bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of NEDD8-Activating Enzyme Induces Rereplication and Apoptosis in Human Tumor Cells Consistent with Deregulating CDT1 Turnover
Authors: Milhollen Michael A. , Narayanan Usha , Soucy Teresa A. , Veiby Petter O. , Smith Peter G. , Amidon Benjamin 
Published: April 2011

Abstract
Loss of NEDD8-activating enzyme (NAE) function by siRNA knockdown or inhibition by the small molecule NAE inhibitor MLN4924 leads to increased steady-state levels of direct Cullin-RING ligase (CRL) substrates by preventing their ubiquitination and proteasome-dependent degradation. Many of these CRL substrates are involved in cell cycle progression, including a critical DNA replication licensing factor CDT1. Cell cycle analysis of asynchronous and synchronous cultures after NAE inhibition revealed effects on cell cycle distribution and activation of DNA break repair signaling pathways similar to that reported for CDT1 overexpression. The siRNA knockdown of cullins critical for the turnover of CDT1 recapitulated the aberrant rereplication phenotype while CDT1 knockdown was suppressing. Although NAE inhibition leads to deregulation of many CRL substrates, these data demonstrate that CDT1 accumulation mediates the DNA rereplication phenotype resulting from loss of NAE function. DNA rereplication is an unrecoverable cellular insult and the small molecule inhibitor MLN4924, currently in phase I trials, represents an unprecedented opportunity to explore this mechanism of cytotoxicity for the treatment of cancer. Cancer Res; 71(8); 3042–51. ©2011 AACR.
IRF8 Regulates Acid Ceramidase Expression to Mediate Apoptosis and Suppresses Myelogeneous Leukemia
Authors: Hu Xiaolin , Yang Dafeng , Zimmerman Mary , Liu Feiyan , Yang Jine , Kannan Swati , Burchert Andreas , Szulc Zdzislaw , Bielawska Alicja , Ozato Keiko , Bhalla Kapil , Liu Kebin 
Published: April 2011

Abstract
IFN regulatory factor 8 (IRF8) is a key transcription factor for myeloid cell differentiation and its expression is frequently lost in hematopoietic cells of human myeloid leukemia patients. IRF8-deficient mice exhibit uncontrolled clonal expansion of undifferentiated myeloid cells that can progress to a fatal blast crisis, thereby resembling human chronic myelogeneous leukemia (CML). Therefore, IRF8 is a myeloid leukemia suppressor. Whereas the understanding of IRF8 function in CML has recently improved, the molecular mechanisms underlying IRF8 function in CML are still largely unknown. In this study, we identified acid ceramidase (A-CDase) as a general transcription target of IRF8. We demonstrated that IRF8 expression is regulated by IRF8 promoter DNA methylation in myeloid leukemia cells. Restoration of IRF8 expression repressed A-CDase expression, resulting in C16 ceramide accumulation and increased sensitivity of CML cells to FasL-induced apoptosis. In myeloid cells derived from IRF8-deficient mice, A-CDase protein level was dramatically increased. Furthermore, we demonstrated that IRF8 directly binds to the A-CDase promoter. At the functional level, inhibition of A-CDase activity, silencing A-CDase expression, or application of exogenous C16 ceramide sensitized CML cells to FasL-induced apoptosis, whereas overexpression of A-CDase decreased CML cells' sensitivity to FasL-induced apoptosis. Consequently, restoration of IRF8 expression suppressed CML development in vivo at least partially through a Fas-dependent mechanism. In summary, our findings determine the mechanism of IRF8 downregulation in CML cells and they determine a primary pathway of resistance to Fas-mediated apoptosis and disease progression. Cancer Res; 71(8); 2882–91. ©2011 AACR.
The Two Faces of Capsaicin
Authors: Bode Ann M. , Dong Zigang 
Published: April 2011

Abstract
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the principal pungent component in hot peppers, including red chili peppers, jalapeños, and habaneros. Consumed worldwide, capsaicin has a long and convoluted history of controversy about whether its consumption or topical application is entirely safe. Conflicting epidemiologic data and basic research study results suggest that capsaicin can act as a carcinogen or as a cancer preventive agent. Capsaicin is unique among naturally occurring irritant compounds because the initial neuronal excitation evoked is followed by a long-lasting refractory period, during which the previously excited neurons are no longer responsive to a broad range of stimuli. This process is referred to as desensitization and has been exploited for its therapeutic potential. Capsaicin-containing creams have been in clinical use for many years to relieve a variety of painful conditions. However, their effectiveness in pain relief is also highly debated and some adverse side effects have been reported. We have found that chronic, long-term topical application of capsaicin increased skin carcinogenesis in mice treated with a tumor promoter. These results might imply that caution should be exercised when using capsaicin-containing topical applications in the presence of a tumor promoter, such as, for example, sunlight. Cancer Res; 71(8); 2809–14. ©2011 AACR.
Elevated B-Type Natriuretic Peptide Is Associated With Increased In-Hospital Mortality or Cardiac Arrest in Patients Undergoing Implantable Cardioverter-Defibrillator Implantation
Authors: Wei Shaokui , Loyo-Berríos Nilsa I. , Haigney Mark C.P. , Cheng Hong , Pinnow Ellen E. , Mitchell Kristi R. , Beachy James H. , Woodward Albert M. , Wang Yongfei , Curtis Jeptha P. , Marinac-Dabic Danica 
Published: April 2011

Background—
The implantable cardioverter-defibrillator (ICD) is the most effective treatment for preventing arrhythmic deaths in patients with heart failure, but periprocedural complications, including in-hospital mortality or cardiac arrest, may occur, and little is known about risk factors. We asked whether elevated B-type natriuretic peptide (BNP) level is associated with increased risk of in-hospital mortality or cardiac arrest in patients undergoing ICD implantation.

Methods and Results—

From the National Cardiovascular Data Registry ICD Registry, we identified 53 198 patients who received ICD implants and underwent preoperative BNP measurement from 2006 to 2008. The patients were categorized into 4 groups by BNP levels (<100, 100 to <300, 300 to <1000, and ≥1000 pg/mL). Complication rates were compared among groups, and odds ratios for in-hospital mortality or cardiac arrest were estimated by multiple hierarchical logistic regressions. There were 2952 complications reported, including 510 in-hospital deaths and 365 cardiac arrests. The rate of in-hospital mortality or cardiac arrest significantly increased with elevated BNP level (
P
<0.001). The adjusted odds ratios of in-hospital mortality or cardiac arrest were statistically significant in all 3 higher BNP groups [odds ratio (95% CI), 1.99 (1.17 to 3.39), 2.49 (1.50 to 4.13), and 4.25 (2.57 to 7.06) in the second, third, and fourth groups using <100 as reference]. Among subgroups, the association was more significant in men, patients with renal dysfunction, and patients undergoing biventricular ICD implantation.

Conclusions—
Elevated BNP level was significantly associated with increased risk of in-hospital mortality or cardiac arrest in patients undergoing ICD implant. Strategies aimed at reducing preprocedural BNP or creating systems to manage procedural risk merit further investigation.
Individual and Population Benefits of Daily Aspirin Therapy
Authors: Sussman Jeremy B. , Vijan Sandeep , Choi HwaJung , Hayward Rodney A. 
Published: April 2011

Background—
Clinical practice guidelines that help clinicians and patients to understand the magnitude of expected individual risks and benefits would help with patient-centered decision-making and prioritization of care. We assessed the net benefit from taking daily aspirin to estimate the individual and public health implications of a more individualized decision-making approach.

Methods and Results—
We used data from the National Health and Nutrition Examination Survey representing all US persons aged 30 to 85 years with no history of myocardial infarction and applied a Markov model based on randomized evidence and published literature to estimate lifetime effects of aspirin treatment in quality-adjusted life years (QALYs). We found that treatment benefit varies greatly by an individual's cardiovascular disease (CVD) risk. Almost all adults have fewer major clinical events on aspirin, but for most, events prevented would be so rare that even a very small distaste for aspirin use would make treatment inappropriate. With minimal dislike of aspirin use (disutility, 0.005 QALY per year), only those with a 10-year cardiac event risk >6.1% would have a net benefit. A disutility of 0.01 QALY moves this benefit cut point to 10.6%. Multiple factors altered the absolute benefit of aspirin, but the strong relationship between CVD risk and magnitude of benefit was robust.

Conclusions—
The benefits of aspirin therapy depend substantially on an individual's risk of CVD and adverse treatment effects. Understanding who benefits from aspirin use and how much can help clinicians and patients to develop a more patient-centered approach to preventive therapy.
Cartilage Pressure Distributions Provide a Footprint to Define Female Anterior Cruciate Ligament Injury Mechanisms
Authors: Quatman Carmen E. , Kiapour Ali , Myer Gregory D. , Ford Kevin R. , Demetropoulos Constantine K. , Goel Vijay K. , Hewett Timothy E. 
Published: April 2011

Background Bone bruises located on the lateral femoral condyle and posterolateral tibia are commonly associated with anterior cruciate ligament (ACL) injuries and may contribute to the high risk for knee osteoarthritis after ACL injury. The resultant footprint (location) of a bone bruise after ACL injury provides evidence of the inciting injury mechanism. Purpose/Hypothesis ( 1 ) To analyze tibial and femoral articular cartilage pressure distributions during normal landing and injury simulations, and ( 2 ) to evaluate ACL strains for conditions that lead to articular cartilage pressure distributions similar to bone bruise patterns associated with ACL injury. The hypothesis was that combined knee abduction and anterior tibial translation injury simulations would demonstrate peak articular cartilage pressure distributions in the lateral femoral condyle and posterolateral tibia. The corollary hypothesis was that combined knee abduction and anterior tibial translation injury conditions would result in the highest ACL strains. Study Design Descriptive laboratory study. Methods Prospective biomechanical data from athletes who subsequently suffered ACL injuries after testing (n = 9) and uninjured teammates (n = 390) were used as baseline input data for finite element model comparisons. Results Peak articular pressures that occurred on the posterolateral tibia and lateral femoral condyle were demonstrated for injury conditions that had a baseline knee abduction angle of 5°. Combined planar injury conditions of abduction/anterior tibial translation, anterior tibial translation/internal tibial rotation, or anterior tibial translation/external tibial rotation or isolated anterior tibial translation, external tibial rotation, or internal tibial rotation resulted in peak pressures in the posterolateral tibia and lateral femur. The highest ACL strains occurred during the combined abduction/anterior tibial translation condition in the group that had a baseline knee abduction angle of 5°. Conclusion The results of this study support a valgus collapse as the major ACL injury mechanism that results from tibial abduction rotations combined with anterior tibial translation or external or internal tibial rotations. Clinical Relevance Reduction of large multiplanar knee motions that include abduction, anterior translation, and internal/external tibial motions may reduce the risk for ACL injuries and associated bone bruises. In particular, prevention of an abduction knee posture during initial contact of the foot with the ground may help prevent ACL injury.
Intra-articular Duration of Durolane™ after Single Injection into the Rabbit Knee
Authors: Edsman Katarina , Hjelm Roland , Lärkner Helena , Nord Lars I. , Karlsson Anders , Wiebensjö Åsa , Höglund A. Urban , Kenne Anne Helander , Näsström Jacques 
Published: April 2011

Objective: The aim of the present study was to investigate the intra-articular duration of Durolane™ in a rabbit model to allow comparison between Durolane™ residence time and data reported for other hyaluronic acid products as well as native hyaluronic acid. Design: 14C-labeled Durolane™ was manufactured by labeling the cross-linker used for stabilization. A single injection of approximately 0.3 mL 14C-labeled Durolane™ was administered intra-articularly in both knee joints of male New Zealand White rabbits. At days 1, 2, 3, 7, 28, 60, 96, and 120 after injection, the knee joints of 4 animals were collected, and the radioactivity of the remaining gel was measured. The obtained data were fitted by exponential models to calculate the half-life of the gel. Two additional rabbits were used for histology of the joint 127 days after the injection. Results: The elimination of 14C-labeled Durolane™ followed first-order kinetics with an apparent half-life of approximately 32 days. Histology showed no morphological changes in the knee joints. Conclusions: This study shows that Durolane™ has a half-life of 32 days in the rabbit knee joint, which is much longer compared to literature data on hyaluronic acid and other modified hyaluronic acid products.
Small molecule Toll-like receptor 7 agonists localize to the MHC class II loading compartment of human plasmacytoid dendritic cells
Authors: Russo Carla , Cornella-Taracido Ivan , Galli-Stampino Luisa , Jain Rishi , Harrington Edmund , Isome Yuko , Tavarini Simona , Sammicheli Chiara , Nuti Sandra , Mbow M. Lamine , Valiante Nicholas M. , Tallarico John , De Gregorio Ennio , Soldaini Elisabetta 
Published: April 2011

AbstractTLR7 and TLR8 are intracellular sensors activated by single-stranded RNA species generated during viral infections. Various synthetic small molecules can also activate TLR7 or TLR8 or both through an unknown mechanism. Notably, direct interaction between small molecules and TLR7 or TLR8 has never been shown. To shed light on how small molecule agonists target TLRs, we labeled 2 imidazoquinolines, resiquimod and imiquimod, and one adenine-based compound, SM360320, with 2 different fluorophores [5(6) carboxytetramethylrhodamine and Alexa Fluor 488] and monitored their intracellular localization in human plasmacytoid dendritic cells (pDCs). All fluorescent compounds induced the production of IFN-α, TNF-α, and IL-6 and the up-regulation of CD80 and CD86 by pDCs showing they retained TLR7-stimulating activity. Confocal imaging of pDCs showed that, similar to CpG-B, all compounds concentrated in the MHC class II loading compartment (MIIC), identified as lysosome-associated membrane protein 1+, CD63, and HLA-DR+ endosomes. Treatment of pDCs with bafilomycin A, an antagonist of the vacuolar-type proton ATPase controlling endosomal acidification, prevented the accumulation of small molecule TLR7 agonists, but not of CpG-B, in the MIIC. These results indicate that a pH-driven concentration of small molecule TLR7 agonists in the MIIC is required for pDC activation.
Assessing the benefits of using mate-pairs to resolve repeats in de novo short-read prokaryotic assemblies
Authors: Wetzel Joshua , Kingsford Carl , Pop Mihai 
Published: April 2011

Abstract

Background
Next-generation sequencing technologies allow genomes to be sequenced more quickly and less expensively than ever before. However, as sequencing technology has improved, the difficulty of de novo genome assembly has increased, due in large part to the shorter reads generated by the new technologies. The use of mated sequences (referred to as mate-pairs) is a standard means of disambiguating assemblies to obtain a more complete picture of the genome without resorting to manual finishing. Here, we examine the effectiveness of mate-pair information in resolving repeated sequences in the DNA (a paramount issue to overcome). While it has been empirically accepted that mate-pairs improve assemblies, and a variety of assemblers use mate-pairs in the context of repeat resolution, the effectiveness of mate-pairs in this context has not been systematically evaluated in previous literature.

Results
We show that, in high-coverage prokaryotic assemblies, libraries of short mate-pairs (about 4-6 times the read-length) more effectively disambiguate repeat regions than the libraries that are commonly constructed in current genome projects. We also demonstrate that the best assemblies can be obtained by 'tuning' mate-pair libraries to accommodate the specific repeat structure of the genome being assembled - information that can be obtained through an initial assembly using unpaired reads. These results are shown across 360 simulations on 'ideal' prokaryotic data as well as assembly of 8 bacterial genomes using SOAPdenovo. The simulation results provide an upper-bound on the potential value of mate-pairs for resolving repeated sequences in real prokaryotic data sets. The assembly results show that our method of tuning mate-pairs exploits fundamental properties of these genomes, leading to better assemblies even when using an off -the-shelf assembler in the presence of base-call errors.

Conclusions
Our results demonstrate that dramatic improvements in prokaryotic genome assembly quality can be achieved by tuning mate-pair sizes to the actual repeat structure of a genome, suggesting the possible need to change the way sequencing projects are designed. We propose that a two-tiered approach - first generate an assembly of the genome with unpaired reads in order to evaluate the repeat structure of the genome; then generate the mate-pair libraries that provide most information towards the resolution of repeats in the genome being assembled - is not only possible, but likely also more cost-effective as it will significantly reduce downstream manual finishing costs. In future work we intend to address the question of whether this result can be extended to larger eukaryotic genomes, where repeat structure can be quite different.
Support for the reproductive ground plan hypothesis of social evolution and major QTL for ovary traits of Africanized worker honey bees (Apis melliferaL.)
Authors: Graham Allie M , Munday Michael D , Kaftanoglu Osman , Page Robert E , Amdam Gro V , Rueppell Olav 
Published: April 2011

Abstract

Background
The reproductive ground plan hypothesis of social evolution suggests that reproductive controls of a solitary ancestor have been co-opted during social evolution, facilitating the division of labor among social insect workers. Despite substantial empirical support, the generality of this hypothesis is not universally accepted. Thus, we investigated the prediction of particular genes with pleiotropic effects on ovarian traits and social behavior in worker honey bees as a stringent test of the reproductive ground plan hypothesis. We complemented these tests with a comprehensive genome scan for additional quantitative trait loci (QTL) to gain a better understanding of the genetic architecture of the ovary size of honey bee workers, a morphological trait that is significant for understanding social insect caste evolution and general insect biology.

Results
Back-crossing hybrid European x Africanized honey bee queens to the Africanized parent colony generated two study populations with extraordinarily large worker ovaries. Despite the transgressive ovary phenotypes, several previously mapped QTL for social foraging behavior demonstrated ovary size effects, confirming the prediction of pleiotropic genetic effects on reproductive traits and social behavior. One major QTL for ovary size was detected in each backcross, along with several smaller effects and two QTL for ovary asymmetry. One of the main ovary size QTL coincided with a major QTL for ovary activation, explaining 3/4 of the phenotypic variance, although no simple positive correlation between ovary size and activation was observed.

Conclusions
Our results provide strong support for the reproductive ground plan hypothesis of evolution in study populations that are independent of the genetic stocks that originally led to the formulation of this hypothesis. As predicted, worker ovary size is genetically linked to multiple correlated traits of the complex division of labor in worker honey bees, known as the pollen hoarding syndrome. The genetic architecture of worker ovary size presumably consists of a combination of trait-specific loci and general regulators that affect the whole behavioral syndrome and may even play a role in caste determination. Several promising candidate genes in the QTL intervals await further study to clarify their potential role in social insect evolution and the regulation of insect fertility in general.
Detection and function of an intramolecular disulfide bond in the pH-responsive CadC of Escherichia coli
Authors: Tetsch Larissa , Koller Christiane , Dönhöfer Alexandra , Jung Kirsten 
Published: April 2011

AbstractBackgroundIn an acidic and lysine-rich environmentEscherichia coliinduces expression of thecadBAoperon which encodes CadA, the lysine decarboxylase, and CadB, the lysine/cadaverine antiporter.cadBAexpression is dependent on CadC, a membrane-integrated transcriptional activator which belongs to the ToxR-like protein family. Activation of CadC requires two stimuli, lysine and low pH. Whereas lysine is detected by an interplay between CadC and the lysine-specific transporter LysP, pH alterations are sensed by CadC directly. Crystal structural analyses revealed a close proximity between two periplasmic cysteines, Cys208 and Cys272.ResultsSubstitution of Cys208 and/or Cys272 by alanine resulted in CadC derivatives that were active in response to only one stimulus, either lysine or pH 5.8. Differentialin vivothiol trapping revealed a disulfide bond between these two residues at pH 7.6, but not at pH 5.8. When Cys208 and Cys272 were replaced by aspartate and lysine, respectively, virtually wild-type behavior was restored indicating that the disulfide bond could be mimicked by a salt bridge.ConclusionA disulfide bond was found in the periplasmic domain of CadC that supports an inactive state of CadC at pH 7.6. At pH 5.8 disulfide bond formation is prevented which transforms CadC into a semi-active state. These results provide new insights into the function of a pH sensor.