bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving Production of Malonyl Coenzyme A-Derived Metabolites by Abolishing Snf1-Dependent Regulation of Acc1
Authors: Shi Shuobo , Chen Yun , Siewers Verena , Nielsen Jens 
Published: May 2014

ABSTRACT

Acetyl coenzyme A (acetyl-CoA) carboxylase (ACCase) plays a central role in carbon metabolism and has been the site of action for the development of therapeutics or herbicides, as its product, malonyl-CoA, is a precursor for production of fatty acids and other compounds. Control of Acc1 activity in the yeast
Saccharomyces cerevisiae
occurs mainly at two levels, i.e., regulation of transcription and repression by Snf1 protein kinase at the protein level. Here, we demonstrate a strategy for improving the activity of ACCase in
S. cerevisiae
by abolishing posttranslational regulation of Acc1 via site-directed mutagenesis. It was found that introduction of two site mutations in Acc1, Ser659 and Ser1157, resulted in an enhanced activity of Acc1 and increased total fatty acid content. As Snf1 regulation of Acc1 is particularly active under glucose-limited conditions, we evaluated the effect of the two site mutations in chemostat cultures. Finally, we showed that our modifications of Acc1 could enhance the supply of malonyl-CoA and therefore successfully increase the production of two industrially important products derived from malonyl-CoA, fatty acid ethyl esters and 3-hydroxypropionic acid.

IMPORTANCE
ACCase is responsible for carboxylation of acetyl-CoA to produce malonyl-CoA, which is a crucial step in the control of fatty acid metabolism. ACCase opened the door for pharmaceutical treatments of obesity and diabetes as well as the development of new herbicides. ACCase is also recognized as a promising target for developing cell factories, as its malonyl-CoA product serves as a universal precursor for a variety of high-value compounds in white biotechnology. Yeast ACCase is a good model in understanding the enzyme’s catalysis, regulation, and inhibition. The present study describes the importance of protein phosphorylation in regulation of yeast ACCase and identifies potential regulation sites. This study led to the generation of a more efficient ACCase, which was applied in the production of two high-value compounds derived from malonyl-CoA, i.e., fatty acid ethyl esters that can be used as biodiesel and 3-hydroxypropionic acid that is considered an important platform chemical.
Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome. A randomised, prospective, controlled study
Authors: Schnorbus Boris , Daiber Andreas , Jurk Kerstin , Warnke Silke , König Jochem , Krahn Ulrike , Lackner Karl , Munzel Thomas , Gori Tommaso 
Published: May 2014

IntroductionParticularly in the setting of acute coronary syndromes, the interplay between vascular and platelet function has been postulated to have direct clinical implications. The present trial is designed to test the effect of clopidogrel, prasugrel and ticagrelor on multiple parameters of vascular function, platelet aggregation, oxidative and inflammatory stress before and up to 4 weeks after coronary artery stenting.Methods and analysisThe study is designed as a three-arm, parallel design, randomised, investigator-blinded study. Patients with unstable angina or non-ST elevation myocardial infarction undergoing coronary intervention with a drug-eluting stent will be randomised to receive 600 mg clopidogrel, 60 mg prasugrel or 180 mg ticagrelor followed by oral therapy with the same drug. The primary endpoint of the trial is the impact of antiplatelet treatments on endothelial function as assessed by flow-mediated dilation at 1 day, 1 week and 1 month in patients who have undergone stenting. Secondary endpoints include the impact of study medications on parameters of macrovascular and microvascular function, platelet reactivity, oxidative and inflammatory stress. The study recruitment is currently ongoing and, after an interim analysis which was performed at 50% of the initially planned population, it is planned to continue until July 2015.Ethics and disseminationThe protocol was approved by the local ethics committee. The trial will provide important pathophysiological insight on the relationship between platelet aggregation and endothelial function, two parameters that have been shown to influence patients’ prognosis.Trial registration numberClinicalTrials.gov Identifier:NCT01700322; EudraCT-Nr.: 2011-005305-73. Current V.1.3, from 24 February 2014.
Excavation-induced fractures network surrounding tunnel: properties and evolution under loading
Authors: De La Vaissière R. , Morel J. , Noiret A. , Côte P. , Helmlinger B. , Sohrabi R. , Lavanchy J.-M. , Leveau F. , Nussbaum C. , Morel J. 
Published: May 2014

Abstract
The investigation of the induced fractures network around seals in drifts or shafts, and in particular its evolution, is a key issue for the performance assessment of an underground waste repository. Within this framework, a specific experiment was designed and implemented in the Meuse/Haute-Marne Underground Research Laboratory (URL). This experiment, called CDZ (Compression of the Damaged Zone), is dedicated to studying the effect of mechanical compression within the induced fractures zone of the Callovo-Oxfordian claystone (COx). An unequalled level of knowledge in the 3D structure of the fractures network has been attained. A multidisciplinary approach was applied to observe not only the initial state of the induced fracture zone but also its evolution during a loading cycle. The investigations show that the fracture network which composed the Excavation Damaged Zone (EDZ) was initially interconnected and open for flow and then partially closed progressively following the increasing mechanical stress applied on the drift wall. Moreover, the evolution of the EDZ after unloading indicates a self-sealing process.
Off-Path TCP Injection Attacks
Authors: Gilad Yossi , Herzberg Amir 
Published: May 2014

We present practical off-path TCP injection attacks for connections between current, nonbuggy browsers and Web servers. The attacks allow
Web-cache poisoning
with malicious objects such as spoofed Web pages and scripts; these objects can be cached for a long period of time, exposing any user of that cache to
cross-site scripting
,
cross-site request forgery
, and
phishing
attacks.

In contrast to previous TCP injection attacks, we do not require MitM capabilities or malware running on the client machine. Instead, our attacks rely on a weaker assumption, that the user only enters a malicious Web site, but does not download or install any application. Our attacks exploit subtle details of the TCP and HTTP specifications, and features of legitimate (and very common) browser implementations. An empirical evaluation of our techniques with current versions of browsers shows that connections with most popular Web sites are vulnerable.
We conclude this work with practical client- and server-end defenses against our attacks.
Toward a Drug Development Path That Targets Metastatic Progression in Osteosarcoma
Authors: Khanna Chand , Fan Timothy M. , Gorlick Richard , Helman Lee J. , Kleinerman Eugenie S. , Adamson Peter C. , Houghton Peter J. , Tap William D. , Welch Danny R. , Steeg Patricia S. , Merlino Glenn , Sorensen Poul H.B. , Meltzer Paul , Kirsch David G. , Janeway Katherine A. , Weigel Brenda , Randall Lor , Withrow Stephen J , Paoloni Melissa , Kaplan Rosandra , Teicher Beverly A. , Seibel Nita L. , Smith Malcolm , Üren Aykut , Patel Shreyaskumar R. , Trent Jeffrey , Savage Sharon A. , Mirabello Lisa , Reinke Denise , Barkaukas Donald A. , Krailo Mark , Bernstein Mark 
Published: May 2014

Abstract
Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a “Perspective” that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting. Clin Cancer Res; 20(16); 4200–9. ©2014 AACR.
TP53 Mutation Spectrum in Breast Cancer Is Subtype Specific and Has Distinct Prognostic Relevance
Authors: Silwal-Pandit Laxmi , Vollan Hans Kristian Moen , Chin Suet-Feung , Rueda Oscar M. , McKinney Steven , Osako Tomo , Quigley David A. , Kristensen Vessela N. , Aparicio Samuel , Børresen-Dale Anne-Lise , Caldas Carlos , Langerød Anita 
Published: May 2014

Abstract
Purpose: In breast cancer, the TP53 gene is frequently mutated and the mutations have been associated with poor prognosis. The prognostic impact of the different types of TP53 mutations across the different molecular subtypes is still poorly understood. Here, we characterize the spectrum and prognostic significance of TP53 mutations with respect to the PAM50 subtypes and integrative clusters (IC).
Experimental Design: TP53 mutation status was obtained for 1,420 tumor samples from the METABRIC cohort by sequencing all coding exons using the Sanger method.
Results: TP53 mutations were found in 28.3% of the tumors, conferring a worse overall and breast cancer-specific survival [HR = 2.03; 95% confidence interval (CI), 1.65–2.48, P &lt; 0.001], and were also found to be an independent marker of poor prognosis in estrogen receptor-positive cases (HR = 1.86; 95% CI, 1.39–2.49, P &lt; 0.001). The mutation spectrum of TP53 varied between the breast cancer subtypes, and individual alterations showed subtype-specific association. TP53 mutations were associated with increased mortality in patients with luminal B, HER2-enriched, and normal-like tumors, but not in patients with luminal A and basal-like tumors. Similar observations were made in ICs, where mutation associated with poorer outcome in IC1, IC4, and IC5. The combined effect of TP53 mutation, TP53 LOH, and MDM2 amplification on mortality was additive.
Conclusion: This study reveals that TP53 mutations have different clinical relevance in molecular subtypes of breast cancer, and suggests diverse roles for TP53 in the biology underlying breast cancer development. Clin Cancer Res; 20(13); 3569–80. ©2014 AACR.
Restoration of miR17/20a in Solid Tumor Cells Enhances the Natural Killer Cell Antitumor Activity by Targeting Mekk2
Authors: Jiang Hong , Wang Ping , Li Xiaohua , Wang Qilong , Deng Zhong-Bin , Zhuang Xiaoying , Mu Jingyao , Zhang Lifeng , Wang Baomei , Yan Jun , Miller Donald , Zhang Huang-Ge 
Published: May 2014

Abstract
Aberrant microRNA (miRNA) expression has been identified in various human solid cancers. However, whether the levels of miRNA expression in tumor cells have any effect on tumor progression has not been determined. In this proof-of-concept study, the restoration of high-level expression of the miR17–92 cluster of miRNAs reveals its function as a tumor suppressor in murine solid cancer cells. Specifically, genetically engineered expression of higher levels of miR17/20a in the miR17–92 cluster in both murine breast cancer and colon cancer cells triggered natural killer (NK)–cell recognition by inhibiting the expression of MHC class I (H-2D) through the Mekk2–Mek5–Erk5 pathway. Results from the mouse tumor studies were recapitulated using samples of human solid tumors. Together, these data indicate that miR17/20a miRNAs function as tumor suppressors by reprogramming tumor cells for NK cell-mediated cytotoxicity. Cancer Immunol Res; 2(8); 789–99. ©2014 AACR.
Randomized Comparison Between Polymer-Free Versus Polymer-Based Paclitaxel-Eluting Stent
Authors: Shiratori Yoshitaka , Cola Clarissa , Brugaletta Salvatore , Alvarez-Contreras Luis , Martín-Yuste Victoria , del Blanco Bruno García , Ruiz-Salmeron Rafael , Díaz Jose , Pinar Eduardo , Martí Vicens , García-Picart Juan , Sabaté Manel 
Published: May 2014

Background—
Most drug-eluting stents currently in use are coated with a polymer carrying the drug that is released for several weeks. However, a durable polymer may provoke hypersensitive reaction, delayed artery healing, and eventually stent thrombosis. The aim of this study was to investigate the safety and efficacy of a polymer-free paclitaxel-eluting stent (PF-PES) versus a polymer-based PES (PB-PES).

Methods and Results—

Eligible patients undergoing percutaneous coronary intervention were randomized 1:1 to receive either PF-PES or PB-PES. The primary end point was late loss at 9 months. Intravascular ultrasound analysis at 9 months and final 2-year clinical follow-up were also performed. From October 2007 to April 2009, 164 patients were enrolled and randomized into 2 groups (PF-PES: n=84; PB-PES: n=80). Mean in-stent lumen loss was 0.90±0.59 mm for PF-PES and 0.49±0.52 mm for PB-PES (
P
<0.001). Mean neointimal area by intravascular ultrasound was higher in PF-PES than in PB-PES (1.42±1.09 versus 0.51±0.61 mm
2
;
P
<0.001). At 2 years, a composite end point of all-cause death, any myocardial infarction, and target vessel revascularization occurred in 36.9% for PF-PES and 16.3% for PB-PES (
P
=0.004), mainly driven by a higher rate of target vessel revascularization (PF-PES: 35.7%; PB-PES: 13.8%;
P
=0.001). One late stent thrombosis was observed in PF-PES.

Conclusions—
Compared with PB-PES, PF-PES was associated with increased neointimal proliferation and subsequent clinical restenosis. Polymer plays an essential role in the performance of drug-eluting stents.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01375855.
Long-Term Clinical Outcomes After Everolimus- and Sirolimus-Eluting Coronary Stent Implantation
Authors: Shiomi Hiroki , Kozuma Ken , Morimoto Takeshi , Igarashi Keiichi , Kadota Kazushige , Tanabe Kengo , Morino Yoshihiro , Akasaka Takashi , Abe Mitsuru , Suwa Satoru , Muramatsu Toshiya , Kobayashi Masakazu , Dai Kazuoki , Nakao Koichi , Uematsu Masaaki , Tarutani Yasuhiro , Fujii Kenshi , Simonton Charles A. , Kimura Takeshi 
Published: May 2014

Background—
Long-term clinical outcomes of everolimus-eluting stent (EES) compared with sirolimus-eluting stent (SES) have not been evaluated fully yet, especially whether EES implantation could positively affect late adverse events reported after SES implantation occurring >1 year.

Methods and Results—

In this all-comer prospective multicenter randomized open-label trial, 3196 patients were assigned randomly to implant either EES (n=1596) or SES (n=1600). At 3 years, EES was noninferior to SES on the primary safety end point (all-cause death or myocardial infarction; 10.1% versus 11.5%; noninferiority
P
<0.001; and superiority
P
=0.19). Cumulative incidence of definite stent thrombosis was low and was not significantly different between the 2 groups (0.5% versus 0.6%;
P
=0.81). There was no significant difference in the efficacy end point of target-lesion revascularization between the EES and SES groups (6.6% versus 7.9%;
P
=0.16). However, the cumulative incidence of target-lesion failure (cardiac death/target-vessel myocardial infarction/ischemia-driven target-lesion revascularization) was significantly lower in the EES group than in the SES group (8.8% versus 11.4%;
P
=0.01). By a landmark analysis at 1 year, the cumulative incidence of very late stent thrombosis and late target-lesion revascularization was not significantly different between the 2 groups (0.2% versus 0.2%;
P
=0.99 and 2.2% versus 2.9%;
P
=0.21, respectively).

Conclusions—
The efficacy and safety outcomes for this trial after EES implantation remained comparable with those after SES implantation through 3-year follow-up. However, improvement of clinical outcome after EES implantation compared with SES implantation was suggested by the significantly lower cumulative incidences of target-lesion failure, which has been the most widely used primary end point in the stent-versus-stent trials.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01035450.
Use of Coronary Artery Calcium Testing to Guide Aspirin Utilization for Primary Prevention: Estimates From the Multi-Ethnic Study of Atherosclerosis
Authors: Miedema Michael D. , Duprez Daniel A. , Misialek Jeffrey R. , Blaha Michael J. , Nasir Khurram , Silverman Michael G. , Blankstein Ron , Budoff Matthew J. , Greenland Philip , Folsom Aaron R. 
Published: May 2014

Background—
Aspirin for the primary prevention of coronary heart disease (CHD) is only recommended for individuals at high risk for CHD although the majority of CHD events occur in individuals who are at low to intermediate risk.

Methods and Results—
To estimate the potential of coronary artery calcium (CAC) scoring to guide aspirin use for primary prevention of CHD, we studied 4229 participants from the Multi-Ethnic Study of Atherosclerosis who were not on aspirin at baseline and were free of diabetes mellitus. Using data from median 7.6-year follow-up, 5-year number-needed-to-treat estimations were calculated by applying an 18% relative CHD reduction to the observed event rates. This was contrasted to 5-year number-needed-to-harm estimations based on the risk of major bleeding reported in an aspirin meta-analysis. Results were stratified by a 10% 10-year CHD Framingham Risk Score (FRS). Individuals with CAC≥100 had an estimated net benefit with aspirin regardless of their traditional risk status (estimated 5-year number needed to treat of 173 for individuals <10% FRS and 92 for individuals ≥10% FRS, estimated 5-year number needed to harm of 442 for a major bleed). Conversely, individuals with zero CAC had unfavorable estimations (estimated 5-year number needed to treat of 2036 for individuals <10% FRS and 808 for individuals ≥10% FRS, estimated 5-year number needed to harm of 442 for a major bleed). Sex-specific and age-stratified analyses showed similar results.

Conclusions—
For the primary prevention of CHD, Multi-Ethnic Study of Atherosclerosis participants with CAC≥100 had favorable risk/benefit estimations for aspirin use while participants with zero CAC were estimated to receive net harm from aspirin.
Reproduction, growth, mortality and exploitation rate of Penaeus semisulcatus De Haan, 1844 (Decapoda, Penaeidae) from Iskenderun Bay (northeastern Mediterranean)
Authors: Manasirli M. , Kiyaga V. B. , Perker M. 
Published: May 2014

Penaeus semisulcatusDe Haan, 1844 was collected in Iskenderun Bay, from November 2009 to October 2010, by monthly bottom trawl operations. The male : female ratio was determined as 1 : 1, and the spawning period was found to be from January to June, while peaking two times a year, namely in January and in March. The andKfor males were estimated at 42.00 mm CL and 1.8 year−1, respectively, and for the females 63.00 mm CL and 1.90 a year−1. Using the andKestimates for both sexes, the instantaneous rate of natural mortality (M) for males and females were calculated as 1.50 and 1.97 year−1, respectively, at 22°C water temperature on average. The instantaneous rates of total mortalities (Z) were 4.04 year−1for males and 6.39 year−1for females, and fishing mortalities (F) for males were 2.24 year−1and for females 4.42 year−1. Thus, the exploitation rates (E) were 0.65 year−1and 0.69 year−1for males and females, respectively. The results clearly indicate overfishing forP. semisulcatusin the study area.
Ceratothoa retusa (Schiœdte & Meinert, 1883) (Isopoda, Cymothoidae), a variable species of fish parasitic marine isopod from the Indian Ocean
Authors: Hadfield Kerry A. , Bruce Niel L. , Szinetár Csaba , Smit Nico J. 
Published: May 2014

Ceratothoa retusa (Schiœdte & Meinert, 1883) is redescribed from the lectotype (here designated) collected from Mozambique, and the range is extended to include the Gulf of Suez in the Red Sea. Ceratothoa retusa is distinctive within the genus with a manifestly small head deeply immersed into pereonite 1, which has prominent, but variable, projecting anterolateral margins. Ceratothoa retusa has a tropical and subtropical Indian Ocean distribution, extending from eastern Africa (and now the Red Sea) eastwards to northern Australia and Indonesia. The only known hosts are the halfbeaks, Hemiramphus far (Forsskål, 1775) and H. robustus Günther, 1866 (Hemiraphidae).
Competing Competences in Adjudication: Reviewing the Relationship between the ECOWAS Court and National Courts
Authors: Ojomo Edefe 
Published: May 2014

Abstract
This article argues that regional access to justice in West Africa provides an alternative to national access to justice through the institution of the ecowas Community Court of Justice. This gives West Africans the option of pursuing justice in national judicial institutions or in the ecowas Court. Therefore, it reveals a situation where both systems compete for effectiveness in meeting the justice demands of citizens while also encouraging greater complementarity in their institutional activities.
الخط الكوفي على عمائر في آسيا الوسطى النشأة والتطور (Kufic Script on the Buildings of Central Asia: The Rise and Development)
Authors: إبراهيم عبيد شبل 
Published: May 2014

Kufic script played an important and effective role in the decoration of many buildings and applied arts in the Eastern Islamic World in general, and in Central Asia specifically, as it was suitable for decorative purposes especially at the top of Arabic letters, which were flexible in decoration, thus this script was suitable for any surface. The studies which dealt with Kufic script on buildings according to that perspective were few, and concentrated on the study of this script on a separate building or on the buildings of a city, or carrying out a survey of the monumental inscriptions on early buildings in Iran and Central Asia. The study of Kufic script on the building of Central Asia and its rise and development was very important, as well as understanding the contributions of the artists in the development of its styles in that area. The study aims at the following: - Follow stages of development of Kufic script on the building of Central Asia, the rise of each stage and the extent of development; - Compare the development of the script and its similarities on the applied arts in the same area, showing the similarities and differences between them; - Show which was earlier in the appearance of Kufic script, Iran or Central Asia; - Highlight the most important Kufic script inscribed on the buildings of Central Asia. They varied between simple Kufic script which appeared at the base of the minaret of Prince Abu l’abass Mamoun ibn Khorezm Shah at Urgansh dating 401AH / 1010-1011CE.
(Please note that this article is in Arabic)