the sample become important. The sample size for which the probability of conformance with the Kingman coalescent is 95% is found to be 1.47 ×N0.31forN∈ [103, 105], showing the pertinence of the asymptotic theory. The probability of no triple collisions is found to be 95% for sample sizes equal to 0.92 ×N0.49, which too is in accord with the asymptotic theory.Varying population sizes are handled using algorithms that calculate the probability of WF coalescence agreeing with the Kingman model or taking place without triple collisions. For a sample of size 100, the probabilities of coalescence according to the Kingman model are 2%, 0%, 1%, and 0% in four models of human population with constantN, constantNexcept for two bottlenecks, recent exponential growth, and increasing recent exponential growth, respectively. For the same four demographic models and the same sample size, the probabilities of coalescence with no triple collision are 92%, 73%, 88%, and 87%, respectively. Visualizations of the algorithm show that even distant bottlenecks can impede agreement between the coalescent and the WF model.Finally, we prove that the WF sample frequency spectrum for samples of sizeN1/3−ϵor smaller converges to the classical answer for the coalescent.
Human placental syncytiotrophoblasts restrictToxoplasma gondiivertical transmission at two distinct stages and induce CCL22 in response to infection
Authors: Ander Stephanie E. , Rudzki Elizabeth N. , Arora Nitin , Sadovsky Yoel , Coyne Carolyn B. , Boyle Jon P. 
Published: August 2017

AbstractToxoplasma gondiiis a major source of congenital disease worldwide, but the cellular and molecular factors associated with its vertical transmission are largely unknown. In humans, the placenta forms the key interface between the maternal and fetal compartments and forms the primary barrier that restricts the hematogenous spread of microorganisms. Here, we utilized primary human trophoblast (PHT) cells isolated from full-term placentas and human mid-gestation chorionic villous explants to determine the mechanisms by which human trophoblasts restrict and respond toT. gondiiinfection. We show that placental syncytiotrophoblasts, multinucleated cells that are in direct contact with maternal blood, restrictT. gondiiinfection at distinct stages of the parasite lytic cycle—at the time of attachment and also during intracellular replication. Utilizing comparative RNAseq transcriptional profiling, we also show that human placental trophoblasts at both mid- and late-stages of gestation induce the chemokine CCL22 in response toT. gondiiinfection, which relies on the secretion of parasite effector(s). Collectively, our findings provide new insights into the mechanisms by which the human placenta restricts the vertical transmission ofT. gondiiat early and late stages of human pregnancy, and demonstrate the existence of at least two interferon-independent pathways that restrictT. gondiiaccess to the fetal compartment.Significance statementToxoplasma gondiiis a major source of congenital disease worldwide and must breach the placental barrier to be transmitted from maternal blood to the developing fetus. The events associated with the vertical transmission of T. gondii are largely unknown. Here, we show that primary human syncytiotrophoblasts, the fetal-derived cells that comprise the primary placental barrier, restrictT. gondiiinfection at two distinct stages of the parasite life cycle and respond to infection through the induction of the chemokine CCL22. Collectively, our findings provide important insights into the mechanisms by which human syncytiotrophoblasts restrictT. gondiiinfection at early and late stages of human pregnancy and identify the placental-enriched signaling pathways induced in response to infection.
A synthetic integral feedback controller for robust tunable regulation in bacteria
Authors: Lillacci Gabriele , Aoki Stephanie , Schweingruber David , Khammash Mustafa 
Published: August 2017

AbstractWe report on the first engineered integral feedback control system in a living cell. The controller is based on the recently published antithetic integral feedback motif [1] which has been analytically shown to have favorable regulation properties. It is implemented along with test circuitry inEscherichia coliusing seven genes and three small-molecule inducers. The closed-loop system is highly tunable, allowing a regulated protein of interest to be driven to a desired level and maintained there with precision. Realized using a sigma/anti-sigma protein pair, the integral controller ensures that regulation is maintained in the face of perturbations that lead to the regulated protein’s degradation, thus serving as a proof-of-concept prototype of integral feedback implementation in living cells. When suitably optimized, this integral controller may be utilized as a general-purpose robust regulator for genetic circuits with unknown or partially-known topologies and parameters.
Cool Enough for School: Second Version of Google Glass Rated by Children Facing Challenges to Social Integration as Desirable to Wear at School
Authors: Sahin Ned T. , Keshav Neha U. , Salisbury Joseph P. , Vahabzadeh Arshya 
Published: August 2017

ABSTRACTBackgroundOn July 18th, 2017, X, a subsidiary of Alphabet Inc. announced the successor to Google Glass. Glass Enterprise Edition could function as an assistive technology for autism spectrum disorder (ASD), yet its acceptability, desirability, and the willingness of children with ASD to wear it, are not known. The authors review key issues surrounding smartglasses and social communication, child development, and the school environment.MethodsThe smartglasses were evaluated by eight children with ASD, who ranged from moderately non-verbal to verbal, in the context of whether they would desire to wear it and use it as an assistive device each day at their respective schools. Children represented the full range of school ages (6 – 17yrs).ResultsAll eight children responded that they would want to wear and use Glass Enterprise Edition at school. Additionally, all eight parents said their child had fun during the testing session, and six of eight parents said the experience went better than they had thought.ConclusionThe results show that children with ASD are willing to use Glass Enterprise Edition in a school setting, highlighting its desirability and social acceptability in this population, as well as its future potential as an assistive technology.
Targeting posttranslational modifications of RioK1 inhibits the progression of colorectal and gastric cancers
Authors: Hong Xuehui , Huang He , Ding Zhijie , Feng Xing , Zhu Yuekun , Zhuo Huiqin , Hou Jingjing , Cai Wangyu , Hong Xinya , Song Hongjiang , Zhang Zhiyong 
Published: August 2017

AbstractRioK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RioK1 is methylated at K411 by SETD7 methyltransferase, and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RioK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RioK1. FBXO6 specifically interacts with K411-methylated RioK1 through its FBA domain to induce RioK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RioK1 at T410, which stabilizes RioK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RioK1. Functional experiments demonstrate the RioK1 methylation reduces the tumor growth and metastasis in CRC and GC. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human CRC tissues. Therefore, this study highlights the importance of a RioK1 methylation-phosphorylation switch in determining CRC and GC development.
Role of duplicate genes in determining the tissue-selectivity of hereditary diseases
Authors: Barshir Ruth , Hekselman Idan , Shemesh Netta , Sharon Moran , Novack Lena , Yeger-Lotem Esti 
Published: August 2017

ABSTRACTA longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues or cell types, while their causal genes are present and expressed throughout the human body. Here we considered a possible role for paralogs of causal genes in affecting this tissue selectivity. It has been shown across organisms that paralogs can compensate for the loss of each other. We hypothesized that specifically in the disease tissue causal genes and their paralogs are imbalanced, leading to insufficient compensation and to the emergence of disease phenotypes. While demonstrated previously in the context of few specific diseases, this hypothesis was never assessed quantitatively at large-scale. For this, we analyzed functional relationships between causal genes and their paralogs associated with 112 tissue-selective hereditary diseases. To test our hypothesis we used several large-scale omics datasets, including RNA sequencing profiles of over 30 different human tissues. Indeed, the expression of causal genes and their paralogs was significantly imbalanced in their disease tissues compared to unaffected tissues. Imbalanced expression was evident across different disease tissues, and was common to causal genes with single or multiple paralogs. This imbalance was driven by significant upregulation of the causal gene in its disease tissue, often combined with significant down-regulation of a paralog. Nevertheless, in additional 20% of the causal genes, a paralog alone was significantly down-regulated in the disease tissue. Our results suggest that dosage relationships between paralogs affect the phenotypic outcome of germline aberrations, adding paralogs as important modifiers of disease manifestation.
An algorithm for template-based prediction of secondary structures of individual RNA sequences
Authors: Pánek Josef , Černý Martin 
Published: August 2017

ABSTRACTWhile understanding the structure of RNA molecules is vital for deciphering their functions, determining RNA structures experimentally is exceptionally hard. At the same time, extant approaches to computational RNA structure prediction have limited applicability and reliability. In this paper we provide a method to solve a simpler yet still biologically relevant problem: prediction of secondary RNA structure using structure of different molecules as a template.Our method identifies conserved and unconserved subsequences within an RNA molecule. For conserved subsequences, the template structure is directly transferred into the generated structure and combined with de-novo predicted structure for the unconserved subsequences with low evolutionary conservation. The method also determines, when the generated structure is unreliable.The method is validated using experimentally identified structures. The accuracy of the method exceeds that of classical prediction algorithms and constrained prediction methods. This is demonstrated by comparison using large number of heterogeneous RNAs. The presented method is fast and robust, and useful for various applications requiring knowledge of secondary structures of individual RNA sequences.