bluuebunny/crossref_metadata_2025_split huggingface dataset:
Empirical Performance of Tree-based Inference of Phylogenetic Networks
Authors: Cao Zhen , Nakhleh Luay 
Published: July 2019

AbstractPhylogenetic networks extend the phylogenetic tree structure and allow for modeling vertical and horizontal evolution in a single framework. Statistical inference of phylogenetic networks is prohibitive and currently limited to small networks. An approach that could significantly improve phylogenetic network space exploration is based on first inferring an evolutionary tree of the species under consideration, and then augmenting the tree into a network by adding a set of “horizontal” edges to better fit the data.In this paper, we study the performance of such an approach on networks generated under a birth-hybridization model and explore its feasibility as an alternative to approaches that search the phylogenetic network space directly (without relying on a fixed underlying tree). We find that the concatenation method does poorly at obtaining a “backbone” tree that could be augmented into the correct network, whereas the popular species tree inference method ASTRAL does significantly better at such a task. We then evaluated the tree-to-network augmentation phase under the minimizing deep coalescence and pseudo-likelihood criteria. We find that even though this is a much faster approach than the direct search of the network space, the accuracy is much poorer, even when the backbone tree is a good starting tree.Our results show that tree-based inference of phylogenetic networks could yield very poor results. As exploration of the network space directly in search of maximum likelihood estimates or a representative sample of the posterior is very expensive, significant improvements to the computational complexity of phylogenetic network inference are imperative if analyses of large data sets are to be performed. We show that a recently developed divide-and-conquer approach significantly outperforms tree-based inference in terms of accuracy, albeit still at a higher computational cost.
Molecular and cellular phenotypic differences distinguish murine syngeneic models from human tumors
Authors: Zhong Wenyan , Myers Jeremy S. , Wang Fang , Wang Kai , Lucas Justin , Rosfjord Edward , Lucas Judy , Hooper Andrea T. , Yang Sharon , Lemon LuAnna , Guffroy Magali , May Chad , Bienkowska Jadwiga R. , Rejto Paul A. 
Published: July 2019

AbstractThe clinical success of immune checkpoint inhibitors that target cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1) demonstrates that reactivation of the human immune system delivers durable responses for some patients and represents an exciting approach for cancer treatment. The combination of multiple immunotherapies as well as the combination of immunotherapy with targeted therapy is being pursued vigorously to increase the rate and extend the duration of response. Preclinical in vivo models for immuno-oncology (IO) typically require immunocompetent mice bearing murine syngeneic tumors. To facilitate translation of preclinical studies into human, we characterized the genomic, transcriptomic, and protein expression of a panel of mouse tumor cell lines grown in vitro culture as well as in vivo tumor samples. Our studies identified many genetic and cellular phenotypic differences that distinguish murine syngeneic models from human cancers. For example, only a small fraction of the somatic single nucleotide variants (SNVs) in mouse cell lines directly match SNVs from human actionable cancer genes. At the cellular level, some epithelial tumor models have a more mesenchymal phenotype with relatively low T-lymphocyte infiltration compared to the corresponding human cancers. Furthermore, in contrast to what has been reported for human tumors, we did not observe a correlation between neoantigen load and cytolytic activity in syngeneic models. Finally, the relative immunogenicity of syngeneic tumors does not typically resemble that of human tumors of the same tissue origin. CT26, a colon tumor model, had the highest immunogenicity and was the most responsive model to CTLA4 inhibitor treatment, by contrast to the relatively low immunogenicity and response rate to checkpoint inhibitor therapies in human colon cancers. These differences highlight limitations of syngeneic models for evaluating novel immune therapies and rationalize some of the challenges associated with translating preclinical findings to clinical studies.
Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms
Authors: Novikova Gloriia , Kapoor Manav , TCW Julia , Abud Edsel M. , Efthymiou Anastasia G. , Cheng Haoxiang , Fullard John F. , Bendl Jaroslav , Roussos Panos , Poon Wayne W. , Hao Ke , Marcora Edoardo , Goate Alison M. 
Published: July 2019

AbstractGenome-wide association studies (GWAS) have identified more than thirty loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown thus impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS signals with myeloid epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it experimentally in human induced pluripotent stem cell (hiPSC)-derived microglia. Combined, these results strongly implicate dysfunction of the myeloid endolysosomal system in the etiology of AD.
Genotypic variation in morphological source and sink traits affects the response of rice photosynthesis and growth to elevated atmospheric CO2
Authors: Fabre Denis , Dingkuhn Michael , Yin Xinyou , Clément-Vidal Anne , Roques Sandrine , Soutiras Armelle , Luquet Delphine 
Published: July 2019

AbstractThis study aimed to understand the response of photosynthesis and growth to e-CO2conditions (800 vs. 400 μmol mol-1) of rice genotypes differing in source-sink relationships. A proxy trait called local C source-sink ratio was defined as the ratio of flag leaf area over the number of spikelets on the corresponding panicle, and five genotypes differing in this ratio were grown in a controlled greenhouse. Differential CO2resources were applied either during the two weeks following heading (EXP1) or during the whole growth cycle (EXP2). Under e-CO2, low source-sink ratio cultivars (LSS) had greater gains in photosynthesis, and they accumulated less nonstructural carbohydrate in the flag leaf than high source-sink ratio cultivars (HSS). In EXP2, grain yield and biomass gain was also greater in LSS probably caused by their strong sink. Photosynthetic capacity response to e-CO2was negatively correlated across genotypes with local C source-sink ratio, a trait highly conserved across environments. HSS were sink-limited under e-CO2, probably associated with low triose phosphate utilization (TPU) capacity. We suggest that the local C source-sink ratio is a potential target for selecting more CO2-responsive cultivars, pending validation for a broader genotypic spectrum and for field conditions.HighlightRice local carbon source-sink ratio and sink plasticity can drive genotypic responses of leaf photosynthesis and plant production in a CO2elevation context.
Unique Cancer Motility Behaviors in Confined Spaces of Microgroove Topography with Acute Wall Angles
Authors: Yaginuma T. , Kushiro K. , Takai M. 
Published: July 2019

AbstractIn recent years, many types of micro-engineered platform have been fabricated to investigate the influences of surrounding microenvironments on cell migration. Previous researches demonstrate that microgroove-based topographies can influence cell motilities of normal and cancerous cells differently. In this paper, the microgroove wall angle is altered from obtuse to acute angles and the resulting differences in the responses of normal and cancer cells are investigated to explore the geometrical characteristics that can efficiently distinguish normal and cancer cells. Interestingly, trends in cell motilities of normal and cancer cells as the wall angles are varied between 60-120° were different, and in particular, invasive cancer cells exhibit a unique, oscillatory migratory behavior. Results from the immunostaining of cell mechanotransduction components suggest that this difference stems from directional extension and adhesion behaviors of each cell type. In addition, the specific behaviors of invasive cancer cells are found to be dependent on the myosin II activity, and modulating the activity can revert cancerous behaviors to normal ones. These novel findings on the interactions of acute angle walls and cancer cell migration provide a new perspective on cancer metastasis and additional strategies via microstructure geometries for the manipulations of cell behaviors in microscale biodevices.Statement of SignificanceCancer metastasis is the leading cause of cancer patient deaths, and yet how the microstructures within the body affect this cell migration phenomenon is not well understood. In this paper, microdevices containing microgroove structures of varying geometries, in particular obtuse and acute angles, were utilized to monitor cell motilities of various cancer cells to understand the influences of the geometrical features of microstructures on cancer metastasis. Surprisingly, it was found that the acute angle geometries lowered the persistence of migration for cancer cells, which was a totally different response from non-cancerous cells. These new findings would enable the next-generation biodevices to analyze, separate and capture cancer cells, as well as shed light onto the underlying mechanisms of cancer metastasis.
Crosstalk between eIF2α and eEF2 phosphorylation pathways optimizes translational arrest in response to oxidative stress
Authors: Sanchez Marisa , Lin Yingying , Yang Chih-Cheng , McQuary Philip , Campos Alexandre Rosa , Blanc Pedro Aza , Wolf Dieter A. 
Published: July 2019

SUMMARYThe cellular stress response triggers a cascade of events leading to transcriptional reprogramming and a transient inhibition of global protein synthesis, which is thought to be mediated by phosphorylation of eukaryotic initiation factor-2α (eIF2α). Using mouse embryonic fibroblasts (MEFs) and the fission yeast S. pombe, we report here that rapid translational arrest and cell survival in response to hydrogen peroxide-induced oxidative stress do not rely on eIF2α kinases and eIF2α phosphorylation. Rather H2O2 induces a block in elongation through phosphorylation of eukaryotic elongation factor 2 (eEF2). Kinetic and dose-response analyses uncovered crosstalk between the eIF2α and eEF2 phosphorylation pathways, indicating that, in MEFs, eEF2 phosphorylation initiates the acute shutdown in translation, which is then maintained by eIF2α phosphorylation. Our results challenge the common conception that eIF2α phosphorylation is the primary trigger of translational arrest in response to oxidative stress and point to integrated control that may facilitate the survival of cancer cells.HIGHLIGHTSOxidative stress-induced translation arrest is independent of eIF2α phosphorylationOxidative stress blocks translation elongationOxidative stress triggers eEF2 kinase activationeEF2K KO cells are hypersensitive to oxidative stress
Acquisition design for direct reflectivity and velocity estimation from blended and irregularly sampled data
Authors: Nakayama Shotaro , Blacquière Gerrit , Ishiyama Tomohide 
Published: July 2019

ABSTRACTBlended acquisition along with efficient spatial sampling is capable of providing high‐quality seismic data in a cost‐effective and productive manner. While deblending and data reconstruction conventionally accompany this way of data acquisition, the recorded data can be processed directly to estimate subsurface properties. We establish a workflow to design survey parameters that account for the source blending as well as the spatial sampling of sources and detectors. The proposed method involves an iterative scheme to derive the survey design leading to optimum reflectivity and velocity estimation via joint migration inversion. In the workflow, we extend the standard implementation of joint migration inversion to cope with the data acquired in a blended fashion along with irregular detector and source geometries. This makes a direct estimation of reflectivity and velocity models feasible without the need of deblending or data reconstruction. During the iterations, the errors in reflectivity and velocity estimates are used to update the survey parameters by integrating a genetic algorithm and a convolutional neural network. Bio‐inspired operators enable the simultaneous update of the blending and sampling operators. To relate the choice of survey parameters to the performance of joint migration inversion, we utilize a convolutional neural network. The applied network architecture discards suboptimal solutions among newly generated ones. Conversely, it carries optimal ones to the subsequent step, which improves the efficiency of the proposed approach. The resultant acquisition scenario yields a notable enhancement in both reflectivity and velocity estimation attributable to the choice of survey parameters.
Biophysical and biological characterization of PEGylated recombinant human endostatin
Authors: Guo Lifang , Xu Benshan , Zhou Daifu , Chang Guodong , Fu Yan , Liu Lihong , Luo Yongzhang 
Published: July 2019

AbstractRecombinant human endostatin (MES), showing potent inhibition on angiogenesis and tumour growth, has great potential as a therapeutic agent for tumours. The aim of this study was to evaluate the biophysical and biological characterization of PEGylated recombinant human endostatin (M2ES). Recombinant human endostatin was mono‐PEGylated by conjugation with methoxy polyethylene glycol aldehyde (mPEG‐ALD), and the modification site was identified by digested peptide mapping and matrix assisted laser desorption/ionization–time of flight–mass spectrometry (MALDI–TOF–MS). The purity was assessed by SDS‐PAGE, high‐performance liquid chromatography (HPLC), and capillary zone electrophoresis. The physicochemical property was analyzed through fluorescence spectroscopy, and circular dichroism. The bioactivity and anti‐tumour efficacy of M2ES were evaluated using an in vitro endothelial cell migration model and a null‐mouse xenograft model of a prostatic cancer, respectively. M2ES molecules contain a single 20 kDa mPEG‐ALD molecule conjugated at the N‐terminal portion of MES. The purity of M2ES was greater than 98%. The physicochemical analysis demonstrated that PEGylation does not change the secondary and tertiary structure of MES. Notably, M2ES retards endothelial cell migration and tumour growth when compared to control group. These biophysical and biological characterization study data contribute to the initiation of the ongoing clinical study.
Validation of a universal set of primers to study animal‐associated microeukaryotic communities
Authors: del Campo Javier , Pons Maria J. , Herranz Maria , Wakeman Kevin C. , del Valle Juana , Vermeij Mark J. A. , Leander Brian S. , Keeling Patrick J. 
Published: July 2019

SummaryThe application of metabarcoding to study animal‐associated microeukaryotes has been restricted because the universal barcode used to study microeukaryotic ecology and distribution in the environment, the Small Subunit of the Ribosomal RNA gene (18S rRNA), is also present in the host. As a result, when host‐associated microbial eukaryotes are analysed by metabarcoding, the reads tend to be dominated by host sequences. We have done an in silico validation against the SILVA 18S rRNA database of a non‐metazoan primer set (primers that are biased against the metazoan 18S rRNA) that recovers only 2.6% of all the metazoan sequences, while recovering most of the other eukaryotes (80.4%). Among metazoans, the non‐metazoan primers are predicted to amplify 74% of Porifera sequences, 4% of Ctenophora, and 15% of Cnidaria, while amplifying almost no sequences within Bilateria. In vivo, these non‐metazoan primers reduce significantly the animal signal from coral and human samples, and when compared against universal primers provide at worst a 2‐fold decrease in the number of metazoan reads and at best a 2800‐fold decrease. This easy, inexpensive, and near‐universal method for the study of animal‐associated microeukaryotes diversity will contribute to a better understanding of the microbiome.
High incidence and morbidity of Clostridium difficile infection among hospitalized patients with inflammatory bowel disease: A prospective observational cohort study
Authors: Chen Xiao Li , Deng Jing , Chen Xin , Wan Shan Shan , Wang Yu , Cao Qian 
Published: July 2019

ObjectiveTo investigate the clinical features of Clostridium difficile infection (CDI) in hospitalized patients with inflammatory bowel disease (IBD) and to analyze the impact of CDI on IBD.MethodsA prospective study on patients newly diagnosed with IBD was conducted at the IBD center at Sir Run Run Shaw Hospital from March 2015 to May 2016. Stool samples for anaerobic culture and polymerase chain reaction were used to test CDI and to detect the different toxins in the groups. The patients were followed up for 2 years.ResultsAltogether 230 patients with IBD were enrolled, including 77 with ulcerative colitis (UC) and 153 with Crohn's disease (CD). The incidence rate of CDI was 13.9% (32/230). Patients with UC were more susceptible to CDI than those with CD (24.7% vs 8.5%, P < 0.01). Among UC patients, a long disease course, prior hospitalization, proton pump inhibitor use, and disease severity were associated with an increased risk of CDI (all P < 0.05). CDI prolonged hospital stay and increased the rate of long‐term surgery rate in UC (both P < 0.05). Among patients with CD, CDI increased both short‐ and long‐term surgery rates during the 2‐year follow‐up (P < 0.05) and increased repeated hospitalization in the follow‐up study (odds ratio 2.41, P = 0.02).ConclusionsA high incidence rate of CDI in patients hospitalized with IBD was related with longer hospital stay and higher surgery rates in our center. Patients with UC are more vulnerable to CDI than those with CD.
Does Other Comprehensive Income Volatility Influence Credit Risk and the Cost of Debt?
Authors: Bao May Xiaoyan , Billett Matthew T. , Smith David B. , Unlu Emre 
Published: July 2019

ABSTRACTWe examine the usefulness of other comprehensive income (OCI) to debt investors in nonfinancial companies. Motivated by Merton's (1974) real options framework, we construct a measure of incremental OCI volatility, designed to capture the effect of OCI on overall firm asset volatility, which is a primary driver of credit risk in Merton's (1974) model. We find that the volatility of incremental OCI influences the likelihood of default, credit ratings, and the cost of debt. Overall, our evidence suggests that creditors use information from OCI in their assessment of firm credit risk and in pricing debt contracts.
Circumstances of death of opioid users being treated with naltrexone
Authors: Darke Shane , Farrell Michael , Duflou Johan , Larance Briony , Lappin Julia 
Published: July 2019

AbstractBackground and aimsNaltrexone is an opioid antagonist used as a maintenance drug for the treatment of opioid dependence and in opioid withdrawal regimens. The current study aimed to: (1) determine the clinical characteristics and circumstances of death of people undergoing naltrexone treatment for opioid dependence; and (2) determine the blood toxicology of cases including naltrexone concentrations, the presence of other drugs and a comparison of morphine concentrations in the presence and absence of naltrexone.DesignRetrospective study of all deaths among people undergoing naltrexone treatment for opioid dependence retrieved from the National Coronial Information System, 2000–17.SettingAustralia‐wide.CasesSeventy‐four cases, with a mean age of 32.5 years; 81.1% male.MeasurementsInformation was collected on demographics, manner of death, naltrexone treatment history, toxicology and major organ pathology.FindingsDeath was attributed to opioid toxicity in 86.5% of cases: accidental (79.7%), deliberate (6.8%). In 55.4% of all cases the decedent was maintained on oral naltrexone and 32.4% had a recent naltrexone implant. In five cases the decedent was undergoing opioid detoxification. Among those screened for naltrexone, naltrexone was present in the blood or urine of 52.5% (15.8% of oral maintenance cases, 85.7% of implant cases). Fourteen cases were known to have died from opioid toxicity with naltrexone present in their blood or urine. The median blood naltrexone concentrations were within the reported therapeutic range.ConclusionsThe primary cause of death among people undergoing naltrexone treatment for opioid dependence in Australia from 2000 to 2017 was opioid toxicity, the majority of cases having been maintained on oral naltrexone. Cases in which naltrexone was not detected indicate the importance of treatment compliance. Deaths due to opioid toxicity where naltrexone was present indicates the possibility of overdose while naltrexone medication is maintained.
Adipocyte‐derived extracellular vesicles modulate appetite and weight through mTOR signalling in the hypothalamus
Authors: Gao Jie , Li Xinyu , Wang You , Cao Yan , Yao Dengju , Sun Lijie , Qin Lv , Qiu Hui , Zhan Xiaorong 
Published: July 2019

AbstractAimType 2 diabetes and obesity are diseases related to surplus energy in the body. Abnormal interaction between the hypothalamus and adipose tissues is a key trigger of energy metabolism dysfunction. Extracellular vesicles (EVs) regulate intercellular communication by transporting intracellular cargo to recipient cells thereby altering the function of recipient cells. This study aimed to evaluate whether adipocyte‐derived EVs can act on hypothalamic neurons to modulate energy intake and to identify the EV‐associated non‐coding RNAs.MethodsConfocal imaging was used to trace the uptake of labelled adipocyte‐derived exosomes by hypothalamic anorexigenic POMC neurons. The effects of adipocyte‐derived EVs on the mammalian target of rapamycin (mTOR) signalling pathway in POMC neurons were evaluated based on mRNA and protein expression in vitro using quantitative real‐time PCR and western blotting. In addition, adipocyte‐derived EVs were injected into recipient mice, and changes in mice body weight and daily food intake were monitored. The biological effects of the EV‐associated MALAT1 on POMC neurons were explored.ResultsAdipocyte‐derived EVs were successfully transferred into POMC neurons in vitro. Results showed that adipocytes of obese mice secreted MALAT1‐containing EVs, which increased appetite and weight when administered to lean mice. Conversely, adipocyte‐derived EVs from lean mice decreased food intake and weight when administered to obese mice.ConclusionAdipocyte‐derived EVs play important roles in mediating the interaction between adipocytes and hypothalamic neurons. Adipocyte‐derived EVs can regulate POMC expression through the hypothalamic mTOR signalling in vivo and in vitro, thereby affecting body energy intake.