bluuebunny/crossref_metadata_2025 huggingface dataset:
2286
Authors: Adams William G. , Mendis Michael , Thomas Shiby , Center David , Curran Sara
Published: May 2018

OBJECTIVES/SPECIFIC AIMS: The primary objective of this effort is to develop and distribute an easy to use i2b2 component that is capable of evaluating diverse complex relationships for a wide variety of exposures and outcomes over time. In this manner we are able to leverage the unique design of the i2b2 database to support health services research, comparative effectiveness, and quality improvement using a single tool. Furthermore, our novel database redesign has the potential to provide user-friendly access to individual and group CHC data for CER. METHODS/STUDY POPULATION: For this project we used software experts, clinical informatics specialists, and the existing i2b2 open-source software to convert our legacy HOME Cell into a web-client version. The tool will be used to study health outcomes within a network of Boston based Community Health Centers and the largest safety-net hospital in New England, Boston Medical Center. RESULTS/ANTICIPATED RESULTS: The new web-client HOME Cell will allow i2b2 users to model virtually any exposure (including therapeutic interventions such as medications or tests) in i2b2 against any outcome accounting for complex temporal relationships and other factors. In addition we plan to use our new Community Health Center views to enhance our community engagement activities by allowing direct access to their data for our partners. DISCUSSION/SIGNIFICANCE OF IMPACT: Our project addresses multiple national priorities related to data sharing, clinical research informatics, and comparative effectiveness. The web-client version of the HOME Cell substantially improves our community’s access to HOME Cell functionality and is a novel, sharable resource for use within the CTSA/NCATS community. Our approach provides a new way to perform large-scale collaborative research without the need to actually move patient-level data and has demonstrated that CER, health services research, and quality measurement can share a common framework. In addition, and as demonstrated in our earlier pilot work, the HOME Cell also has the potential to support large-scale multivariate analyses in a distributed manner that does not require sharing of patient-level data. We believe our approach has great promise for supporting the reuse of clinical data for rapid, transparent, health outcome assessments on a national scale. Our efforts support multiple strategic goals including: (1) support for building national clinical and translational research capacity by enhancing a broadly adopted informatics tool (i2b2); (2) enhanced consortium-wide collaborations by offering a tool that can be easily shared within the CTSA network to support multi-institutional collaboration; and (3) improving the health of our communities by offering a tool that has the potential to provide new insights into health care processes and outcomes that could drive innovation and improvement activities.
2356
Authors: Gower Adam C. , Spira Avrum , Lenburg Marc E.
Published: May 2018

OBJECTIVES/SPECIFIC AIMS: Microarray technology has produced large volumes of gene expression data profiling differences in gene expression in a vast array of conditions, much of which is publicly available. Methods to query these data for similarities in patterns of gene regulation are limited to comparisons between preannotated groups. In response, we developed openSESAME to find experiments where a set of genes is similarly coregulated without regard to experimental design. An important application of openSESAME is drug repositioning: if a pattern associated with disease is reversed by a given drug, the drug might target disease-related processes. METHODS/STUDY POPULATION: Experiments from the Gene Expression Omnibus (GEO) were normalized, signature-association (SA) scores computed for each sample, experiments assigned enrichment scores, and ANOVAs used to assign significance to experimental variables automatically extracted from GEO. SA scores were also generated for hundreds of publicly available signatures, and pairwise correlations used to create a relevance network. RESULTS/ANTICIPATED RESULTS: Using signatures of estrogen and p63, we recovered relevant experimental variables, and with the network approach, we recovered previously reported associations between disease states and/or drug treatments. DISCUSSION/SIGNIFICANCE OF IMPACT: openSESAME has the potential to illuminate “dark data” and discover novel relationships between drugs and diseases on the basis of common patterns of differential gene expression.
2456
Authors: Dennis Jessica , Zuckerman Scott , Yengo-Kahn Aaron , Cox Nancy , Solomon Gary
Published: May 2018

OBJECTIVES/SPECIFIC AIMS: To develop an algorithm that identifies post-concussion syndrome (PCS) cases and controls from among patients with mild traumatic brain injury (mTBI) in a large academic biobank. METHODS/STUDY POPULATION: The Vanderbilt University Medical Center’s (VUMC) electronic medical record (EMR) research database includes longitudinal medical record data on 2.5 million people. DNA and genotype data were also available for >225,000 of these individuals. Our algorithm used a combination of billing codes and natural language processing to apply inclusion and exclusion criteria. We defined PCS cases as those with a PCS billing code (ICD-9 310.2 or ICD-10 F07.81) and/or symptoms of PCS within 1–6 months of a qualifying mTBI. We will compare the positive predictive value of our algorithm to that of 2 simpler case selection schemes: (1) 1 instance of the PCS billing code anywhere in the medical record; and (2) 2 or more instances of the PCS billing code anywhere in the medical record. RESULTS/ANTICIPATED RESULTS: An mTBI was diagnosed in 28,720 patients regularly attending VUMC, and 528 of these patients were classified as PCS cases by our algorithm. The characteristics of our EMR sample reflected known risk factors for PCS. Our cases were more likely than controls to be female (49.4% vs. 38.4%), to have sustained a previous TBI (31.0% vs. 12.0%) and to have comorbid mood disorders. Our PCS cases were also more likely than controls to be <18 years of age (42.4% vs. 33.6%) and to have a sports-related keyword associated with the mTBI (44.1% vs. 25.2%), emphasizing the relevance of PCS to young athletes. Nonetheless, the number of PCS cases identified by our algorithm was small, and within the VUMC EMR, there were 5039 patients with 1 PCS billing code, and 2457 patients with 2 or more PCS billing codes anywhere in their EMR. Our next step is to calculate the positive predictive values of each selection scheme by manually reviewing the EMR of a selection of cases. Ultimately, we will implement the selection scheme that maximizes both positive predictive value and sample size, and in future work, we will genotype the selected patients to better understand the genetic architecture of PCS. DISCUSSION/SIGNIFICANCE OF IMPACT: EMR and biobanks are the future of human health research, and we asked whether complex algorithms or simple billing codes were best for studying the genetics of recovery after mTBI within the VUMC EMR. Our results are relevant to other studies of brain injury phenotypes within biobanks, including recovery from moderate or severe TBI, recovery from stroke, or the occurrence of delirium after routine surgery, and will help transform biobanks into fruitful research tools.
2469
Authors: Gouripeddi Ram , Cummins Mollie , Madsen Randy , LaSalle Bernie , Middleton Redd Andrew , Paige Presson Angela , Ye Xiangyang , Facelli Julio C. , Green Tom , Harper Steve
Published: May 2018

OBJECTIVES/SPECIFIC AIMS: Key factors causing irreproducibility of research include those related to inappropriate study design methodologies and statistical analysis. In modern statistical practice irreproducibility could arise due to statistical (false discoveries, p-hacking, overuse/misuse of p-values, low power, poor experimental design) and computational (data, code and software management) issues. These require understanding the processes and workflows practiced by an organization, and the development and use of metrics to quantify reproducibility. METHODS/STUDY POPULATION: Within the Foundation of Discovery – Population Health Research, Center for Clinical and Translational Science, University of Utah, we are undertaking a project to streamline the study design and statistical analysis workflows and processes. As a first step we met with key stakeholders to understand the current practices by eliciting example statistical projects, and then developed process information models for different types of statistical needs using Lucidchart. We then reviewed these with the Foundation’s leadership and the Standards Committee to come up with ideal workflows and model, and defined key measurement points (such as those around study design, analysis plan, final report, requirements for quality checks, and double coding) for assessing reproducibility. As next steps we are using our finding to embed analytical and infrastructural approaches within the statisticians’ workflows. This will include data and code dissemination platforms such as Box, Bitbucket, and GitHub, documentation platforms such as Confluence, and workflow tracking platforms such as Jira. These tools will simplify and automate the capture of communications as a statistician work through a project. Data-intensive process will use process-workflow management platforms such as Activiti, Pegasus, and Taverna. RESULTS/ANTICIPATED RESULTS: These strategies for sharing and publishing study protocols, data, code, and results across the spectrum, active collaboration with the research team, automation of key steps, along with decision support. DISCUSSION/SIGNIFICANCE OF IMPACT: This analysis of statistical methods and process and computational methods to automate them ensure quality of statistical methods and reproducibility of research.
2506
Authors: Demment Margaret , Fernandez Diana , Li Dongmei , Groth Susan , Dozier Ann , Chang Jack , Dye Tim
Published: May 2018

OBJECTIVES/SPECIFIC AIMS: To share lessons learned from implementing a health survey to a global sample of mTWs. METHODS/STUDY POPULATION: mTWs were paid $0.50 for taking a 15 minute survey to ascertain attitudes and intentions toward participating in genetic research. Two phases included: pilot survey targeting 7 global regions and a large-scale implementation in English in United States, India, and other countries and in Spanish in Spanish speaking countries. Administrative and descriptive information were collected and analyzed by region/country including: completions by location, demographics, time to complete, and survey satisfaction. RESULTS/ANTICIPATED RESULTS: There are 4 key lessons: (1) MTurk is fast. The US sample (n=505) accrual took <2 days and the Indian sample (n=505) took 11 days, while the response from other countries (n=118) generally exceeded 30 days. (2) Using Amazon country specification was the best way to ensure responses from specific countries and regions. (3) Demographic differences exist in mTWs between countries. For example, US mTWs were significantly more likely female (60.1%) compared with India (30.2%) and other countries (34.2%). (4) mTWs found the survey understandable/acceptable. mTWs reported high understandability and acceptability of the survey, which did not vary significantly across countries or by language. DISCUSSION/SIGNIFICANCE OF IMPACT: mTurk provides an efficient platform for survey research from diverse US and Indian samples. In other countries and in Spanish, the mTurk mechanism yielded a smaller sample more slowly but was still effective.
Rotating thermal convection in liquid gallium: multi-modal flow, absent steady columns
Authors: Aurnou Jonathan M. , Bertin Vincent , Grannan Alexander M. , Horn Susanne , Vogt Tobias
Published: May 2018

Earth’s magnetic field is generated by convective motions in its liquid metal core. In this fluid, the heat diffuses significantly more than momentum, and thus the Prandtl number $Pr$ is well below unity. The thermally driven convective flow dynamics of liquid metals are very different from moderate-$Pr$ fluids, such as water and those used in current dynamo simulations. In order to characterise rapidly rotating thermal convection in low-$Pr$ number fluids, we have performed laboratory experiments in a cylinder of aspect ratio $\unicode[STIX]{x1D6E4}=1.94$ using liquid gallium ($Pr\simeq 0.025$) as the working fluid. The Ekman number varies from $E\simeq 5\times 10^{-6}$ to $5\times 10^{-5}$ and the Rayleigh number varies from $Ra\simeq 2\times 10^{5}$ to $1.5\times 10^{7}$. Using spectral analysis stemming from point-wise temperature measurements within the fluid and measurements of the Nusselt number $Nu$, we characterise the different styles of low-$Pr$ rotating convective flow. The convection threshold is first overcome in the form of container-scale inertial oscillatory modes. At stronger forcing, sidewall-attached modes are identified for the first time in liquid metal laboratory experiments. These wall modes coexist with the bulk oscillatory modes. At $Ra$ well below the values where steady rotating columnar convection occurs, the bulk flow becomes turbulent. Our results imply that rotating convective flows in liquid metals do not develop in the form of quasisteady columns, as in moderate-$Pr$ fluids, but in the form of oscillatory convective motions. Thus, thermally driven flows in low-$Pr$ geophysical and astrophysical fluids can differ substantively from those occurring in $Pr\simeq 1$ models. Furthermore, our experimental results show that relatively low-frequency wall modes are an essential dynamical component of rapidly rotating convection in liquid metals.
Surface and Nonlocal Effects on Coupled In-Plane Shear Buckling and Vibration of Single-Layered Graphene Sheets Resting on Elastic Media and Thermal Environments using DQM
Authors: Abdollahi F. , Ghassemi A.
Published: May 2018

In this article, surface and nonlocal effects are explored in the analysis of buckling and vibration in rectangular single-layered graphene sheets embedded in elastic media and subjected to coupled in-plane loadings and thermal conditions. The small-scale and surface effects are taken into account using the Eringen's nonlocal elasticity and Gurtin-Murdoch's theory, respectively. Using the principle of virtual work, the governing equations considering small-scale are derived for the nanoplate bulk and surface. The differential quadrature method (DQM) is utilized for the solution of the relevant problems and the results are validated against Navier's solutions. The impacts of the nonlocal parameter, Winkler and shear elastic moduli, temperature rise, boundary conditions, and the in-plane biaxial, uniaxial, and shear loadings on the surface effects of buckling and vibration are investigated. Numerical results show that increasing nonlocal parameter leads to enhanced surface effects on both buckling and vibration. This is in contrast to those reported elsewhere. Moreover, increasing in-plane loads are observed to enhance surface effects on vibration. On the other hand, the nonlocal parameter is observed to have more pronounced effects on shear buckling and vibration of plates subjected to coupled in-plane shear loads than those subjected to biaxial and uniaxial loads. This is while surface effects have greater impacts on biaxial buckling and vibration of nanoplates than on shear buckling and vibration.
Modelling Pulsar Glitches: The Hydrodynamics of Superfluid Vortex Avalanches in Neutron Stars
Authors: Khomenko V. , Haskell B.
Published: May 2018

The dynamics of quantised vorticity in neutron star interiors is at the heart of most pulsar glitch models. However, the large number of vortices (up to ≈1013) involved in a glitch and the huge disparity in scales between the femtometre scale of vortex cores and the kilometre scale of the star makes quantum dynamical simulations of the problem computationally intractable. In this paper, we take a first step towards developing a mean field prescription to include the dynamics of vortices in large-scale hydrodynamical simulations of superfluid neutron stars. We consider a one-dimensional setup and show that vortex accumulation and differential rotation in the neutron superfluid lead to propagating waves, or ‘avalanches’, as solutions for the equations of motion for the superfluid velocities. We introduce an additional variable, the fraction of free vortices, and test different prescriptions for its advection with the superfluid flow. We find that the new terms lead to solutions with a linear component in the rise of a glitch, and that, in specific setups, they can give rise to glitch precursors and even to decreases in frequency, or ‘anti-glitches’.
Selective flowers to attract and enhanceTelenomus laeviceps(Hymenoptera: Scelionidae): a released biocontrol agent ofMamestra brassicae(Lepidoptera: Noctuidae)
Authors: Barloggio G. , Tamm L. , Nagel P. , Luka H.
Published: May 2018

The importance of the right food source for the survival and reproduction of certain insect species is well documented. In the case of biocontrol agents, this is even more important in order to reach a high predation or parasitation performance. The egg parasitoidTelenomus laeviceps(Förster, 1861) (Hymenoptera: Scelionidae) is a promising candidate for mass release as a biological control agent of the cabbage mothMamestra brassicae(Linnaeus, 1758) (Lepidoptera: Noctuidae). However, adultT. laevicepsneed a sugar-rich food source to increase their parasitation performance and produce a good amount of female offspring. Released biocontrol agents were shown to benefit from conservation biocontrol, which includes the provision of selected flowers as nectar resources for beneficial insects. In Switzerland,Centaurea cyanusL. (Asteraceae),Fagopyrum esculentumMoench (Polygonaceae) andVicia sativaL. (Fabaceae) are successfully implemented in the field to attract and promote natural enemies of different cabbage pests. In this study, we investigated the potential of these selected flowers to attract and promoteT. laevicepsunder laboratory conditions. In Y-tube olfactometer experiments, we first tested whether the three nectar providing plant species are attractive toT. laeviceps. Furthermore, we assessed their effects on survival and parasitation performance of adultT. laeviceps. We found that flowers ofF. esculentumandC. cyanuswere attractive in contrast toV. sativa.Also fecundity and the number of female offspring produced were higher for females kept onF. esculentumandC. cyanusthan onV. sativa.In contrast, survival was similar on all treatments. Our findings present a further key step towards the implementation ofT. laevicepsas a biocontrol agent.
LEAVENED APPREHENSIONS: BREAD SUBSIDIES AND MORAL ECONOMIES IN HASHEMITE JORDAN
Authors: Martínez José Ciro
Published: May 2018

This article analyzes the microprocesses that imbue bread with meaning and the macropolitics that shape its subsidized provision. It begins by outlining bread's multiple forms of value and significance, some easily quantifiable, others not. It problematizes the predominant approach to studying moral economies before putting forth an alternative framework. Drawing on eighteen months of fieldwork in Jordan, the following empirical sections examine the different ways in which bureaucrats, bakers, and ordinary citizens portray the government's universal subsidy of Arabic bread. I unpack the diverse opinions encountered in the field and discuss their links to the Hashemite regime's polyvalent legitimating discourse. The article then dissects the politics of provisions that contribute to the bread subsidy's paradoxical persistence. It concludes by considering the relationship between moral economies, opposition politics, and authoritarian power in the context of Jordan's ongoing food subsidy debate.
CINEMATIC GOVERNMENTALITY: CINEMA AND EDUCATION IN MODERN IRAN, 1900S–1930S
Authors: Rekabtalaei Golbarg
Published: May 2018

Much of the scholarship on the history of Iranian cinema considers film spectatorship in the first three decades of the 20th century as a leisure practice with origins in royalist and elitist entertainment forms. However, a close reading of archival material from this era reveals that cinema's significance extended well beyond its role as a pastime, as it became engaged in the governance of the self and disciplinary strategies of the state in Iran's experience of modernity in the early 20th century. In this article, I reperiodize the history of cinema in Iran by demonstrating the entanglement of cinema in popular nationalist discourses on education prior to cinema's institutionalization in the 1930s. Drawing on newspaper articles, film announcements, official documents, and poems, I show how, despite the absence of a centralized cinema institution in the 1910s and early 1920s, cosmopolitan citizens in dialogue with global trends promoted cinema as a means for the governance of selfhood and moral edification in the service of national progress. With the appropriation of cinema by the Pahlavi state in the 1930s, cinema was used as a technique of governmentality that aimed to conduct the conduct of individuals and shape an Iranian civic society.
Generation of large-scale vorticity in rotating stratified turbulence with inhomogeneous helicity: mean-field theory
Authors: Kleeorin N. , Rogachevskii I.
Published: May 2018

We discuss a mean-field theory of the generation of large-scale vorticity in a rotating density stratified developed turbulence with inhomogeneous kinetic helicity. We show that the large-scale non-uniform flow is produced due to either a combined action of a density stratified rotating turbulence and uniform kinetic helicity or a combined effect of a rotating incompressible turbulence and inhomogeneous kinetic helicity. These effects result in the formation of a large-scale shear, and in turn its interaction with the small-scale turbulence causes an excitation of the large-scale instability (known as a vorticity dynamo) due to a combined effect of the large-scale shear and Reynolds stress-induced generation of the mean vorticity. The latter is due to the effect of large-scale shear on the Reynolds stress. A fast rotation suppresses this large-scale instability.
Urban Histories of Place and Labour: The Chillia Taximen of Bombay/Mumbai
Authors: BEDI TARINI
Published: May 2018

When it comes to historical and ethnographic accounts of transport labour outside the West, scholars have only recently intervened to correct the paucity of systematic scholarship in this area. This article is in conversation with scholarship in both labour history and urban anthropology through which it links the modern history of a particular mode of urban transport (the taxi) and the labouring history of those who drive, move, and fix it. Through a focus on a community of hereditary taxi drivers known aschilliain the Indian city of Bombay/Mumbai, this article expands our understanding of labour experiences of the city through the twentieth century and into the present. It moves between historical archives, oral history, and lived experience to illuminate how the labour of transport workers structures circulations, collective identities, and urban space. It explores several dimensions of the history and present of transport labour in India. First, it is concerned with the connection between the work of hereditary motoring and the reconfiguration and constitution of communal identities in contexts of urban labour migration. Second, it is interested how labour practices become embedded in broader social and cultural space. Third, given that chillia have continued in the trade for over 100 years, the article explores the circuits of work and labour surrounding their trade to illuminate intersections between political and cultural shifts in Mumbai, changing conditions of work in contemporary contexts of globalizing capital, and the forms of ‘non-consent’ that emerge out of these networks.
Positive periodic solutions for singular fourth-order differential equations with a deviating argument
Authors: Kong Fanchao , Liang Zaitao
Published: May 2018

In this paper, we study the singular fourth-order differential equation with a deviating argument:

By using Mawhin's continuation theorem and some analytic techniques, we establish some criteria to guarantee the existence of positive periodic solutions. The significance of this paper is that g has a strong singularity at x = 0 and satisfies a small force condition at x = ∞, which is different from the known ones in the literature.
Revocation of Citizenship and Rule of Law: How Judicial Review Defeated Britain's First Denaturalization Regime
Authors: Weil Patrick , Handler Nicholas
Published: May 2018

Over the past decade, the United Kingdom has deprived an increasing number of British subjects of their citizenship. This policy, known as “denaturalization,” has been applied with particular harshness in cases where foreign-born subjects have been accused of terrorist activity. The increase is part of a global trend. In recent years, Canada, Australia, France, and the Netherlands have either debated or enacted denaturalization statutes. But Britain remains an outlier among Western democracies. Since 2006, the United Kingdom home secretary has revoked the citizenship of at least 373 Britons, of whom at least 53 have had alleged links to terrorism. This is more than the total number of revocations by Canada, France, Australia, and Netherlands combined. These developments are troubling, as the right to be secure in one's citizenship has been a cornerstone of the postwar European liberal political order, and of the international community's commitment to human rights.
Evaluation of the effectiveness of a latrine intervention in the reduction of childhood diarrhoeal health in Nyando District, Kisumu County, Kenya
Authors: Babb C. , Makotsi N. , Heimler I. , Bailey R. C. , Hershow R. C. , Masanga P. , Mehta S. D.
Published: May 2018

Community-led total sanitation (CLTS) is an intervention that strives to end the practice of open defaecation. This study measured the effectiveness of CLTS in Nyando District by examining the association between community open defaecation-free (ODF) status and childhood diarrhoeal illness. A cross-sectional study design was used among households with children ⩽5 years old to ascertain information on acute diarrhoea in the past year (outcome), sanitation and health behaviours. Water testing was conducted to determine Escherichia coli and turbidity levels for 55 water sources. Data were obtained from 210 parents or caregivers from an ODF community and 216 parents or caregivers in a non-ODF community. The non-ODF participants reported a non-significant 16% increased risk of diarrhoea compared with the participants from the ODF community. Children's HIV positivity (adjusted prevalence ratio (aPR) = 2.29; 95% CI 2.07–2.53), unsafe child stool disposal (aPR = 1.92; 95% CI 1.74–2.12) and low household income (aPR = 1.93; 95% CI 1.46–2.56) were associated with diarrhoea, in the non-ODF community. The ODF location had a higher percentage of E. coli in the drinking water compared with the non-ODF location (76.7% vs. 60%). Diarrhoeal disease rates in children ⩽5 years old did not differ by whether a latrine intervention was implemented. Water sampling findings suggest water safety may have decreased the effectiveness of the CLTS’ improvement of childhood diarrhoea. Improved water treatment practices, safe stool disposal and education may improve the CLTS intervention in ODF communities and therefore reduced the risk of childhood diarrhoea.
Hurricane Harvey Links to Ocean Heat Content and Climate Change Adaptation
Authors: Trenberth Kevin E. , Cheng Lijing , Jacobs Peter , Zhang Yongxin , Fasullo John
Published: May 2018

While hurricanes occur naturally, human‐caused climate change is supercharging them and exacerbating the risk of major damage. Here using ocean and atmosphere observations, we demonstrate links between increased upper ocean heat content due to global warming with the extreme rainfalls from recent hurricanes. Hurricane Harvey provides an excellent case study as it was isolated in space and time. We show that prior to the beginning of northern summer of 2017, ocean heat content was the highest on record both globally and in the Gulf of Mexico, but the latter sharply decreased with hurricane Harvey via ocean evaporative cooling. The lost ocean heat was realized in the atmosphere as moisture, and then as latent heat in record‐breaking heavy rainfalls. Accordingly, record high ocean heat values not only increased the fuel available to sustain and intensify Harvey but also increased its flooding rains on land. Harvey could not have produced so much rain without human‐induced climate change. Results have implications for the role of hurricanes in climate. Proactive planning for the consequences of human‐caused climate change is not happening in many vulnerable areas, making the disasters much worse.
Avoiding the Guise of an Anonymous Review
Authors: Sheikholeslami Razi , Razavi Saman
Published: May 2018

Anonymous review of scientific manuscripts was intended to encourage reviewers to speak freely, but other models may be better for accountability and inclusivity.
The Three‐Dimensional Bow Shock of Mars as Observed by MAVEN
Authors: Gruesbeck Jacob R. , Espley Jared R. , Connerney John E. P. , DiBraccio Gina A. , Soobiah Yasir I. , Brain David , Mazelle Christian , Dann Julian , Halekas Jasper , Mitchell David L.
Published: May 2018

The Martian magnetosphere is a product of the interaction of Mars with the interplanetary magnetic field and the supersonic solar wind. The location of the bow shock has been previously modeled as conic sections using data from spacecraft such as Phobos 2, Mars Global Surveyor, and Mars Express. The Mars Atmosphere and Volatile EvolutioN (MAVEN) mission spacecraft arrived in orbit about Mars in November 2014 resulting in thousands of crossings to date. We identify over 1,000 bow shock crossings. We model the bow shock as a three‐dimensional surface accommodating asymmetry caused by crustal magnetic fields. By separating MAVEN's bow shock encounters based on solar condition, we also investigate the variability of the surface. We find that the shock surface varies in shape and location in response to changes in the solar radiation, the solar wind Mach number, dynamic pressure of the solar wind, and the relative local time location of the strong crustal magnetic fields (i.e., whether they are on the dayside or on the nightside).
USP49 participates in the DNA damage response by forming a positive feedback loop with p53
Authors: Tu Rongfu , Kang Wenqian , Yang Xuefei , Zhang Qi , Xie Xiaoyu , Liu Wenbin , Zhang Jinxiang , Zhang Xiao-Dong , Wang Hui , Du Run-Lei
Published: May 2018

The p53 tumor suppressor is a critical factor in the DNA damage response (DDR), and regulation of p53 stability has a key role in this process. In our study, we identified USP49 as a novel deubiquitinase (DUB) for p53 from a library consisting of 80 DUBs and found that USP49 has a positive effect on p53 transcriptional activity and protein stability. Investigation of the mechanism revealed that USP49 interacts with the N terminus of p53 and suppresses several types of p53 ubiquitination. Furthermore, USP49 rendered HCT116 cells more sensitive to etoposide (Eto)-induced DNA damage and was upregulated in response to several types of cell stress, including DNA damage. Remarkably, USP49 expression was regulated by p53 and USP49 in knockout mice, which are more susceptible to azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumors. These findings suggest that USP49 has an important role in DDR and may act as a potential tumor suppressor by forming a positive feedback loop with p53.
p53 attenuates acetaminophen-induced hepatotoxicity by regulating drug-metabolizing enzymes and transporter expression
Authors: Sun Jiahong , Wen Yajie , Zhou Yanying , Jiang Yiming , Chen Yixin , Zhang Huizheng , Guan Lihuan , Yao Xinpeng , Huang Min , Bi Huichang
Published: May 2018

Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Inhibition of APAP metabolic activation and promotion in APAP disposition are important to protect against APAP-induced liver injury. Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic regulation. Our previous study reported that p53 promoted bile acid disposition and alleviated cholestastic syndrome. Here, we examined the effect of doxorubicin (Dox)-mediated p53 activation on APAP-induced hepatotoxicity in mice and revealed a novel role of p53 in regulating APAP metabolism and disposition. Histopathological and biochemical assessments demonstrated that administration of Dox (10 mg/kg/d) before APAP treatment (400 mg/kg) significantly alleviated APAP-induced hepatotoxicity. Dox treatment prevented APAP-induced GSH depletion and lipid peroxidation. p53-null mice were more susceptible to APAP-induced liver injury. Further, we found that the expression of drug-metabolizing enzymes and transporters CYPs, SULTs and MRPs was regulated by p53. Dox treatment also promoted Nrf2 activation and increased the expression of Nrf2 target genes including GSTα/μ and NQO1, which contribute to APAP detoxification. Overall, this study is the first to demonstrate the protective role of p53 in regulating APAP metabolism and disposition, which provides a potential new therapeutic target for APAP-induced liver injury.
Reducing protein regulator of cytokinesis 1 as a prospective therapy for hepatocellular carcinoma
Authors: Liu Xinran , Li Yangkai , Meng Lijing , Liu Xin-Yuan , Peng Anlin , Chen Yuchen , Liu Chengyu , Chen Hong , Sun Sheng , Miao Xiaoping , Zhang Yu , Zheng Ling , Huang Kun
Published: May 2018

Proteins that bind to microtubule are important for cell cycle, and some of these proteins show oncogenic characteristics with mechanisms not fully understood. Herein we demonstrate overexpression of protein regulator of cytokinesis 1 (PRC1), a microtubule-associated regulator of mitosis, in human hepatocellular carcinoma (HCC). Moreover, upregulated PRC1 is associated with lower survival rates of HCC patients. Mechanistically, reducing PRC1 blocks mitotic exit of HCC cells at telophase in a spindle assembly checkpoint independent manner, and acts synergistically with microtubule-associated agents (MTAs) to suppress p53-wt or p53-null HCC cells in a p53- or p14ARF-dependent manner; while overexpressing PRC1 increases the resistance of HCC to taxol. A combined treatment of taxol/shPRC1 results in 90% suppression of tumor growth in subcutaneous HCC xenograft models. In orthotopic xenograft mice, reducing PRC1 significantly alleviates HCC development and hepatic injury. Together, our results suggest a dual-mitotic suppression approach against HCC by combining MTAs with cytokinesis inhibition, which blocks mitosis at both metaphase and telophase.
Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation
Authors: Yang Fan , Wu Rongrong , Jiang Zhi , Chen Jinghai , Nan Jinliang , Su Sheng’an , Zhang Na , Wang Chen , Zhao Jing , Ni Cheng , Wang Yingchao , Hu Wangxing , Zeng Zhiru , Zhu Keyang , Liu Xianbao , Hu Xinyang , Zhu Wei , Yu Hong , Huang Jinyu , Wang Jian’an
Published: May 2018

Accumulating evidence revealed that mesenchymal stem cells (MSCs) confer cardioprotection against myocardial infarction (MI). However, the poor survival and engraftment rate of the transplanted cells limited their therapeutic efficacy in the heart. The enhanced leptin production associated with hypoxia preconditioning contributed to the improved MSCs survival. Mitochondrial integrity determines the cellular fate. Thus, we aimed to investigate whether leptin can enhance mitochondrial integrity of human MSCs (hMSCs) to protect against various stress. In vivo, transplantation of leptin-overexpressing hMSCs into the infarcted heart resulted in improved cell viability, leading to enhanced angiogenesis and cardiac function. In vitro, pretreatment of hMSCs with recombinant leptin (hMSCs-Leppre) displayed improved cell survival against severe ischemic condition (glucose and serum deprivation under hypoxia), which was associated with increased mitochondrial fusion. Subsequently, Optic atrophy 1 (OPA1), a mitochondrial inner membrane protein that regulates fusion and cristae structure, was significantly elevated in the hMSCs-Leppre group, and the protection of leptin was abrogated by targeting OPA1 with a selective siRNA. Furthermore, OMA1, a mitochondrial protease that cleaves OPA1, decreased in a leptin-dependent manner. Pretreatment of cells with an inhibitor of the proteasome (MG132), prevented leptin-induced OMA1 degradation, implicating the ubiquitination/proteasome system as a part of the protective leptin pathway. In addition, GSK3 inhibitor (SB216763) was also involved in the degradation of OMA1. In conclusion, in the hostile microenvironment caused by MI, (a) leptin can maintain the mitochondrial integrity and prolong the survival of hMSCs; (b) leptin-mediated mitochondrial integrity requires phosphorylation of GSK3 as a prerequisite for ubiquitination-depended degradation of OMA1 and attenuation of long-OPA1 cleavage. Thus, leptin targeting the GSK3/OMA1/OPA1 signaling pathway can optimize hMSCs therapy for cardiovascular diseases such as MI.
Targeting circular RNA-ZRANB1 for therapeutic intervention in retinal neurodegeneration
Authors: Wang Jia-Jian , Shan Kun , Liu Bai-Hui , Liu Chang , Zhou Rong-Mei , Li Xiu-Miao , Dong Rui , Zhang Shu-Jie , Zhang Sheng-Hai , Wu Ji-Hong , Yan Biao
Published: May 2018

Glaucoma is a neurodegenerative disease characterized by retinal ganglion cell (RGC) loss, optic disc excavation, and progressive visual field loss. Direct or indirect ameliorating retinal neurodegeneration is a promising therapeutic therapy for glaucoma. Circular RNAs (circRNAs) are a class of covalently closed circular RNA transcripts and have emerged as potential regulators in several neurodegenerative diseases. In this study, we show that cZRANB1 expression is significantly upregulated in retinal neurodegeneration induced by glaucoma. cZRANB1 knockdown decreases retinal reactive gliosis, glial cell activation, and facilitates RGC survival in vivo. cZRANB1 knockdown directly regulates Müller cell function and indirectly regulates RGC function in vitro. cZRANB1 acts as miRNA sponge to regulate Müller cell function through cZRANB1/miR-217/RUNX2 network. Intervention of cZRANB1 expression would become an effective strategy for treating retinal neurodegeneration.
RXRα provokes tumor suppression through p53/p21/p16 and PI3K-AKT signaling pathways during stem cell differentiation and in cancer cells
Authors: Zhang Rui , Li Hui , Zhang Shuangshuang , Zhang Yujie , Wang Nan , Zhou Hao , He Hongpeng , Hu Guang , Zhang Tong-Cun , Ma Wenjian
Published: May 2018

Abstract

The retinoid X receptor alpha (RXRα) is an important therapeutic target impacting diverse biological processes. Activation of RXRα is known to suppress cancer cell growth. However, the cellular mechanism has been elusive. In the present study, we addressed its role during stem cell differentiation and the underlying connections with carcinogenesis. RXRα was significantly upregulated following the differentiation of human mesenchymal stem cell (hMSC) toward the formation of endothelial cell (EC). However, overexpression of RXRα in hMSC provoked a senescence-like phenotype accompanied by the elevation of tumor suppressor p53, p21, and p16. Consistently, RXRα level was suppressed in cancer cells (~five times lower compared to differentiated hMSC), and its elevation could inhibit the proliferation, migration, and angiogenesis of cancer cells. We further demonstrated that these inhibitory effects were related to RXRα’s interaction with estrogen receptor α (ERα) as well as EGF and ANGPTL3 through modulating PI3K/AKT signaling pathway by AKT and FAK phosphorylation. Moreover, RXRα inhibited glycolytic metabolism in cancer cells, which might be underlying its inhibition of differentiation and carcinogenic features. These data suggest that RXRα acts as a suppressor rather than a driving force during stem cell differentiation, and unbalanced RXRα can trigger multiple yet connected signaling pathways in preventing carcinogenesis.
NVP-BEZ235, a dual PI3K-mTOR inhibitor, suppresses the growth of FaDu hypopharyngeal squamous cell carcinoma and has a synergistic effect with Cisplatin
Authors: Hsu Cheng-Ming , Lin Pai-Mei , Tsai Yao-Te , Tsai Ming-Shao , Tseng Chun-Han , Lin Sheng-Fung , Yang Ming-Yu
Published: May 2018

NVP-BEZ235 is a dual phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor. A dual approach targeting more than one downstream effector is a promising strategy for treating cancers. The aim of this study was to evaluate the effect of NVP-BEZ235 in treating FaDu hypopharyngeal squamous cell carcinoma (HSCC), either alone or in combination with cisplatin. We found mTOR expression was higher in patients with HSCC. In the in vitro study, treatment with NVP-BEZ235 alone attenuated cell proliferation and suppressed p-p70S6K and p-4E-BP1 expression in FaDu cells. When NVP-BEZ235 was combined with Cisplatin, apoptosis was induced more effectively than with either drug alone. In mice with a FaDu xenograft, cotreatment with NVP-BEZ235 and Cisplatin engendered synergistic effects and produced a greater antitumor response than did treatment with either drug alone. Resected tumor samples also showed decreased p-p70S6K expression. Collectively, these data demonstrate that NVP-BEZ235 inhibits HSCC growth through phospho-p70S6K suppression and has a synergistic effect with Cisplatin in treating HSCC. The data also provide a strategy for more effective HSCC treatment.
In vitro DNA SCRaMbLE
Authors: Wu Yi , Zhu Rui-Ying , Mitchell Leslie A. , Ma Lu , Liu Rui , Zhao Meng , Jia Bin , Xu Hui , Li Yun-Xiang , Yang Zu-Ming , Ma Yuan , Li Xia , Liu Hong , Liu Duo , Xiao Wen-Hai , Zhou Xiao , Li Bing-Zhi , Yuan Ying-Jin , Boeke Jef D.
Published: May 2018

The power of synthetic biology has enabled the expression of heterologous pathways in cells, as well as genome-scale synthesis projects. The complexity of biological networks makes rational de novo design a grand challenge. Introducing features that confer genetic flexibility is a powerful strategy for downstream engineering. Here we develop an in vitro method of DNA library construction based on structural variation to accomplish this goal. The “in vitro SCRaMbLE system” uses Cre recombinase mixed in a test tube with purified DNA encoding multiple loxPsym sites. Using a β-carotene pathway designed for expression in yeast as an example, we demonstrate top-down and bottom-up in vitro SCRaMbLE, enabling optimization of biosynthetic pathway flux via the rearrangement of relevant transcription units. We show that our system provides a straightforward way to correlate phenotype and genotype and is potentially amenable to biochemical optimization in ways that the in vivo system cannot achieve.
Author Correction: Fermiology and electron dynamics of trilayer nickelate La4Ni3O10
Authors: Li Haoxiang , Zhou Xiaoqing , Nummy Thomas , Zhang Junjie , Pardo Victor , Pickett Warren E. , Mitchell J. F. , Dessau D. S.
Published: May 2018

The original version of this Article contained errors in Fig. 2, Fig. 3a–c and Supplementary Fig. 2. In Fig. 2g and Supplementary Fig. 2, the band structure plot calculated from density function theory (DFT) had a missing band of mainly z2 character that starts at about – 0.25 eV at the Y point and disperses downwards towards the Γ point. This band was inadvertently neglected when transferring the lines from the original band plot to the enhanced version for publication. Also in Fig. 2g, the points labelled M and Y were not exactly at (1/2 1/2 0) and (0 1/2 0), but rather (0.52 0.48 0) and (0 0.48 0) due to a bug in XCrysDen for low-symmetry structures that the authors failed to identify before publication. Thus, the bands presented were slightly off the true M–Y direction and additional splitting incorrectly appeared (in particular for the highly dispersive bands of x2–y2 character). The correct versions of Fig. 2g (cited as Fig. 1) and Supplementary Fig. 2 (cited as Fig. 2) are:

which replaces the previous incorrect version, cited here as Fig. 3 and Fig. 4:

Neither of these errors in Fig. 2g or Supplementary Fig. 2 affects either the discussion or any of the interpretations of the ARPES data provided in the paper. The authors discussed the multilayer band splitting along the Γ–M direction (δ band and α band as assigned in the paper), and ARPES did not see any split band. The authors did not discuss the further splitting that arises due to back folding along the M–Y direction.

In Fig. 3a–c, the errors in the M and Y points in Fig. 2g cause subtle changes to the DFT dispersions. The correct version of Fig. 3a–c is cited here as Fig 5:

which replaces the previous incorrect version (Fig. 6):

However, the influence on the effective mass results of Fig. 3d is negligible.

These errors have now been corrected in both the PDF and HTML versions of the Article. The authors acknowledge James Rondinelli and Danilo Puggioni from Northwestern University for calling our attention to these issues.
A joint view on genetic variants for adiposity differentiates subtypes with distinct metabolic implications
Authors: Winkler Thomas W , Günther Felix , Höllerer Simon , Zimmermann Martina , Loos Ruth JF , Kutalik Zoltán , Heid Iris M
Published: May 2018

The problem of the genetics of related phenotypes is often addressed by analyzing adjusted-model traits, but such traits warrant cautious interpretation. Here, we adopt a joint view of adiposity traits in ~322,154 subjects (GIANT consortium). We classify 159 signals associated with body mass index (BMI), waist-to-hip ratio (WHR), or WHR adjusted for BMI (WHRadjBMI) at P < 5 × 10−8, into four classes based on the direction of their effects on BMI and WHR. Our classes help differentiate adiposity genetics with respect to anthropometry, fat depots, and metabolic health. Class-specific Mendelian randomization reveals that variants associated with both WHR-decrease and BMI increase are linked to metabolically rather favorable adiposity through beneficial hip fat. Class-specific enrichment analyses implicate digestive systems as a pathway in adiposity genetics. Our results demonstrate that WHRadjBMI variants capture relevant effects of “unexpected fat distribution given the BMI” and that a joint view of the genetics underlying related phenotypes can inform on important biology.
Hollow organic capsules assemble into cellular semiconductors
Authors: Zhang Boyuan , Hernández Sánchez Raúl , Zhong Yu , Ball Melissa , Terban Maxwell W. , Paley Daniel , Billinge Simon J. L. , Ng Fay , Steigerwald Michael L. , Nuckolls Colin
Published: May 2018

Self-assembly of electroactive molecules is a promising route to new types of functional semiconductors. Here we report a capsule-shaped molecule that assembles itself into a cellular semiconducting material. The interior space of the capsule with a volume of ~415 Å3 is a nanoenvironment that can accommodate a guest. To self-assemble these capsules into electronic materials, we functionalize the thiophene rings with bromines, which encode self-assembly into two-dimensional layers held together through halogen bonding interactions. In the solid state and in films, these two-dimensional layers assemble into the three-dimensional crystalline structure. This hollow material is able to form the active layer in field effect transistor devices. We find that the current of these devices has strong response to the guest’s interaction within the hollow spaces in the film. These devices are remarkable in their ability to distinguish, through their electrical response, between small differences in the guest.