bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of Time to Transport to a Higher Level Facility on the Clinical Outcomes of US Combat Casualties with TBI: A Multicenter 7-Year Study
Authors: Maddry Joseph K , Arana Allyson A , Perez Crystal A , Medellin Kimberly L , Paciocco Joni A , Mora Alejandra G , Holder William G , Davis William T , Herson Paco , Bebarta Vikhyat S 
Published: July 2019

AbstractIntroductionTraumatic brain injury (TBI) is a leading cause of death and disability worldwide and is associated with mortality rates as high as 30%. Patients with TBI are at high risk for secondary injury and need to be transported to definitive care expeditiously. However, the physiologic effects of aeromedical evacuation are not well understood and may compound these risks. Combat TBI patients may benefit from delayed aeromedical evacuation. The goal of this study was to evaluate the impact of transport timing out of theater via Critical Care Air Transport Teams (CCATT) to a higher level facility on the clinical outcomes of combat casualties with TBI.Materials and MethodsWe performed a retrospective review of patients with TBI who were evacuated out of theater by CCATT from January 2007 to May 2014. Data abstractors collected flight information, vital signs, procedures, in-flight assessments, and outcomes. Time to transport was defined as the time from injury to CCATT evacuation out of combat theater. We calculated descriptive statistics and constructed regression models to determine the association between time to transport and clinical outcomes. This study was approved by the U.S. Air Force 59th Medical Wing Institutional Review Board.ResultsWe analyzed the records of 438 patients evacuated out of theater via CCATT and categorized them into three groups: patients who were transported in one day or less (n = 165), two days (n = 163), and three or more days (n = 110). We used logistic regression models to compare outcomes among patients who were evacuated in two days or three or more days to those who were transported within one day while adjusting for demographics, injury severity, and injury type. Patients who were evacuated in two days or three or more days had 50% lower odds of being discharged on a ventilator and were twice as likely to return to duty or be discharged home than those who were evacuated within one day. Additionally, patients transported in three or more days were 70% less likely to be ventilated at discharge with a GCS of 8 or lower and had 30% lower odds of mortality than those transported within one day.ConclusionsIn patients with moderate to severe TBI, a delay in aeromedical evacuation out of the combat theater was associated with improved mortality rates and a higher likelihood of discharge to home and return to duty dispositions. This study is correlational in nature and focused on CCATT transports from Role III to Role IV facilities; as such, care must be taken in interpreting our findings and future studies are needed to establish a causal link between delayed evacuation and improved discharge disposition. Our study suggests that delaying aeromedical evacuation of TBI patients when feasible may confer benefit.
A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity
Authors: Santos Sean M. , Icyuz Mert , Pound Ilya , William Doreen , Guo Jingyu , McKinney Brett A. , Niederweis Michael , Rodgers John , Hartman John L. 
Published: July 2019

AbstractKnowledge about synthetic lethality can be applied to enhance the efficacy of anti-cancer therapies in individual patients harboring genetic alterations in their cancer that specifically render it vulnerable. We investigated the potential for high-resolution phenomic analysis in yeast to predict such genetic vulnerabilities by systematic, comprehensive, and quantitative assessment of drug-gene interaction for gemcitabine and cytarabine, substrates of deoxycytidine kinase that have similar molecular structures yet distinct anti-tumor efficacy. Human deoxycytidine kinase (dCK) was conditionally expressed in theS. cerevisiaegenomic library of knockout and knockdown (YKO/KD) strains, to globally and quantitatively characterize differential drug-gene interaction for gemcitabine and cytarabine. Pathway enrichment analysis revealed that autophagy, histone modification, chromatin remodeling, and apoptosis-related processes influence gemcitabine specifically, while drug-gene interaction specific to cytarabine was less enriched in Gene Ontology. Processes having influence over both drugs were DNA repair and integrity checkpoints and vesicle transport and fusion. Non-GO-enriched genes were also informative. Yeast phenomic and cancer cell line pharmacogenomics data were integrated to identify yeast-human homologs with correlated differential gene expression and drug-efficacy, thus providing a unique resource to predict whether differential gene expression observed in cancer genetic profiles are causal in tumor-specific responses to cytotoxic agents.
Altering microtubule dynamics is synergistically toxic with inhibition of the spindle checkpoint
Authors: Schukken Klaske M. , Lin Yi-Chih , Schubert Michael , Preuss Stephanie F. , Simon Judith E. , van den Bos Hilda , Storchova Zuzana , Colome-Tatche Maria , Bastians Holger , Spierings Diana C.J. , Foijer Floris 
Published: July 2019

AbstractChromosome instability (CIN) and aneuploidy are hallmarks of cancer. As the majority of cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings therefore suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.
Heterologous caffeic acid biosynthesis in Escherichia coli is affected by choice of tyrosine ammonia lyase and redox partners for bacterial Cytochrome P450
Authors: Haslinger Kristina , Prather Kristala L.J. 
Published: July 2019

AbstractBackgroundCaffeic acid is industrially recognized for its antioxidant activity and therefore its potential to be used as an anti-inflammatory, anticancer, antiviral, antidiabetic and antidepressive agent. It is traditionally isolated from lignified plant material under energy-intensive and harsh chemical extraction conditions. However, over the last decade bottom-up biosynthesis approaches in microbial cell factories have been established, that have the potential to allow for a more tailored and sustainable production. One of these approaches has been implemented in Escherichia coli and only requires a two-step conversion of supplemented L-tyrosine by the actions of a tyrosine ammonia lyase and a bacterial Cytochrome P450 monooxygenase. Although the feeding of intermediates demonstrated the great potential of this combination of heterologous enzymes compared to others, no de novo synthesis of caffeic acid from glucose has been achieved utilizing the bacterial Cytochrome P450 thus far.ResultsThe herein described work aimed at improving the efficiency of this two-step conversion in order to establish de novo caffeic acid formation from glucose. We implemented alternative tyrosine ammonia lyases that were reported to display superior substrate binding affinity and selectivity, and increased the efficiency of the Cytochrome P450 by altering the electron-donating redox system. With this strategy we were able to achieve final titers of more than 300 μM or 47 mg/L caffeic acid over 96 h in an otherwise wild type E. coli MG1655(DE3) strain with glucose as the only carbon source. We observed that the choice and gene dose of the redox system strongly influenced the Cytochrome P450 catalysis. In addition, we were successful in applying a tethering strategy that rendered even an initially unproductive Cytochrome P450/ redox system combination productive.ConclusionsThe caffeic acid titer achieved in this study is about 25% higher than titers reported for other heterologous caffeic acid pathways in wildtype E. coli without L-tyrosine supplementation. The tethering strategy applied to the Cytochrome P450 appears to be particularly useful for non-natural Cytochrome P450/redox partner combinations and could be useful for other recombinant pathways utilizing bacterial Cytochromes P450.
Mutations in CalDAG-GEFI Lead to Striatal Signaling Deficits and Psychomotor Symptoms in Multiple Species Including Human
Authors: Crittenden Jill R. , Sauvage Magdalena , Kitsukawa Takashi , Burguière Eric , Cepeda Carlos , André Véronique M. , Canault Matthias , Thomsen Morgane , Zhang Hui , Costa Cinzia , Martella Giuseppina , Ghiglieri Veronica , Pescatore Karen A. , Unterwald Ellen M. , Jackson Walker , Housman David E. , Caine S. Barak , Sulzer David , Calabresi Paolo , Levine Michael S. , Brefel-Courbon Christine , Smith Anne C. , Alessi Marie-Christine , Azulay Jean-Phillipe , Graybiel Ann M. 
Published: July 2019

SUMMARYSyndromes caused by mutations in Ras-MAP kinase signaling molecules are known as RASopathies and share features such as developmental delay, autistic traits, and cancer. Syndromic features of Rap-MAP kinase signaling defects remain undefined. CalDAG-GEFI is a calcium-responsive Rap-GTPase activator that is enriched in the matrix of the sensorimotor striatum and down-regulated in Huntington’s disease. We show here that CalDAG-GEFI mutations, including striatum-specific deletions and spontaneous mutations in the enzymatic domain, are associated with psychomotor phenotypes in humans, dogs and mice. The identification of these neural mutants was guided by the overt bleeding phenotype in CalDAG-GEFI knockout mice, and then in humans and other species with conserved platelet signaling deficits. Knockout mice exhibit loss of striatal long-term potentiation and deficits in dopamine, acetylcholine and glutamate signaling, along with delayed motor learning and drug-induced perseverative behaviors. Thus, loss of CalDAG-GEFI signaling produces an evolutionarily conserved syndrome characterized by bleeding and psychomotor dysfunction.
Phylogenetic diversity efficiently and accurately prioritizes the conservation of aquatic macroinvertebrate communities
Authors: Weglarz Kathryn M. , Saunders W. Carl , Van Wagenen Andrew , Pearse William D. 
Published: July 2019

AbstractLand degradation is a leading cause of biodiversity loss yet its consequences on freshwater ecosystems are poorly understood, exacerbating difficulties with assessing ecosystem quality and the effectiveness of restoration practices.Many monitoring programs rely on macroinvertebrates to assess the biotic effects of degradation and/or restoration and management actions on freshwater ecosystems. The ratio of Observed (O) to Expected (E) macroinvertebrate taxa at a given site—O/E—is often used for this purpose, despite the amount of modeling and data required to generate expectations and difficulties quantitatively assessing the degree of degradation at a site.Despite widespread use in academic biology, phylogenetic diversity is rarely applied in management, regardless of empirical correlations between phylogenetic diversity and management targets such as ecosystem structure and function.We use macroinvertebrate data from 1,400 watersheds to evaluate the potential for phylogenetic metrics to inform evaluations of management practices. These data have been collected since 1998, and have been used to determine the effectiveness of conservation management for the maintenance and restoration of riparian and aquatic systems.Phylogenetic diversity detected degradation as effectively as O/E, despite not having baseline ‘expectation’ data. Site disturbance, road density, and broader environmental drivers such as mean annual temperature strongly predicted site phylogenetic diversity, providing concrete management objectives to increase site health.Synthesis and applications.Management efforts targeted solely at taxonomic metrics, such as O/E, have been successfully used to manage sites. We show here that phylogenetic diversity metrics can support such efforts by providing additional information about the kind of species at sites. Given the ease with which such approaches can be applied, we call on others to use them to supplement existing prioritization schemes.
Machine learning aided analyses of thousands of draft genomes reveal plant- and environment-specific features of activated sludge process
Authors: Ye Lin , Mei Ran , Liu Wen-Tso , Ren Hongqiang , Zhang Xuxiang 
Published: July 2019

AbstractMicroorganisms in activated sludge (AS) play key roles in the wastewater treatment process. However, the ecological behavior of microorganisms in AS and their differences with microorganisms in other environments have mainly been studied using 16S rRNA gene that may not truly represent their in-situ functions. Here, we present 2045 bacterial and archaeal metagenome-assembled genomes (MAGs) recovered from 1.35 Tb of metagenomic sequencing data generated from 114 AS samples of 23 full-scale wastewater treatment plants (WWTPs). The average completeness and contamination of the MAGs are 82.0% and 2.0%, respectively. We find that the AS MAGs have obviously plant-specific features and few proteins are shared by different WWTPs, especially for WWTPs located in geographically distant areas. Despite the differences, specific functional traits (e.g. functions related to aerobic metabolism, nutrient sensing/acquisition, biofilm formation, etc.) of AS MAGs could be identified by a machine learning approach, and based on these traits, AS MAGs could be differentiated from MAGs of other environments with an accuracy of 96.6%. Our work provides valuable genome resources for future investigation of the AS microbiome and also introduces a novel approach to understand the microbial ecology in different ecosystems.
Cooption and Specialization of Endothelin Signaling Pathways Drove Elaboration of the Neural Crest in Early Vertebrates
Authors: Square Tyler A. , Jandzik David , Massey James L. , Romášek Marek , Stein Haley P. , Hansen Andrew W. , Purkayastha Amrita , Cattell Maria V. , Medeiros Daniel M. 
Published: July 2019

AbstractThe neural crest (NC) is a vertebrate-specific embryonic tissue that forms an array of clade-defining adult features. A key step in the formation of these diverse derivatives is the partitioning of NC cells into subpopulations with distinct migration routes and potencies1. The evolution of these developmental modules is poorly understood. Endothelin (Edn) signaling is unique to vertebrates, and performs various functions in different NC subpopulations2–5. To better understand the evolution of NC patterning, we used CRISPR/Cas9-driven mutagenesis to disrupt Edn receptors, ligands, and Dlx transcription factors in the sea lamprey,Petromyzon marinus. Lampreys and modern gnathostomes last shared a common ancestor 500 million years ago6. Thus, comparisons between the two groups can identify deeply conserved and divergent features of vertebrate development. UsingXenopus laevisto facilitate side-by-side analyses, we show here that lamprey and gnathostomes display fundamental differences in Edn signaling function. Unlike gnathostomes, both lamprey Ednrs cooperate during oropharyngeal skeleton development. Furthermore, neither paralog regulateshandtranscription factors, which are required for mandible development in gnathostomes. We also identify conserved roles for Edn signaling indlxgene regulation, pigment cell, and heart development. Together our results illustrate the stepwise neofunctionalization and specialization of this vertebrate-specific signaling pathway, and suggest key intermediate stages in the early evolution of the NC.
Genome-wide survey of ribosome collision
Authors: Han Peixun , Mito Mari , Shichino Yuichi , Hashimoto Satoshi , Udagawa Tsuyoshi , Kohno Kenji , Mishima Yuichiro , Inada Toshifumi , Iwasaki Shintaro 
Published: July 2019

AbstractIn protein synthesis, ribosome movement is not always smooth and is rather often impeded for numerous reasons. Although the deceleration of the ribosome defines the fates of the mRNAs and synthesizing proteins, fundamental issues remain to be addressed, including where ribosomes pause in mRNAs, what kind of RNA/amino acid sequence causes this pause, and the physiological significance of this slowdown of protein synthesis. Here, we surveyed the positions of ribosome collisions caused by ribosome pausing in humans and zebrafish on a genome-wide level using modified ribosome profiling. The collided ribosomes, i.e., disomes, emerged at various sites: the proline-proline-lysine motif, stop codons, and the 3′ untranslated region (UTR). The number of ribosomes involved in a collision is not limited to two, but rather four to five ribosomes can form a queue of ribosomes. In particular, XBP1, a key modulator of the unfolded protein response, shows striking queues of collided ribosomes and thus acts as a substrate for ribosome-associated quality control (RQC) to avoid the accumulation of undesired proteins in the absence of stress. Our results provide an insight into the causes and consequences of ribosome slowdown by dissecting the specific architecture of ribosomes.
25 years of propagation in suspension cell culture results in substantial alterations of theArabidopsis thalianagenome
Authors: Pucker Boas , Rückert Christian , Stracke Ralf , Viehöver Prisca , Kalinowski Jörn , Weisshaar Bernd 
Published: July 2019

AbstractArabidopsis thalianais one of the best studied plant model organisms. Besides cultivation in greenhouses, cells of this plant can also be propagated in suspension cell culture. At7 is one such cell line that has been established about 25 years ago. Here we report the sequencing and the analysis of the At7 genome. Large scale duplications and deletions compared to the Col-0 reference sequence were detected. The number of deletions exceeds the number of insertions thus indicating that a haploid genome size reduction is ongoing. Patterns of small sequence variants differ from the ones observed betweenA. thalianaaccessions e.g. the number of single nucleotide variants matches the number of insertions/deletions. RNA-Seq analysis reveals that disrupted alleles are less frequent in the transcriptome than the native ones.
Mathematical modeling with single-cell sequencing data
Authors: Cho Heyrim , Rockne Russell C. 
Published: July 2019

AbstractSingle-cell sequencing technologies have revolutionized molecular and cellular biology and stimulated the development of computational tools to analyze the data generated from these technology platforms. However, despite the recent explosion of computational analysis tools, relatively few mathematical models have been developed to utilize these data. Here we compare and contrast two approaches for building mathematical models of cell state-transitions with single-cell RNA-sequencing data with hematopoeisis as a model system; by solving partial differential equations on a graph representing discrete cell state relationships, and by solving the equations on a continuous cell state-space. We demonstrate how to calibrate model parameters from single or multiple time-point single-cell sequencing data, and examine the effects of data processing algorithms on the model calibration and predictions. As an application of our approach, we demonstrate how the calibrated models may be used to mathematically perturb normal hematopoeisis to simulate, predict, and study the emergence of novel cell types during the pathogenesis of acute myeloid leukemia. The mathematical modeling framework we present is general and can be applied to study cell state-transitions in any single-cell genome sequencing dataset.Author summaryHere we compare and contrast graph- and continuum-based approaches for constructing mathematical models of cell state-transitions using single-cell RNA-sequencing data. Using two publicly available datasets, we demonstrate how to calibrate mathematical models of hematopoeisis and how to use the models to predict dynamics of acute myeloid leukemia pathogenesis by mathematically perturbing the process of cellular proliferation and differentiation. We apply these modeling approaches to study the effects of perturbing individual or sets of genes in subsets of cells, or by modeling the dynamics of cell state-transitions directly in a reduced dimensional space. We examine the effects of different graph abstraction and trajectory inference algorithms on calibrating the models and the subsequent model predictions. We conclude that both the graph- and continuum-based modeling approaches can be equally well calibrated to data and discuss situations in which one method may be preferable over the other. This work presents a general mathematical modeling framework, applicable to any single-cell sequencing dataset where cell state-transitions are of interest.
Early fate of Exogenous promoters in E. coli
Authors: Yousuf Malikmohamed , Iuliani Ilaria , Veetil Reshma T. , Seshasayee Aswin Sai Narain , Sclavi Bianca , Lagomarsino Marco Cosentino 
Published: July 2019

ABSTRACTGene gain by horizontal gene transfer is a major pathway of genome innovation in bacteria. The current view posits that acquired genes initially need to be silenced and that a bacterial chromatin protein, H-NS, plays a role in this silencing. However, we lack direct observation of the early fate of a horizontally transferred gene to prove this theory. We combine sequencing, flow cytometry and sorting, and microscopy to monitor gene expression and its variability after large-scale random insertions of a reporter gene in a population. We find that inserted promoters have a wide range of gene-expression variability related to their location. We find that high-expression clones carry insertions that are not correlated with H-NS binding. Conversely, binding of H-NS correlates with silencing. Finally, while most promoters show a common level of extrinsic noise, some insertions show higher noise levels. Analysis of these high-noise clones supports a scenario of switching due to transcriptional interference from divergent ribosomal promoters. Altogether, our findings point to evolutionary pathways where newly-acquired genes are not necessarily silenced, but may immediately explore a wide range of expression levels to probe the optimal ones.