bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Coronavirus 229E Remains Infectious on Common Touch Surface Materials
Authors: Warnes Sarah L. , Little Zoë R. , Keevil C. William 
Published: November 2015

ABSTRACT
The evolution of new and reemerging historic virulent strains of respiratory viruses from animal reservoirs is a significant threat to human health. Inefficient human-to-human transmission of zoonotic strains may initially limit the spread of transmission, but an infection may be contracted by touching contaminated surfaces. Enveloped viruses are often susceptible to environmental stresses, but the human coronaviruses responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) have recently caused increasing concern of contact transmission during outbreaks. We report here that pathogenic human coronavirus 229E remained infectious in a human lung cell culture model following at least 5 days of persistence on a range of common nonbiocidal surface materials, including polytetrafluoroethylene (Teflon; PTFE), polyvinyl chloride (PVC), ceramic tiles, glass, silicone rubber, and stainless steel. We have shown previously that noroviruses are destroyed on copper alloy surfaces. In this new study, human coronavirus 229E was rapidly inactivated on a range of copper alloys (within a few minutes for simulated fingertip contamination) and Cu/Zn brasses were very effective at lower copper concentration. Exposure to copper destroyed the viral genomes and irreversibly affected virus morphology, including disintegration of envelope and dispersal of surface spikes. Cu(I) and Cu(II) moieties were responsible for the inactivation, which was enhanced by reactive oxygen species generation on alloy surfaces, resulting in even faster inactivation than was seen with nonenveloped viruses on copper. Consequently, copper alloy surfaces could be employed in communal areas and at any mass gatherings to help reduce transmission of respiratory viruses from contaminated surfaces and protect the public health.

IMPORTANCE
Respiratory viruses are responsible for more deaths globally than any other infectious agent. Animal coronaviruses that “host jump” to humans result in severe infections with high mortality, such as severe acute respiratory syndrome (SARS) and, more recently, Middle East respiratory syndrome (MERS). We show here that a closely related human coronavirus, 229E, which causes upper respiratory tract infection in healthy individuals and serious disease in patients with comorbidities, remained infectious on surface materials common to public and domestic areas for several days. The low infectious dose means that this is a significant infection risk to anyone touching a contaminated surface. However, rapid inactivation, irreversible destruction of viral RNA, and massive structural damage were observed in coronavirus exposed to copper and copper alloy surfaces. Incorporation of copper alloy surfaces in conjunction with effective cleaning regimens and good clinical practice could help to control transmission of respiratory coronaviruses, including MERS and SARS.
In Vitro
CRISPR/Cas9 System for Efficient Targeted DNA Editing
Authors: Liu Yunkun , Tao Weixin , Wen Shishi , Li Zhengyuan , Yang Anna , Deng Zixin , Sun Yuhui 
Published: November 2015

ABSTRACT

The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system, an RNA-guided nuclease for specific genome editing
in vivo
, has been adopted in a wide variety of organisms. In contrast, the
in vitro
application of the CRISPR/Cas9 system has rarely been reported. We present here a highly efficient

i
n vitro

C
RISPR/Cas9-mediated
e
diting (ICE) system that allows specific refactoring of biosynthetic gene clusters in
Streptomyces
bacteria and other large DNA fragments. Cleavage by Cas9 of circular pUC18 DNA was investigated here as a simple model, revealing that the 3′→5′ exonuclease activity of Cas9 generates errors with 5 to 14 nucleotides (nt) randomly missing at the editing joint. T4 DNA polymerase was then used to repair the Cas9-generated sticky ends, giving substantial improvement in editing accuracy. Plasmid pYH285 and cosmid 10A3, harboring a complete biosynthetic gene cluster for the antibiotics RK-682 and holomycin, respectively, were subjected to the ICE system to delete the
rkD
and
homE
genes in frame. Specific insertion of the ampicillin resistance gene (
bla
) into pYH285 was also successfully performed. These results reveal the ICE system to be a rapid, seamless, and highly efficient way to edit DNA fragments, and a powerful new tool for investigating and engineering biosynthetic gene clusters.

IMPORTANCE
Recent improvements in cloning strategies for biosynthetic gene clusters promise rapid advances in understanding and exploiting natural products in the environment. For manipulation of such biosynthetic gene clusters to generate valuable bioactive compounds, efficient and specific gene editing of these large DNA fragments is required. In this study, a highly efficient
in vitro
DNA editing system has been established. When combined with end repair using T4 DNA polymerase, Cas9 precisely and seamlessly catalyzes targeted editing, including in-frame deletion or insertion of the gene(s) of interest. This
in vitro
CRISPR editing (ICE) system promises a step forward in our ability to engineer biosynthetic pathways.
The kinematic linkage of the Dent, Craven and related faults of Northern England
Authors: Thomas C.W. , Woodcock N.H. 
Published: November 2015

New mapping of the southern part of the Dent Fault reveals three segments, each 5–6 km long, overlapping at two left-stepping zones 1–2 km wide. The main fault strands probably dip steeply WNW. A faulted footwall syncline in Carboniferous strata indicates reverse dip-slip, with a stratigraphic throw of at least 750 m. Locally developed plunging folds and imbricate fault duplexes developed at fault bends reveal a strike-slip component, indicated to be sinistral from limited slickenline data. Silurian strata in the hanging wall lack the Variscan folds observed further north. The northern overstep hosts up-faulted slivers of older Silurian and Ordovician rocks. The southern overstep zone hosts a younger faulted block compatible with releasing kinematics in sinistral strike-slip.
The Dent Fault converges at its southern end with the Barbon Fault; an upfaulted wedge of Silurian strata lies between them near the branch point. The two faults swing southeastward, joining the Craven fault system via splays and linkages. Regionally, the Dent and Barbon faults form the innermost pair of a fan of ~N–S striking faults splaying off the northwest end of the South Craven–Morley-Campsall Fault System around the southwestern corner of the Askrigg Block.
The kinematics of the Dent, Barbon and Craven faults fit shortening orientated NNW–SSE during late Carboniferous Variscan deformation. The rigid Askrigg Block focussed displacements around its west and south margins where fault and fold orientations were influenced by pre-existing structures, at least Acadian in age to the west and early Carboniferous to the south.
Combined MYC Activation and Pten Loss Are Sufficient to Create Genomic Instability and Lethal Metastatic Prostate Cancer
Authors: Hubbard Gretchen K. , Mutton Laura N. , Khalili May , McMullin Ryan P. , Hicks Jessica L. , Bianchi-Frias Daniella , Horn Lucas A. , Kulac Ibrahim , Moubarek Michael S. , Nelson Peter S. , Yegnasubramanian Srinivasan , De Marzo Angelo M. , Bieberich Charles J. 
Published: November 2015

Abstract
Genetic instability, a hallmark feature of human cancers including prostatic adenocarcinomas, is considered a driver of metastasis. Somatic copy number alterations (CNA) are found in most aggressive primary human prostate cancers, and the overall number of such changes is increased in metastases. Chromosome 10q23 deletions, encompassing PTEN, and amplification of 8q24, harboring MYC, are frequently observed, and the presence of both together portends a high risk of prostate cancer-specific mortality. In extant genetically engineered mouse prostate cancer models (GEMM), isolated MYC overexpression or targeted Pten loss can each produce early prostate adenocarcinomas, but are not sufficient to induce genetic instability or metastases with high penetrance. Although a previous study showed that combining Pten loss with focal MYC overexpression in a small fraction of prostatic epithelial cells exhibits cooperativity in GEMMs, additional targeted Tp53 disruption was required for formation of metastases. We hypothesized that driving combined MYC overexpression and Pten loss using recently characterized Hoxb13 transcriptional control elements that are active in prostate luminal epithelial cells would induce the development of genomic instability and aggressive disease with metastatic potential. Neoplastic lesions that developed with either MYC activation alone (Hoxb13-MYC) or Pten loss alone (Hoxb13-Cre∣PtenFl/Fl) failed to progress beyond prostatic intraepithelial neoplasia and did not harbor genomic CNAs. By contrast, mice with both alterations (Hoxb13-MYC∣Hoxb13-Cre∣PtenFl/Fl, hereafter, BMPC mice) developed lethal adenocarcinoma with distant metastases and widespread genome CNAs that were independent of forced disruption of Tp53 and telomere shortening. BMPC cancers lacked neuroendocrine or sarcomatoid differentiation, features uncommon in human disease but common in other models of prostate cancer that metastasize. These data show that combined MYC activation and Pten loss driven by the Hoxb13 regulatory locus synergize to induce genomic instability and aggressive prostate cancer that phenocopies the human disease at the histologic and genomic levels. Cancer Res; 76(2); 283–92. ©2015 AACR.
Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma
Authors: De Rienzo Assunta , Archer Michael A. , Yeap Beow Y. , Dao Nhien , Sciaranghella Daniele , Sideris Antonios C. , Zheng Yifan , Holman Alexander G. , Wang Yaoyu E. , Dal Cin Paola S. , Fletcher Jonathan A. , Rubio Renee , Croft Larry , Quackenbush John , Sugarbaker Peter E. , Munir Kiara J. , Battilana Jesse R. , Gustafson Corinne E. , Chirieac Lucian R. , Ching Soo Meng , Wong James , Tay Liang Chung , Rudd Stephen , Hercus Robert , Sugarbaker David J. , Richards William G. , Bueno Raphael 
Published: November 2015

Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer that occurs more frequently in men, but is associated with longer survival in women. Insight into the survival advantage of female patients may advance the molecular understanding of MPM and identify therapeutic interventions that will improve the prognosis for all MPM patients. In this study, we performed whole-genome sequencing of tumor specimens from 10 MPM patients and matched control samples to identify potential driver mutations underlying MPM. We identified molecular differences associated with gender and histology. Specifically, single-nucleotide variants of BAP1 were observed in 21% of cases, with lower mutation rates observed in sarcomatoid MPM (P &lt; 0.001). Chromosome 22q loss was more frequently associated with the epithelioid than that nonepitheliod histology (P = 0.037), whereas CDKN2A deletions occurred more frequently in nonepithelioid subtypes among men (P = 0.021) and were correlated with shorter overall survival for the entire cohort (P = 0.002) and for men (P = 0.012). Furthermore, women were more likely to harbor TP53 mutations (P = 0.004). Novel mutations were found in genes associated with the integrin-linked kinase pathway, including MYH9 and RHOA. Moreover, expression levels of BAP1, MYH9, and RHOA were significantly higher in nonepithelioid tumors, and were associated with significant reduction in survival of the entire cohort and across gender subgroups. Collectively, our findings indicate that diverse mechanisms highly related to gender and histology appear to drive MPM. Cancer Res; 76(2); 319–28. ©2015 AACR.
The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma
Authors: Infarinato Nicole R. , Park Jin H. , Krytska Kateryna , Ryles Hannah T. , Sano Renata , Szigety Katherine M. , Li Yimei , Zou Helen Y. , Lee Nathan V. , Smeal Tod , Lemmon Mark A. , Mossé Yael P. 
Published: November 2015

Abstract
Neuroblastomas harboring activating point mutations in anaplastic lymphoma kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain mutations conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target intractable ALK variants such as F1174L. We find that PF-06463922 has high potency across ALK variants and inhibits ALK more effectively than crizotinib in vitro. Most importantly, PF-06463922 induces complete tumor regression in both crizotinib-resistant and crizotinib-sensitive xenograft mouse models of neuroblastoma, as well as in patient-derived xenografts harboring the crizotinib-resistant F1174L or F1245C mutations. These studies demonstrate that PF-06463922 has the potential to overcome crizotinib resistance and exerts unprecedented activity as a single targeted agent against F1174L and F1245C ALK-mutated xenograft tumors, while also inducing responses in an R1275Q xenograft model. Taken together, these results provide the rationale to move PF-06463922 into clinical trials for treatment of patients with ALK-mutated neuroblastoma.
Significance: The next-generation ALK/ROS1 inhibitor PF-06463922 exerts unparalleled activity in ALK-driven neuroblastoma models with primary crizotinib resistance. Our biochemical and in vivo data provide the preclinical rationale for fast-tracking the development of this agent in children with relapsed/refractory ALK-mutant neuroblastoma. Cancer Discov; 6(1); 96–107. ©2015 AACR.
See related commentary by Versteeg and George, p. 20.
This article is highlighted in the In This Issue feature, p. 1
Individualized Risk Communication and Outreach for Primary Cardiovascular Disease Prevention in Community Health Centers
Authors: Persell Stephen D. , Brown Tiffany , Lee Ji Young , Shah Shreya , Henley Eric , Long Timothy , Luther Stephanie , Lloyd-Jones Donald M. , Jean-Jacques Muriel , Kandula Namratha R. , Sanchez Thomas , Baker David W. 
Published: November 2015

Background—
Many eligible primary cardiovascular disease prevention candidates are not treated with statins. Electronic health record data can identify patients with increased cardiovascular disease risk.

Methods and Results—
We performed a pragmatic randomized controlled trial at community health centers in 2 states. Participants were men aged ≥35 years and women ≥45 years, without cardiovascular disease or diabetes mellitus, and with a 10-year risk of coronary heart disease of at least 10%. The intervention group received telephone and mailed outreach, individualized based on patients’ cardiovascular disease risk and uncontrolled risk factors, provided by lay health workers. Main outcomes included: documented discussion of medication treatment for cholesterol with a primary care clinician, receipt of statin prescription within 6 months, and low-density lipoprotein (LDL)-cholesterol repeated and at least 30 mg/dL lower than baseline within 1 year. Six hundred forty-six participants (328 and 318 in the intervention and control groups, respectively) were included. At 6 months, 26.8% of intervention and 11.6% of control patients had discussed cholesterol treatment with a primary care clinician (odds ratio, 2.79; [95% confidence interval, 2.25–3.46]). Statin prescribing occurred for 10.1% in the intervention group and 6.0% in the control group (odds ratio, 1.76; [95% confidence interval, 0.90–3.45]). The cholesterol outcome did not differ, and the majority of patients did not repeat lipid levels during follow-up.

Conclusions—
Risk communication and lay outreach increased cholesterol treatment discussions with primary care clinicians. However, most discussions did not result in statin prescribing. For outreach to be successful, it should be combined with interventions to encourage clinicians to follow contemporary risk-based cholesterol treatment guidelines.

Clinical Trial Registration—

URL:
http://www.clincialtrials.gov
. Unique identifier: NCT01610609.
Health and Economic Implications of National Treatment Coverage for Cardiovascular Disease in India
Authors: Basu Sanjay , Bendavid Eran , Sood Neeraj 
Published: November 2015

Background—
Whether to cover cardiovascular disease costs is an increasingly pressing question for low- and middle-income countries. We sought to identify the impact of expanding national insurance to cover primary prevention, secondary prevention, and tertiary treatment for cardiovascular disease in India.

Methods and Results—
We incorporated data from coverage experiments into a validated microsimulation model of myocardial infarction and stroke in India to evaluate the cost-effectiveness of alternate coverage strategies. Coverage of primary prevention alone saved 3.6 million disability-adjusted life-years (DALY) per annum at an incremental cost-effectiveness ratio of $469 per DALY averted when compared with the status quo of no coverage. Coverage of primary and secondary preventions was dominated by a strategy of covering primary prevention and tertiary treatment, which prevented 6.6 million DALYs at an incremental cost-effectiveness ratio of $2241 per DALY averted, when compared with that of primary prevention alone. The combination of all 3 categories yielded the greatest impact at an incremental cost per DALY averted of $5588 when compared with coverage of primary prevention plus tertiary treatment. When compared with the status quo of no coverage, coverage of all 3 categories of prevention/treatment yielded an incremental cost-effectiveness ratio of $1331 per DALY averted. In sensitivity analyses, coverage of primary preventive treatments remained cost-effective even if adherence and access to therapy were low, but tertiary coverage would require avoiding unnecessary procedures to remain cost-effective.

Conclusions—
Coverage of all 3 major types of cardiovascular treatment would be expected to have high impact and reasonable cost-effectiveness in India across a broad spectrum of access and adherence levels.
Cost-Effectiveness of Screening for Primary Aldosteronism and Subtype Diagnosis in the Resistant Hypertensive Patients
Authors: Lubitz Carrie C. , Economopoulos Konstantinos P. , Sy Stephen , Johanson Colden , Kunzel Heike E. , Reincke Martin , Gazelle G. Scott , Weinstein Milton C. , Gaziano Thomas A. 
Published: November 2015

Background—
Primary aldosteronism (PA) is a common and underdiagnosed disease with significant morbidity potentially cured by surgery. We aim to assess if the long-term cardiovascular benefits of identifying and treating surgically correctable PA outweigh the upfront increased costs in patients at the time patients are diagnosed with resistant hypertension (RH).

Methods and Results—
A decision-analytic model compares aggregate costs and systolic blood pressure changes of 6 recommended or implemented diagnostic strategies for PA in a simulated population of at-risk RH patients. We also evaluate a 7th “treat all” strategy wherein all patients with RH are treated with a mineralocorticoid-receptor antagonist without further testing at RH diagnosis. Changes in systolic blood pressure are subsequently converted into gains in quality-adjusted life years (QALYs) by applying National Health and Nutrition Examination Survey data on concomitant risk factors to an existing cardiovascular disease simulation model. QALYs and lifetime costs were then used to calculate incremental cost-effectiveness ratios for the competing strategies. The incremental cost-effectiveness ratio for the strategy of computerized tomography (CT) followed by adrenal venous sampling (AVS) was $82 000/QALY compared with treat all. Incremental cost-effectiveness ratios for CT alone and AVS alone were $200 000/QALY and $492 000/QALY; the other strategies were more costly and less effective. Integrating differential patient-reported health-related quality of life adjustments for patients with PA, and incremental cost-effectiveness ratios for screening patients with CT followed by AVS, CT alone, and AVS alone were $52 000/QALY, $114 000/QALY, and $269 000/QALY gained.

Conclusions—
CT scanning followed by AVS was a cost-effective strategy to screen for PA among patients with RH.
Estimating Weight of Patients With Acute Stroke When Dosing for Thrombolysis
Authors: Barrow Tom , Khan Muhammad S. , Halse Omid , Bentley Paul , Sharma Pankaj 
Published: November 2015

Background and Purpose—
Estimating patient weight forms an important part of emergency ischemic stroke management guiding the dose of alteplase (tissue-type plasminogen activator). Weighing patients with stroke can be logistically challenging and time consuming, potentially delaying treatment times. We aimed to assess the reliability of approximating weight to determine recombinant tissue-type plasminogen activator dose and whether potential inaccurate dosing affected patient outcomes.

Methods—
Two hundred forty-two consecutive patients were studied at a large tertiary stroke center. Estimated and actual measured weight, alteplase dose, and pre-and post-modified Rankin Scale/National Institute of Health Stroke Scale outcome were recorded for each patient.

Results—

Clinicians significantly underestimated weights by 1.13 kg (range, −43 to +18 kg; SD, 7.14;
P
<0.05). The difference between estimated and actual weight proved to be greatest in the heaviest third of patients (−4.51 kg; SD, 8.35;
P
<0.001), resulting in 19.7% of patients receiving a deviation of at least 10% from the recommended recombinant tissue-type plasminogen activator dose. On average, the heaviest third of patients received an underdose of 0.04 mg/kg and were found to have a greater baseline National Institute of Health Stroke Scale on admission (
P
<0.001). National Institute of Health Stroke Scale improvement by day 7 or on discharge was significantly reduced in patients weighing >78 kg (National Institute of Health Stroke Scale score difference of 4.0 points,
P
<0.05) than in lighter individuals.

Conclusions—
Clinicians are poor at approximating the weights of patients with stroke in the acute setting, especially when patients lie at the extremes of weight. Beds capable of weighing patients should be mandated in emergency rooms for patients with acute stroke.
A new species and a key to 19 species of the genus Traulia Stål, 1873 (Orthoptera: Catantopidae) from China
Authors: CAO CHENG-QUAN , SHI JIAN-PING , YIN ZHAN 
Published: November 2015

A new species of the genus Traulia Stål, 1873 namely Traulia xiai sp. nov. is described from China in this paper. The new species is similar to Traulia brachypeza Bi, 1986, but differs from the latter by the short tegmina, reaching the middle of third abdominal tergite only. The new species is also similar to Traulia ornate Shiraki, 1910, but differs from the latter by hind tibia all orange red and furculae of male absent. We think that Traulia yifengensis Wang, Xiangyu & Liu, 1997 is a valid species, not a synonym of Traulia brachypeza Bi, 1985 by Wei & Huang (2012), because the tegmina of Traulia yifengensis is very long, extending over the end of abdomen distinctly. A key to 19 species of this genus from China is also given in this paper. The type specimens are deposited in the National Museum of Natural Science, Taichung, Taiwan, China.