bluuebunny/crossref_metadata_2025_split huggingface dataset:
Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture
Authors: de Wilde Adriaan H. , Jochmans Dirk , Posthuma Clara C. , Zevenhoven-Dobbe Jessika C. , van Nieuwkoop Stefan , Bestebroer Theo M. , van den Hoogen Bernadette G. , Neyts Johan , Snijder Eric J. 
Published: May 2014

ABSTRACTCoronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. The 2003 outbreak of severe acute respiratory syndrome (SARS) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. In 2012, a similar previously unknown coronavirus emerged, Middle East respiratory syndrome coronavirus (MERS-CoV), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being recorded over recent months. The human MERS fatality rate of ∼30% is alarmingly high, even though many deaths were associated with underlying medical conditions. Registered therapeutics for the treatment of coronavirus infections are not available. Moreover, the pace of drug development and registration for human use is generally incompatible with strategies to combat emerging infectious diseases. Therefore, we have screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. If such compounds proved sufficiently potent, their efficacy might be directly assessed in MERS patients. We identified four compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibiting MERS-CoV replication in the low-micromolar range (50% effective concentrations [EC50s], 3 to 8 μM). Moreover, these compounds also inhibit the replication of SARS coronavirus and human coronavirus 229E. Although their protective activity (alone or in combination) remains to be assessed in animal models, our findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction may create a window during which to mount a protective immune response.
Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection
Authors: Dyall Julie , Coleman Christopher M. , Hart Brit J. , Venkataraman Thiagarajan , Holbrook Michael R. , Kindrachuk Jason , Johnson Reed F. , Olinger Gene G. , Jahrling Peter B. , Laidlaw Monique , Johansen Lisa M. , Lear-Rooney Calli M. , Glass Pamela J. , Hensley Lisa E. , Frieman Matthew B. 
Published: May 2014

ABSTRACT

Outbreaks of emerging infections present health professionals with the unique challenge of trying to select appropriate pharmacologic treatments in the clinic with little time available for drug testing and development. Typically, clinicians are left with general supportive care and often untested convalescent-phase plasma as available treatment options. Repurposing of approved pharmaceutical drugs for new indications presents an attractive alternative to clinicians, researchers, public health agencies, drug developers, and funding agencies. Given the development times and manufacturing requirements for new products, repurposing of existing drugs is likely the only solution for outbreaks due to emerging viruses. In the studies described here, a library of 290 compounds was screened for antiviral activity against Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Selection of compounds for inclusion in the library was dependent on current or previous FDA approval or advanced clinical development. Some drugs that had a well-defined cellular pathway as target were included. In total, 27 compounds with activity against both MERS-CoV and SARS-CoV were identified. The compounds belong to 13 different classes of pharmaceuticals, including inhibitors of estrogen receptors used for cancer treatment and inhibitors of dopamine receptor used as antipsychotics. The drugs identified in these screens provide new targets for
in vivo
studies as well as incorporation into ongoing clinical studies.
Unconventional Maturation of Dendritic Cells Induced by Particles from the Laminated Layer of Larval Echinococcus granulosus
Authors: Casaravilla Cecilia , Pittini Álvaro , Rückerl Dominik , Seoane Paula I. , Jenkins Stephen J. , MacDonald Andrew S. , Ferreira Ana M. , Allen Judith E. , Díaz Álvaro 
Published: May 2014

ABSTRACT

The larval stage of the cestode parasite
Echinococcus granulosus
causes hydatid disease in humans and livestock. This infection is characterized by the growth in internal organ parenchymae of fluid-filled structures (hydatids) that elicit surprisingly little inflammation in spite of their massive size and persistence. Hydatids are protected by a millimeter-thick layer of mucin-based extracellular matrix, termed the laminated layer (LL), which is thought to be a major factor determining the host response to the infection. Host cells can interact both with the LL surface and with materials that are shed from it to allow parasite growth. In this work, we analyzed the response of dendritic cells (DCs) to microscopic pieces of the native mucin-based gel of the LL (pLL).
In vitro
, this material induced an unusual activation state characterized by upregulation of CD86 without concomitant upregulation of CD40 or secretion of cytokines (interleukin 12 [IL-12], IL-10, tumor necrosis factor alpha [TNF-α], and IL-6). When added to Toll-like receptor (TLR) agonists, pLL-potentiated CD86 upregulation and IL-10 secretion while inhibiting CD40 upregulation and IL-12 secretion.
In vivo
, pLL also caused upregulation of CD86 and inhibited CD40 upregulation in DCs. Contrary to expectations, oxidation of the mucin glycans in pLL with periodate did not abrogate the effects on cells. Reduction of disulfide bonds, which are known to be important for LL structure, strongly diminished the impact of pLL on DCs without altering the particulate nature of the material. In summary, DCs respond to the LL mucin meshwork with a “semimature” activation phenotype, both
in vitro
and
in vivo
.
Integrons: Past, Present, and Future
Authors: Gillings Michael R. 
Published: May 2014

SUMMARY
Integrons are versatile gene acquisition systems commonly found in bacterial genomes. They are ancient elements that are a hot spot for genomic complexity, generating phenotypic diversity and shaping adaptive responses. In recent times, they have had a major role in the acquisition, expression, and dissemination of antibiotic resistance genes. Assessing the ongoing threats posed by integrons requires an understanding of their origins and evolutionary history. This review examines the functions and activities of integrons before the antibiotic era. It shows how antibiotic use selected particular integrons from among the environmental pool of these elements, such that integrons carrying resistance genes are now present in the majority of Gram-negative pathogens. Finally, it examines the potential consequences of widespread pollution with the novel integrons that have been assembled via the agency of human antibiotic use and speculates on the potential uses of integrons as platforms for biotechnology.
Utility of a Paediatric Trigger Tool in a Norwegian department of paediatric and adolescent medicine
Authors: Solevåg Anne Lee , Nakstad Britt 
Published: May 2014

ObjectivesThe British National Health Service (NHS) Paediatric Trigger Tool (PTT) was made based on various trigger tools developed for use in adults. The PTT has not previously been developed or used in Nordic units. We aimed to compare harm identified through PTT screening with voluntary incidence reports in our department. A secondary aim was to assess utility of the different triggers, including predictive value for identifying harm. We hypothesised that the NHS PTT would need adjustments for the setting in which it is used.SettingA Norwegian level II department of paediatric and adolescent medicine.ParticipantsA convenience sample of 761 acute medical and surgical patient contacts March–May 2011. Median age (IQR) for the trigger positive patients was 2.5 (1.0–8.0) years; range 0–18 years.Primary and secondary outcome measuresIncidence, type and severity of harm identified with the PTT compared with the department's voluntary incidence reports. The type and rate of identified triggers and positive predictive value for harm.ResultsThe PTT revealed a harm rate of 5% for medical patients, as compared to 0.5% in the incidence reports the same months. PTT screening revealed other types of harm than those reported by healthcare personnel themselves. We identified only 20 of the 39 NHS PTT triggers. The most frequent trigger was readmission within 30 days. Hypoxia, which was the second most frequent trigger, did not predict any patient harm.ConclusionsThis study showed that the NHS PTT identifies more and other types of harm than voluntary incidence reports. The presence of adult-oriented triggers, triggers that were not identified at all, as well as triggers with a low predictive value for harm may indicate the need for modification of the PTT to different settings. More studies are needed before a final decision is made to exclude triggers from the screening.
Black hole interior mass formula
Authors: Pradhan Parthapratim 
Published: May 2014

AbstractWe argue by explicit computations that, although the area product, horizon radii product, entropy product, and irreducible mass product of the event horizon and Cauchy horizon are universal, the surface gravity product, the surface temperature product and the Komar energy product of the said horizons do not seem to be universal for Kerr–Newman black hole spacetimes. We show the black hole mass formula on the Cauchy horizon following the seminal work by Smarr [Phys Rev Lett 30:71 (1973), Phys Rev D 7:289 (1973)] for the outer horizon. We also prescribe the four laws of black hole mechanics for the inner horizon. A new definition of the extremal limit of a black hole is discussed.
Interactions between continent-like ‘drift’, rifting and mantle flow on Venus: gravity interpretations and Earth analogues
Authors: Harris Lyal B. , Bédard Jean H. 
Published: May 2014

Abstract
Regional shear zones are interpreted from Bouguer gravity data over northern polar to low southern latitudes of Venus. Offset and deflection of horizontal gravity gradient edges (‘worms’) and lineaments interpreted from displacement of Bouguer anomalies portray crustal structures, the geometry of which resembles both regional transcurrent shear zones bounding or cross-cutting cratons and fracture zones in oceanic crust on Earth. High Bouguer anomalies and thinned crust comparable to the Mid-Continent Rift in North America suggest underplating of denser, mantle-derived mafic material beneath extended crust in Sedna and Guinevere planitia on Venus. These rifts are partitioned by transfer faults and flank a zone of mantle upwelling (Eistla Regio) between colinear hot, upwelling mantle plumes. Data support the northward drift and indentation of Lakshmi Planum in western Ishtar Terra and >1000 km of transcurrent displacement between Ovda and Thetis regiones. Large displacements of areas of continent-like crust on Venus are interpreted to result from mantle tractions and pressure acting against their deep lithospheric mantle ‘keels’ commensurate with extension in adjacent rifts. Displacements of Lakshmi Planum and Ovda and Thetis regiones on Venus, a planet without plate tectonics, cannot be attributed to plate boundary forces (i.e. ridge push and slab pull). Results therefore suggest that a similar, subduction-free geodynamic model may explain deformation features in Archaean greenstone terrains on Earth. Continent-like ‘drift’ on Venus also resembles models for the late Cenozoic–Recent Earth, where westward translation of the Americas and northward displacement of India are interpreted as being driven by mantle flow tractions on the keels of their Precambrian cratons.

Supplementary material:

Bouguer gravity and topographic images over a segment of the Mid-Atlantic ridge and Ross Island and surrounds in Antarctica, principal horizontal stress trajectories about mantle plumes on Earth, map and interactive 3D representations of cratonic keels beneath North America from seismic tomography, and a centrifuge simulation for comparison with Venus in support of our tectonic model are available at
http://www.geolsoc.org.uk/SUP18736
.
Inactivation of p53 Is Insufficient to Allow B Cells and B-Cell Lymphomas to Survive Without Dicer
Authors: Adams Clare M. , Eischen Christine M. 
Published: May 2014

Abstract
Inactivation of p53, the master regulator of cellular stress and damage signals, often allows cells that should die or senesce to live. Loss of Dicer, an RNase III–like enzyme critical in microRNA biogenesis, causes embryonic lethality and activation of the p53 pathway. Several nonhematopoietic cell types that contain inactivated p53 have been shown to survive Dicer deletion, suggesting that p53 loss may protect cells from the negative consequences of Dicer deletion. However, here, we report that loss of p53 did not provide a survival advantage to B cells, as they underwent rapid apoptosis upon Dicer deletion. Moreover, a deficiency in p53 neither rescued the Dicer deletion-induced delay in Myc-driven B-cell lymphomagenesis, nor allowed a single B-cell lymphoma to develop with biallelic deletion of Dicer. A p53 deficiency did, however, restore the pre-B/B-cell phenotype and CD19 surface expression of the lymphomas that emerged in conditional Dicer knockout Eμ-myc transgenic mice. Moreover, p53 loss in transformed B cells did not confer protection from apoptosis, as Dicer deletion in established p53-null B-cell lymphomas induced apoptosis, and all of the 1,260 B-cell lymphoma clones analyzed that survived Cre-mediated Dicer deletion retained at least one allele of Dicer. Moreover, Dicer deletion in lymphomas in vivo reduced tumor burden and prolonged survival. Therefore, inactivation of p53 is insufficient to allow untransformed B cells and B-cell lymphomas to survive without Dicer, presenting a potential therapeutic opportunity for the treatment of B-cell lymphomas. Cancer Res; 74(14); 3923–34. ©2014 AACR.
Decline in Physical Activity Level in the Childhood Cancer Survivor Study Cohort
Authors: Wilson Carmen L. , Stratton Kayla , Leisenring Wendy L. , Oeffinger Kevin C. , Nathan Paul C. , Wasilewski-Masker Karen , Hudson Melissa M. , Castellino Sharon M. , Stovall Marilyn , Armstrong Gregory T. , Brinkman Tara M. , Krull Kevin R. , Robison Leslie L. , Ness Kirsten K. 
Published: May 2014

Abstract
Background: We aimed to identify demographic and health-related predictors of declining physical activity levels over a four-year period among participants in the Childhood Cancer Survivor Study.
Methods: Analyses included 7,287 ≥5-year childhood cancer survivors and 2,107 siblings who completed multiple follow-up questionnaires. Participants were classified as active if they met the Centers for Disease Control and Prevention guidelines for physical activity. Generalized linear models were used to compare participants whose physical activity levels declined from active to inactive over the study to those who remained active. In addition, selected chronic conditions (CTCAE v4.03 Grade 3 and 4) were evaluated as risk factors in an analysis limited to survivors only.
Results: The median age at last follow-up among survivors and siblings was 36 (range, 21–58) and 38 (range, 21–62) years, respectively. The rate of decline did not accelerate over time among survivors when compared with siblings. Factors that predicted declining activity included body mass index ≥30 kg/m2 [RR = 1.32; 95% confidence interval (CI), 1.19–1.46, P &lt; 0.01], not completing high school (RR = 1.31; 95% CI, 1.08–1.60, P &lt; 0.01), and female sex (RR = 1.33; 95% CI, 1.22–1.44, P &lt; 0.01). Declining physical activity levels were associated with the presence of chronic musculoskeletal conditions (P = 0.034), but not with the presence of cardiac (P = 0.10), respiratory (P = 0.92), or neurologic conditions (P = 0.21).
Conclusions: Interventions designed to maximize physical activity should target female, obese, and less educated survivors. Survivors with chronic musculoskeletal conditions should be monitored, counseled, and/or referred for physical therapy.
Impact: Clinicians should be aware of low activity levels among subpopulations of childhood cancer survivors, which may heighten their risk for chronic illness. Cancer Epidemiol Biomarkers Prev; 23(8); 1619–27. ©2014 AACR.
The Waziri Chain Shift
Authors: Miller Corey 
Published: May 2014

Abstract
The Waziri dialect of the Pashto language, spoken in Afghanistan and Pakistan, features a vowel shift with respect to other varieties of Pashto. Kieffer calls this process metaphony, but referring to it as a vowel shift facilitates comparison with similar phenomena in other languages. This shift involves three standard vowels, /ā/, /o/ and /u/, which in Waziri can shift to /o/, /e/ and /i/, respectively. We will discuss the phonetic processes involved, and find parallels in languages genetically near and far. In addition, we will discuss the status of the change, through the quantitative analysis of three geographically and chronologically separated glossaries (Lorimer, Hallberg, Septfonds).
Learning Through Practice
Authors: Tanner Harold M. 
Published: May 2014

Abstract
American scholars of Chinese history have generally explained the outcome of China’s civil war (1945-1949) by reference to social, economic, and political factors rather than by looking at the conduct of the war itself. Recently, military historians have begun to shift the focus to Communist strategy and operations. However, the question of how the Chinese Communist forces made the transition from guerrilla to conventional warfare has still not received sufficient attention. Using Mao Zedong’s theories of guerrilla warfare and Peter Senge’s model of the “learning organization” to analyze Lin Biao’s conduct of the war against the Nationalists in China’s Northeast (Manchuria), we can better understand how the Northeast People’s Liberation Army transformed itself from a force characterized by “guerrilla-ism” to the powerful army capable of defeating Jiang Jieshi’s best troops. The Communists performed poorly when they first encountered American-trained Nationalist units in the Northeast. Lin Biao and his staff responded to defeat by devising principles of tactics which they applied in a series of campaigns beginning with the “Three Expeditions/Four Defenses” (winter 1946-47). The Communist forces continued to derive lessons from their experience and to incorporate those lessons into programs of education and training. As a result, they made great strides forward in terms of the coordination of infantry, artillery, and armor in order to be able to pull off a conventional combined arms operation on the scale of the Liao-Shen Campaign. The Communist forces would bring these strengths with them when they entered the Korean War in 1950.
Spatial Accuracy of Climate Networks: A Case Study in Nebraska
Authors: Coop Andrea J. , Hubbard Kenneth G. , Shulski Martha D. , You Jinsheng , Marx David B. 
Published: May 2014

AbstractClimate data are increasingly scrutinized for accuracy because of the need for reliable input for climate-related decision making and assessments of climate change. Over the last 30 years, vast improvements to U.S. instrumentation, data collection, and station siting have created more accurate data. This study explores the spatial accuracy of daily maximum and minimum air temperature data in Nebraska networks, including the U.S. Historical Climatology Network (HCN), the Automated Weather Data Network (AWDN), and the more recent U.S. Climate Reference Network (CRN). The spatial structure of temperature variations at the earth’s surface is compared for timeframes 2005–09 for CRN and AWDN and 1985–2005 for AWDN and HCN. Individual root-mean-square errors between candidate station and surrounding stations were calculated and used to determine the spatial accuracy of the networks. This study demonstrated that in the 5-yr analysis CRN and AWDN were of high spatial accuracy. For the 21-yr analysis the AWDN proved to have higher spatial accuracy (smaller errors) than the HCN for both maximum and minimum air temperature and for all months. In addition, accuracy was generally higher in summer months and the subhumid area had higher accuracy than did the semiarid area. The findings of this study can be used for Nebraska as an estimate of the uncertainty associated with using a weather station’s data at a decision point some distance from the station.
Persistent Contrails and Contrail Cirrus. Part I: Large-Eddy Simulations from Inception to Demise
Authors: Lewellen D. C. , Meza O. , Huebsch W. W. 
Published: May 2014

Abstract
Large-eddy simulations with size-resolved microphysics are used to model persistent aircraft contrails and contrail-induced cirrus from a few wing spans behind the aircraft until their demise after many hours. Schemes for dynamic local ice binning and updating coupled radiation dynamically as needed in individual columns were developed for numerical efficiency, along with a scheme for maintaining realistic ambient turbulence over long times. These capabilities are used to study some of the critical dynamics involved in contrail evolution and to explore the simulation features required for adequate treatment of different components. A “quasi 3D” approach is identified as a useful approximation of the full dynamics, reducing the computation to allow a larger parameter space to be studied. Ice crystal number loss involving competition between different crystal sizes is found to be significant for both young contrails and aging contrail cirrus. As a consequence, the sensitivity to the initial number of ice crystals in the contrail above a threshold is found to decrease significantly over time, and uncertainties in the ice deposition coefficient and Kelvin effect for ice crystals assume an increased importance. Atmospheric turbulence is found to strongly influence contrail properties and lifetime in some regimes. Water from fuel consumption is found to significantly reduce aircraft-wake-induced ice crystal loss in colder contrails. Ice crystal shape effects, coupled radiation, and precipitation dynamics are also considered. An extensive set of simulations exploring a large parameter space with this model are analyzed in a companion paper.