bluuebunny/crossref_metadata_2025 huggingface dataset:
Single Nucleotide Polymorphisms in the Phospholipase A2 Receptor Gene Are Associated with Genetic Susceptibility to Idiopathic Membranous Nephropathy
Authors: Kim Sejoong , Chin Ho Jun , Na Ki Young , Kim Suhnggwon , Oh Jieun , Chung Wookyung , Noh Jung Woo , Lee Young Ki , Cho Jong Tae , Lee Eun Kyoung , Chae Dong-Wan ,   Progressive Renal Disease and Medical Informatics and Genomics Research (PREMIER) members
Published: September 2010

Background: The phospholipase A2 receptor (PLA2R) is a major antigen found in patients with idiopathic membranous nephropathy (MN). The relationship of genetic polymorphisms of PLA2R with the susceptibility and clinical outcomes of this disease is unknown. Methods: We studied 199 patients with idiopathic MN followed up for 3.7 ± 3.2 years. We enrolled 33 patients with secondary MN and 356 subjects with normal blood pressure and no proteinuria. PLA2R single nucleotide polymorphisms (SNPs) were genotyped. Results: The allele frequencies of C in rs35771982 and G in rs3828323 were 73.6 and 73.9%, respectively. Subjects with the CC genotype in rs35771982 had a higher susceptibility to idiopathic MN compared to subjects with other genotypes (odds ratio 2.6; 95% confidence interval 1.8–4.0). Patients with secondary MN were not different from controls with regard to PLA2R genotype. No impact of genetic polymorphisms on renal survival was detected. Conclusion: The findings of this study suggest that PLA2R SNPs might be associated with the risk of developing MN.
An Oxidized Extracellular Oxidation-Reduction State Increases Nox1 Expression and Proliferation in Vascular Smooth Muscle Cells Via Epidermal Growth Factor Receptor Activation
Authors: Stanic Bojana , Katsuyama Masato , Miller Francis J.
Published: September 2010

Objective—

To examine the effect of an oxidized extracellular oxidation-reduction (redox) state (E
h
) on the expression of NADPH oxidases in vascular cells.

Methods and Results—

The generation of reactive oxygen species by NADPH oxidase (Nox)-based NADPH oxidases activates redox-dependent signaling pathways and contributes to the development of “oxidative stress” in vascular disease. An oxidized plasma redox state is associated with cardiovascular disease in humans; however, the cellular mechanisms by which the extracellular redox state may cause disease are not known. Aortic segments and cultured aortic smooth muscle cells were exposed to E
h
between −150 mV (reduced) and 0 mV (oxidized) by altering the concentration of cysteine and its disulfide, cystine, the predominant redox couple in plasma. A more oxidized E
h
increased the expression of Nox1 and resulted in Nox1-dependent proliferation of smooth muscle cells. Oxidized E
h
rapidly induced epidermal growth factor receptor phosphorylation via shedding of epidermal growth factor–like ligands from the plasma membrane and caused extracellular signal–regulated kinase 1/2–dependent phosphorylation of the transcription factors activating transcription factor-1 and cAMP-response element–binding protein. Inhibition of epidermal growth factor receptor or extracellular signal–regulated kinase 1/2 activation, or addition of small interference RNA to activating transcription factor-1, prevented the increase in Nox1 expression.

Conclusion—

Our results identify a novel mechanism by which extracellular oxidative stress increases expression and activity of Nox1 NADPH oxidase and contributes to vascular disease.
Inhibition of Elevated Ca2+/Calmodulin-Dependent Protein Kinase II Improves Contractility in Human Failing Myocardium
Authors: Sossalla Samuel , Fluschnik Nina , Schotola Hanna , Ort Katharina R. , Neef Stefan , Schulte Timo , Wittköpper Katrin , Renner André , Schmitto Jan D. , Gummert Jan , El-Armouche Ali , Hasenfuss Gerd , Maier Lars S.
Published: September 2010

Rationale:

Heart failure (HF) is known to be associated with increased Ca2+/calmodulin-dependent protein kinase (CaMK)II expression and activity. There is still controversial discussion about the functional role of CaMKII in HF. Moreover, CaMKII inhibition has never been investigated in human myocardium.

Objective:

We sought to investigate detailed CaMKIIδ expression in end-stage failing human hearts (dilated and ischemic cardiomyopathy) and the functional effects of CaMKII inhibition on contractility.

Methods and Results:

Expression analysis revealed that CaMKIIδ, both cytosolic δCand nuclear δBsplice variants, were significantly increased in both right and left ventricles from patients with dilated or ischemic cardiomyopathy versus nonfailing. Experiments with isometrically twitching trabeculae revealed significantly improved force frequency relationships in the presence of CaMKII inhibitors (KN-93 and AIP). Increased postrest twitches after CaMKII inhibition indicated an improved sarcoplasmic reticulum (SR) Ca2+loading. This was confirmed in isolated myocytes by a reduced SR Ca2+spark frequency and hence SR Ca2+leak, resulting in increased SR Ca2+load when inhibiting CaMKII. Ryanodine receptor type 2 phosphorylation at Ser2815, which is known to be phosphorylated by CaMKII thereby contributing to SR Ca2+leak, was found to be markedly reduced in KN-93–treated trabeculae. Interestingly, CaMKII inhibition did not influence contractility in nonfailing sheep trabeculae.

Conclusions:

The present study shows for the first time that CaMKII inhibition acutely improves contractility in human HF where CaMKIIδ expression is increased. The mechanism proposed consists of a reduced SR Ca2+leak and consequently increased SR Ca2+load. Thus, CaMKII inhibition appears to be a possible therapeutic option for patients with HF and merits further investigation.
Differential Regulation of Proteasome Function in Isoproterenol-Induced Cardiac Hypertrophy
Authors: Drews Oliver , Tsukamoto Osamu , Liem David , Streicher John , Wang Yibin , Ping Peipei
Published: September 2010

Rationale:

Proteasomal degradation is altered in many disease phenotypes including cardiac hypertrophy, a prevalent condition leading to heart failure. Our recent investigations identified heterogeneous subpopulations of proteasome complexes in the heart and implicated multiple mechanisms for their regulation.

Objective:

The study aimed at identification of molecular mechanisms changing proteasome function in the hypertrophic heart.

Method and Results:

Proteasome function, expression, and assembly were analyzed during the development of cardiac hypertrophy induced by β-adrenergic stimulation. The analysis revealed, for the first time, divergent regulation of proteasome function in cardiac hypertrophy. Proteasome complexes have 3 different proteolytic activities, which are ATP-dependent for 26S complexes (19S assembled with 20S) and ATP-independent for 20S core particles. The 26S activities were enhanced in hypertrophic hearts, partially because of increased expression and assembly of 19S subunits with 20S core complexes. In contrast, caspase- and trypsin-like 20S activities were significantly decreased. Activation of endogenous cAMP-dependent protein kinase (PKA) rescued the depressed 20S functions, supporting the notion that PKA signaling is a positive regulator of protein degradation in the heart. Chymotrypsin-like 20S activity was stably maintained during cardiac remodeling, indicating a switch in proteasome subpopulations, which was supported by altered expression and incorporation of inducible β subunits.

Conclusions:

Three novel mechanisms for the regulation of proteasome activities were discovered in the development of cardiac hypertrophy: (1) increased incorporation of inducible subunits in 20S proteasomes; (2) enhanced 20S sensitivity to PKA activation; and (3) increased 26S assembly. PKA modulation of proteasome complexes may provide a novel therapeutic avenue for restoration of cardiac function in the diseased myocardium.
Prediction of Major Vascular Events in Patients With Transient Ischemic Attack or Ischemic Stroke
Authors: Wijnhoud Annemarie D. , Maasland Lisette , Lingsma Hester F. , Steyerberg Ewout W. , Koudstaal Peter J. , Dippel Diederik W.J.
Published: September 2010

Background and Purpose—

In patients with a recent TIA or minor stroke, prediction of long-term risk of major vascular events is important, but difficult. We aimed to study the external validity of currently available prediction models.

Methods—

We validated predictions from 3 population-based models (Framingham, SCORE, and INDIANA project) and 4 stroke cohort-based models (Stroke Prognosis Instrument II, Oxford TIA, Dutch TIA study, and the ABCD

2

study) in an independent cohort of patients with a recent TIA or minor stroke. The validation cohort consisted of 592 patients with TIA or minor stroke, with a mean follow-up of 2 years. The primary outcome was the 2-year risk of the composite outcome event of nonfatal stroke, myocardial infarction, or vascular death. We used calibration graphs and c-statistics to evaluate the 7 models.

Results—

The 2-year risk of the primary outcome event was 12%. Calibration was adequate for stroke population-based studies. After adjustment for baseline risk and for prevalence of risk factors, calibration was adequate for the Dutch TIA, the ABCD
2
, and Stroke Prognosis Instrument II models. Discrimination ranged from 0.61 to 0.68.

Conclusions—

Discrimination was poor for all currently available risk prediction models for patients with a recent TIA or minor stroke, indicating the need for stronger predictors. Clinical usefulness may be best for the ABCD
2
model, which had a limited number of easily obtainable variables, a reasonable c-statistic (0.64), and good calibration.
Polarimetric Attenuation Correction in Heavy Rain at C Band
Authors: Gu Ji-Young , Ryzhkov A. , Zhang P. , Neilley P. , Knight M. , Wolf B. , Lee Dong-In
Published: September 2010

The ability of C-band polarimetric radar to account for strong attenuation/differential attenuation is demonstrated in two cases of heavy rain that occurred in the Chicago, Illinois, metropolitan area on 5 August 2008 and in central Oklahoma on 10 March 2009. The performance of the polarimetric attenuation correction scheme that separates relative contributions of “hot spots” (i.e., strong convective cells) and the rest of the storm to the path-integrated total and differential attenuation has been explored. It is shown that reliable attenuation correction is possible if the radar signal is attenuated by as much as 40 dB. Examination of the experimentally derived statistics of the ratios of specific attenuation Ah and differential attenuation ADP to specific differential phase KDP in hot spots is included in this study. It is shown that these ratios at C band are highly variable within the hot spots. Validation of the attenuation correction algorithm at C band has been performed through cross-checking with S-band radar measurements that were much less affected by attenuation. In the case of the Oklahoma storm, a comparison was made between the data collected by closely located C-band and S-band polarimetric radars.
Satellite Sampling and Retrieval Errors in Regional Monthly Rain Estimates from TMI, AMSR-E, SSM/I, AMSU-B, and the TRMM PR
Authors: Fisher Brad , Wolff David B.
Published: September 2010

Passive and active microwave rain sensors on board Earth-orbiting satellites estimate monthly rainfall from the instantaneous rain statistics collected during satellite overpasses. It is well known that climate-scale rain estimates from meteorological satellites incur sampling errors resulting from the process of discrete temporal sampling and statistical averaging. Sampling and retrieval errors ultimately become entangled in the estimation of the mean monthly rain rate. The sampling component of the error budget effectively introduces statistical noise into climate-scale rain estimates that obscures the error component associated with the instantaneous rain retrieval. Estimating the accuracy of the retrievals on monthly scales therefore necessitates a decomposition of the total error budget into sampling and retrieval error quantities. This paper presents results from a statistical evaluation of the sampling and retrieval errors for five different spaceborne rain sensors on board nine orbiting satellites. Using an error decomposition methodology developed by one of the authors, sampling and retrieval errors were estimated at 0.25° resolution within 150 km of ground-based weather radars located at Kwajalein, Marshall Islands, and Melbourne, Florida. Error and bias statistics were calculated according to the land, ocean, and coast classifications of the surface terrain mask developed for the Goddard Profiling (GPROF) rain algorithm. Variations in the comparative error statistics are attributed to various factors related to differences in the swath geometry of each rain sensor, the orbital and instrument characteristics of the satellite, and the regional climatology. The most significant result from this study found that each of the satellites incurred negative long-term oceanic retrieval biases of 10%–30%.
Cancer, Employment, and American Indians: A Participatory Action Research Pilot Study
Authors: Johnson Sharon R. , Finifrock DeAnna , Marshall Catherine A. , Jaakola Julia (Bunny) , Setterquist Janette , Burross Heidi L. , Hodge Felicia Schanche
Published: September 2010

American Indian cancer survivors are an underserved and understudied group. In this pilot study we attempted to address, through participatory action research, missing information about those factors that serve to either facilitate employment or hinder it for adult cancer survivors. One task of the study was to develop and/or modify instrumentation that could be used in a subsequent, in-depth census study. The pilot sample consisted of 10 cancer survivors, all members of a Northern Minnesota American Indian tribe, and 10 family members. All survivors reported having health problems such as fatigue since their cancer treatments. Rehabilitation counselors can assist survivors and their family members by advising them in regard to employment discrimination and accommodations such as flexible work schedules.
The Show Must Go On
Authors: Paerregaard Karsten
Published: September 2010

Exploration of the migration history of the community of Cabanaconde, in Peru’s southern highlands, and the impact of transnational migration on the fiesta system calls attention to the role of the fiesta in strengthening migrants’ ties to the networks they draw on to migrate and adapt to their new settings in the United States. It also suggests that the transnationalization of the fiesta contributes to an emerging division of villagers into those who have access to migrant networks and those who do not. By serving as a public showcase for Cabaneños’ positions in migrant networks, the fiesta not only intensifies economic and social divisions within the community but also underpins the exclusiveness of those networks and reminds them and their fellow villagers of their new social status as both transnational villagers and global cosmopolitans.
Communication theory and research in Spain: A paradigmatic case of a socio-humanistic discipline
Authors: Alsina Miquel Rodrigo , Jiménez Leonarda García
Published: September 2010

This article analyses the situation of communication research in Spain. First, a history of the development of communication research is presented. Then the authors describe and analyse the status of research at the beginning of the 21st century and present the opinion of researchers themselves concerning this situation. Subsequently, using the Delphi method, an analysis of the panorama of research in Spain is offered from the perspective of a group of Spanish researchers and lecturers in the field. Finally, the future prospects are discussed for communication theory and research in this European country. In general, this work aims to reflect on the state of communication theory as a social and humanistic science, in those democratic countries from the first world which incorporated the study of communication theory in their universities in the 1970s, based on an observation of the Spanish situation. Consequently, the issues analysed, the epistemological precept and the solutions proposed can be extrapolated to all those zones where the discipline is currently in a complete phase of consolidation, definition and maturity.
Visual metacontrast masking in migraine
Authors: Shepherd Alex J , Wyatt Geddes , Tibber Marc S
Published: September 2010

Background: In visual metacontrast masking, the visibility of a brief target stimulus can be reduced substantially if it is preceded (forward masking) or followed (backward masking) by a non-overlapping mask. These effects have been attributed to inhibitory processes within the visual system. Two previous studies have used metacontrast masking to assess inhibitory function in migraine and control groups, however, each used different types of masking and obtained different results.

Subjects and Methods: Forward, backward and combined forward and backward masking were compared in migraine (15 with visual aura, 15 without) and control ( n = 15) groups. Baseline trials were also included (target only).

Results: For all types of masking, both migraine groups were more accurate than the control group. When performance for the masking trials was expressed relative to baseline, however, there were no significant group differences. Performance in certain conditions nevertheless correlated significantly with migraine frequency and with the recency of the last attack.

Conclusions: The inhibitory processes involved in the masking tasks employed in this study do not appear to be impaired in migraine. Their better overall performance may reflect a sensitivity difference, perhaps as a consequence of a heightened neuronal response, which varies with the migraine cycle.
Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet): Case Definition in Surveillance for Childhood-Onset Duchenne/Becker Muscular Dystrophy
Authors: Mathews Katherine D. , Cunniff Chris , Kantamneni Jiji R. , Ciafaloni Emma , Miller Timothy , Matthews Dennis , Cwik Valerie , Druschel Charlotte , Miller Lisa , Meaney F. John , Sladky John , Romitti Paul A.
Published: September 2010

The Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) is a multisite collaboration to determine the prevalence of childhood-onset Duchenne/Becker muscular dystrophy and to characterize health care and health outcomes in this population. MD STARnet uses medical record abstraction to identify patients with Duchenne/Becker muscular dystrophy born January 1, 1982 or later who resided in 1 of the participating sites. Critical diagnostic elements of each abstracted record are reviewed independently by >4 clinicians and assigned to 1 of 6 case definition categories (definite, probable, possible, asymptomatic, female, not Duchenne/Becker muscular dystrophy) by consensus. As of November 2009, 815 potential cases were reviewed. Of the cases included in analysis, 674 (82%) were either ‘‘definite’’ or ‘‘probable’’ Duchenne/Becker muscular dystrophy. These data reflect a change in diagnostic testing, as case assignment based on genetic testing increased from 67% in the oldest cohort (born 1982-1987) to 94% in the cohort born 2004 to 2009.
Protective effects of thymoquinone against methotrexate-induced testicular injury
Authors: Gökçe Ahmet , Oktar Suleyman , Koc Ahmet , Yonden Zafer
Published: September 2010

Thymoquinone is the major active component derived from Nigella sativa. Methotrexate is a folic acid antagonist widely used in clinic. Aim of this study was to investigate the possible protective role of thymoquinone on testicular toxicity of methotrexate. Experiments were performed on male C57BL/6 mice (6 weeks old, 20 ± 2 g). The animals were divided into four groups with six mice in each group. Equivalent volumes of saline were injected intraperitoneally (i.p.) in the control group. In the thymoquinone group, mice received thymoquinone i.p. with a dose of 10 mg/kg/day for 4 days. Mice in the methotrexate group received single dose of methotrexate i.p., with a dose of 20 mg/kg. Finally, in the methotrexate plus thymoquinone group, in the first and the following 3 days after methotrexate administration, thymoquinone was injected with a dose of 10 mg/kg/day, i.p. At the end of the experiment, the left testis was quickly removed and divided into two parts for histological examination and biochemical analysis. Methotrexate alone increased total antioxidant capacity and myeloperoxidase activity compared to the controls. Thymoquinone treatment decreased total antioxidant capacity and prevented the increase in the myeloperoxidase activity. Light microscopy showed in mice that receiving methotrexate resulted in interstitial space dilatation, edema, severe disruption of the seminiferous epithelium and reduced diameter of the seminiferous tubules. Administration of thymoquinone reversed histological changes of methotrexate significantly. We suggest that thymoquinone use may decrease the destructive effects of methotrexate on testicular tissue of patients using this agent.
Liver transplantation in systemic lupus erythematosus: case report and review of the literature
Authors: Zazzetti F , Buschiazzo A , Villamil FG , Barreira JC
Published: September 2010

Severe liver involvement requiring liver transplantation is a rare complication in systemic lupus erythematosus (SLE), but very few cases have been reported. We describe a 39-year-old woman with SLE who underwent successful liver transplantation due to acute liver failure. The patient persisted without reactivation of SLE and with good long-term survival. Management and diagnosis considerations are reviewed.
The Noble Eightfold Relationship Matrix
Authors: Ginsburg Phil , Eckstein Daniel , Lin Yu-Fen , Li Chi-Sing , Mullener Bill
Published: September 2010

The authors have created the Noble Eightfold Path Relationship Matrix for assisting couples in considering their relationships. Three relationship examples are provided to demonstrate how the eight principles relate to their own marriage. An interview with a counselor who uses the concepts in her own private practice is also featured. Implications for relationship enhancement conclude the article.
Looking Across the Divide: Analyzing Cross-Disciplinary Approaches for Teaching Business Communication
Authors: Laster Nicole M. , Russ Travis L.
Published: September 2010

This study elucidates pedagogical differences and similarities between the ways in which instructors from business and communication disciplines teach the introductory business communication course. During the spring of 2008, the authors surveyed 444 instructors teaching this course at colleges and universities across the United States. Their findings highlight several cross-disciplinary commonalities and disparities. The article discusses potential implications for the complementary and contradictory instructional approaches and call for more cross-disciplinary uniformity in contemporary business communication education.
Creating ‘value’ beyond the point of production: branding, financialization and market capitalization
Authors: Willmott Hugh
Published: September 2010

The contemporary significance of branding as a source of value is explored by situating the creation and valorization of brand equity within ‘the full circuit of capital’. Conceived as a form of co-production occurring in the sphere of circulation (as well as production), brand-building is connected to: the surpluses generated by the labour of user-consumers as well as the designers and producers of branded products and services; the realization of surplus through control of revenues derived from sales of these products and services and the appropriation of surpluses, including the conversion of brand equity into brand value after deduction of costs. Contemporary investment in branding is related to the financialization of brands as intangibles that make a growing contribution to market capitalization. By attending to multiple facets of the circuit of capital, including the co-production brand equity by user-consumers, some pointers are proposed for developing a more ‘joined-up’ view of the ‘bigger picture’ of contemporary capitalist reproduction.
Health in All Policies: From rhetoric to action
Authors: Ollila Eeva
Published: September 2010

Aims: The fact that health is largely constructed outside the remits of the health sector has been known for a long time. However, implementing intersectoral health policies is difficult. The aim of this article is to study possibilities for strengthening the implementation of Health in All Policies (HiAP) approach. Methods: The article analyses earlier efforts in intersectoral health policy-making and adapts Kingdon’s theory on policy change for exploring opportunities and challenges for strengthening HiAP approach. Results: Opportunities for HiAP can be identified by analysing possibilities for amending health determinants on the one hand, and by analysing policy trends, proposals, and actors, especially in fields other than health, on the other. Four basic strategies for HiAP are identified, namely: health strategy, win—win strategy, cooperation strategy, and damage limitation strategy. Their strengths in various situations are explored. Using an adaptation of Kingdon’s framework, possibilities for creating opportunities for HiAP by raising health issues on the agenda, developing appropriate tools and by creating conducive momentums are discussed. Conclusions: It is concluded that systematic efforts of experts in public health, health policy, and international health are important in identifying and prioritising the needs for HiAP, in analysing health implications of policies and policy proposals and making these understood by the policy-makers, as well as in suggesting feasible solutions. Improving health literacy of the public, the policy-makers, and the media is key for improved understanding on health implications of policies. Participatory and transparent approaches to policy-making are prerequisites for strengthening HiAP.
Look who’s talking: Parliamentary debate in the European Union
Authors: Slapin Jonathan B , Proksch Sven-Oliver
Published: September 2010

Legislative speeches are an important part of parliamentary activity in the European Parliament (EP). Using a new dataset on EP speeches, this paper offers an explanation for participation in legislative debates. We argue that floor speeches partially serve as a communication tool between members of parliament, their national parties, and their European political groups. EP group dissidents often go on record by taking the floor when there is a conflict between their national party and their European political group. In this instance, members give speeches for two reasons: to explain their national party’s position to other members of their EP political group, and to create a positive record for themselves in the eyes of the national party to serve their own reelection purposes.
International regime formation revisited: Explaining ratification behaviour with respect to long-range transboundary air pollution agreements in Europe
Authors: Perrin Sophie , Bernauer Thomas
Published: September 2010

We draw on the policy diffusion literature to shed more light on the determinants of treaty ratification, a crucial step in the formation of international regimes. Our hypotheses stipulate that a country’s ratification behaviour is influenced by the ratification choices of other countries in general, or of specific types of other countries. The underlying argument is that the ratification behaviour of (specific) other countries sends particular signals — for instance signals about implementation costs, competitiveness effects or reputation costs — to the country in question. The empirical testing is done on data for ratification of the UN Economic Commission for Europe’s agreements on long-range transboundary air pollution. The results show that international factors are as important in influencing ratification choices as domestic factors. This result raises interesting questions about the relative importance of international and domestic determinants in different policy areas and at different stages of international regime formation.
Developing an Exchange Mindset
Authors: Thackeray Rosemary
Published: September 2010

Exchange is a fundamental concept that underlies all social marketing efforts. In a successful exchange, both parties receive something of value and the benefits that they desire in return for a price. The purpose of this article is to describe how practitioners can develop an “exchange mindset.” A practitioner’s answer to five basic questions will enable him or her to see the exchange through the eyes of the customer and increase the likelihood of creating a successful exchange that will benefit both parties involved and result in positive behavior change.
PtdIns3P and Rac direct the assembly of the NADPH oxidase on a novel, pre-phagosomal compartment during FcR-mediated phagocytosis in primary mouse neutrophils
Authors: Anderson Karen E. , Chessa Tamara A. M. , Davidson Keith , Henderson Robert B. , Walker Simon , Tolmachova Tanya , Grys Katarzyna , Rausch Oliver , Seabra Miguel C. , Tybulewicz Victor L. J. , Stephens Len R. , Hawkins Phillip T.
Published: September 2010

The generation of reactive oxygen species (ROS) by the nicotinamide adenine dinucleotide phosphate oxidase is an important mechanism by which neutrophils kill pathogens. The oxidase is composed of a membrane-bound cytochrome and 4 soluble proteins (p67phox, p40phox, p47phox, and GTP-Rac). These components form an active complex at the correct time and subcellular location through a series of incompletely understood mutual interactions, regulated, in part, by GTP/GDP exchange on Rac, protein phosphorylation, and binding to lipid messengers. We have used a variety of assays to follow the spatiotemporal assembly of the oxidase in genetically engineered primary mouse neutrophils, during phagocytosis of both serum- and immunoglobulin G-opsonized targets. The oxidase assembles directly on serum-Staphylococcus aureus–containing phagosomes within seconds of phagosome formation; this process is only partially dependent (∼ 30%) on PtdIns3P binding to p40phox, but totally dependent on Rac1/2 binding to p67phox. In contrast, in response to immunoglobulin G-targets, the oxidase first assembles on a tubulovesicular compartment that develops at sites of granule fusion to the base of the emerging phagosome; oxidase assembly and activation is highly dependent on both PtdIns3P-p40phox and Rac2-p67phox interactions and delivery to the phagosome is regulated by Rab27a. These results define a novel pathway for oxidase assembly downstream of FcR-activation.
Sample size and statistical power considerations in high-dimensionality data settings: a comparative study of classification algorithms
Authors: Guo Yu , Graber Armin , McBurney Robert N , Balasubramanian Raji
Published: September 2010

Background

Data generated using 'omics' technologies are characterized by high dimensionality, where the number of features measured per subject vastly exceeds the number of subjects in the study. In this paper, we consider issues relevant in the design of biomedical studies in which the goal is the discovery of a subset of features and an associated algorithm that can predict a binary outcome, such as disease status. We compare the performance of four commonly used classifiers (K-Nearest Neighbors, Prediction Analysis for Microarrays, Random Forests and Support Vector Machines) in high-dimensionality data settings. We evaluate the effects of varying levels of signal-to-noise ratio in the dataset, imbalance in class distribution and choice of metric for quantifying performance of the classifier. To guide study design, we present a summary of the key characteristics of 'omics' data profiled in several human or animal model experiments utilizing high-content mass spectrometry and multiplexed immunoassay based techniques.

Results

The analysis of data from seven 'omics' studies revealed that the average magnitude of effect size observed in human studies was markedly lower when compared to that in animal studies. The data measured in human studies were characterized by higher biological variation and the presence of outliers. The results from simulation studies indicated that the classifier Prediction Analysis for Microarrays (PAM) had the highest power when the class conditional feature distributions were Gaussian and outcome distributions were balanced. Random Forests was optimal when feature distributions were skewed and when class distributions were unbalanced. We provide a free open-source R statistical software library (MVpower) that implements the simulation strategy proposed in this paper.

Conclusion

No single classifier had optimal performance under all settings. Simulation studies provide useful guidance for the design of biomedical studies involving high-dimensionality data.
Multiple imputation for estimation of an occurrence rate in cohorts with attrition and discrete follow-up time points: a simulation study
Authors: Soullier Noémie , de La Rochebrochard Elise , Bouyer Jean
Published: September 2010

Background

In longitudinal cohort studies, subjects may be lost to follow-up at any time during the study. This leads to attrition and thus to a risk of inaccurate and biased estimations. The purpose of this paper is to show how multiple imputation can take advantage of all the information collected during follow-up in order to estimate the cumulative probability P(E) of an event E, when the first occurrence of this event is observed at t successive time points of a longitudinal study with attrition.

Methods

We compared the performance of multiple imputation with that of Kaplan-Meier estimation in several simulated attrition scenarios.

Results

In missing-completely-at-random scenarios, the multiple imputation and Kaplan-Meier methods performed well in terms of bias (less than 1%) and coverage rate (range = [94.4%; 95.8%]). In missing-at-random scenarios, the Kaplan-Meier method was associated with a bias ranging from -5.1% to 7.0% and with a very poor coverage rate (as low as 0.2%). Multiple imputation performed much better in this situation (bias <2%, coverage rate >83.4%).

Conclusions

Multiple imputation shows promise for estimation of an occurrence rate in cohorts with attrition. This study is a first step towards defining appropriate use of multiple imputation in longitudinal studies.
The chondrogenic response to exercise in the proximal femur of normal and mdx mice
Authors: Nye David J , Costas Jeffrey M , Henley Jessica B , Kim Jin-Kwang , Plochocki Jeffrey H
Published: September 2010

Background

Submaximal exercise is used in the management of muscular dystrophy. The effects of mechanical stimulation on skeletal development are well understood, although its effects on cartilage growth have yet to be investigated in the dystrophic condition. The objective of this study was to investigate the chondrogenic response to voluntary exercise in dystrophin-deficient mice.

Methods

Control and dystrophin-deficient (mdx) mice were divided into sedentary and exercise-treated groups and tested for chondral histomorphometric differences at the proximal femur.

Results

Control mice ran 7 km/week further than mdx mice on average, but this difference was not statistically significant (P> 0.05). However, exercised control mice exhibited significantly enlarged femur head diameter, articular cartilage thickness, articular cartilage tissue area, and area of calcified cartilage relative to sedentary controls and exercised mdx mice (P< 0.05). No differences were found between other treatment groups.

Conclusions

Mdx mice exhibit a reduced chondrogenic response to increased mechanical stimulation relative to controls. However, no significant reduction in articular dimensions was found, indicating loss of chondral tissue may not be a clinical concern with dystrophinopathy.
Coordination of glioblastoma cell motility by PKCι
Authors: Baldwin R Mitchell , Barrett Gordon M , Parolin Doris AE , Gillies Jana K , Paget Judith A , Lavictoire Sylvie J , Gray Douglas A , Lorimer Ian AJ
Published: September 2010

Background

Glioblastoma is one of the deadliest forms of cancer, in part because of its highly invasive nature. The tumor suppressor PTEN is frequently mutated in glioblastoma and is known to contribute to the invasive phenotype. However the downstream events that promote invasion are not fully understood. PTEN loss leads to activation of the atypical protein kinase C, PKCι. We have previously shown that PKCι is required for glioblastoma cell invasion, primarily by enhancing cell motility. Here we have used time-lapse videomicroscopy to more precisely define the role of PKCι in glioblastoma.

Results

Glioblastoma cells in which PKCι was either depleted by shRNA or inhibited pharmacologically were unable to coordinate the formation of a single leading edge lamellipod. Instead, some cells generated multiple small, short-lived protrusions while others generated a diffuse leading edge that formed around the entire circumference of the cell. Confocal microscopy showed that this behavior was associated with altered behavior of the cytoskeletal protein Lgl, which is known to be inactivated by PKCι phosphorylation. Lgl in control cells localized to the lamellipod leading edge and did not associate with its binding partner non-muscle myosin II, consistent with it being in an inactive state. In PKCι-depleted cells, Lgl was concentrated at multiple sites at the periphery of the cell and remained in association with non-muscle myosin II. Videomicroscopy also identified a novel role for PKCι in the cell cycle. Cells in which PKCι was either depleted by shRNA or inhibited pharmacologically entered mitosis normally, but showed marked delays in completing mitosis.

Conclusions

PKCι promotes glioblastoma motility by coordinating the formation of a single leading edge lamellipod and has a role in remodeling the cytoskeleton at the lamellipod leading edge, promoting the dissociation of Lgl from non-muscle myosin II. In addition PKCι is required for the transition of glioblastoma cells through mitosis. PKCι therefore has a role in both glioblastoma invasion and proliferation, two key aspects in the malignant nature of this disease.
18F-FDG PET/CT-based gross tumor volume definition for radiotherapy in head and neck Cancer: a correlation study between suitable uptake value threshold and tumor parameters
Authors: Kao Chia-Hung , Hsieh Te-Chun , Yu Chun-Yen , Yen Kuo-Yang , Yang Shih-Neng , Wang Yao-Ching , Liang Ji-An , Chien Chun-Ru , Chen Shang-Wen
Published: September 2010

Background

To define a suitable threshold setting for gross tumor volume (GTV) when using 18Fluoro-deoxyglucose positron emission tomography and computed tomogram (PET/CT) for radiotherapy planning in head and neck cancer (HNC).

Methods

Fifteen HNC patients prospectively received PET/CT simulation for their radiation treatment planning. Biological target volume (BTV) was derived from PET/CT-based GTV of the primary tumor. The BTVs were defined as the isodensity volumes when adjusting different percentage of the maximal standardized uptake value (SUVmax), excluding any artifact from surrounding normal tissues. CT-based primary GTV (C-pGTV) that had been previously defined by radiation oncologists was compared with the BTV. Suitable threshold level (sTL) could be determined when BTV value and its morphology using a certain threshold level was observed to be the best fitness of the C-pGTV. Suitable standardized uptake value (sSUV) was calculated as the sTL multiplied by the SUVmax.

Results

Our result demonstrated no single sTL or sSUV method could achieve an optimized volumetric match with the C-pGTV. The sTL was 13% to 27% (mean, 19%), whereas the sSUV was 1.64 to 3.98 (mean, 2.46). The sTL was inversely correlated with the SUVmax [sTL = -0.1004 Ln (SUVmax) + 0.4464; R2 = 0.81]. The sSUV showed a linear correlation with the SUVmax (sSUV = 0.0842 SUVmax + 1.248; R2 = 0.89). The sTL was not associated with the value of C-pGTVs.

Conclusion

In PET/CT-based BTV for HNC, a suitable threshold or SUV level can be established by correlating with SUVmax rather than using a fixed threshold.
Validation Testing of Drift Reduction Technology Testing Protocol
Authors: Khan Faruque A. , Ellenberger Jay S. , Birchfield Norman B. , Kosusko Michael , Rothman Gabriel S.
Published: September 2010

A number of pesticide application technologies offer the potential to reduce spray drift from pesticide applications. However, limited information exists on the effectiveness of these technologies in reducing spray drift. Working with a stakeholder technical panel under EPA’s Environmental Technology Council, the Office of Pesticide Programs in EPA has developed and is in the process of validating a testing protocol to verify the effectiveness of drift reduction technologies (DRTs). The DRT testing protocol was adapted from standard test methods and regulatory methods used in other countries and describes the testing approach that will be used to generate high-quality, peer-reviewed data for DRTs, including test design and quality assurance aspects. Both low-speed and high-speed wind tunnel tests were completed using a reference nozzle and two test nozzles to evaluate the performance of the generic DRT testing protocol. By Summer 2010, EPA anticipates to finalize this testing protocol based on the test results performed by EPA and other stakeholders. As a next step, EPA intends to encourage equipment manufacturers to voluntarily use the protocol for testing their equipment. Tested technologies that are proven to significantly reduce spray drift may be considered for addition to pesticide product labels by pesticide registrants and by EPA in its risk assessment and management decisions for the registration of new pesticide and uses and registration review (reevaluation) of currently registered pesticides. Pesticide product labels citing the use of DRTs could have reduced restrictions for applications, provide applicators with greater flexibility, and result in less off-target pesticide deposition. This paper will provide an update of EPA’s efforts to validate the DRT testing protocol and discuss future plans for using a validated protocol in evaluating DRTs in an effort to reduce load from unintended spray drift of pesticides in the environment.
Empirical Modeling of the Time-Dependent Structural Build-up of Lead-Free Solder Pastes Used in the Electronics Assembly Applications
Authors: Mallik S. , Ekere N. N. , Bhatti R.
Published: September 2010

Solder paste is the primary bonding material used in the assembly of surface mount devices in electronics industries. It generally has a flocculated structure, which may break-down on shearing and slowly rebuild at rest. The proper characterization of the time-dependent rheological behaviors of solder pastes is crucial for establishing the relationships between the pastes’ structure and flow behavior and for correlating the physical parameters with paste printing performance. In this paper, we present a novel method that has been developed for characterizing the time-dependent and non-Newtonian rheological behavior of solder pastes and flux mediums as a function of shear rates. The objective of the study reported in this paper was to investigate the thixotropic build-up behavior of solder paste and flux mediums. The stretched exponential model has been used to model the structural changes during the build-up process and to correlate model parameters with the paste printing process. As expected, for solder paste samples, the rate of structural recovery was found dependent on the applied shear rate. The model parameters, such as equilibrium viscosity and characteristic time, have been correlated with the shear-thinning and slumping behaviors of solder paste during the stencil printing process.
Prediction of Genetic Values of Quantitative Traits in Plant Breeding Using Pedigree and Molecular Markers
Authors: Crossa José , Campos Gustavo de los , Pérez Paulino , Gianola Daniel , Burgueño Juan , Araus José Luis , Makumbi Dan , Singh Ravi P , Dreisigacker Susanne , Yan Jianbing , Arief Vivi , Banziger Marianne , Braun Hans-Joachim
Published: September 2010

The availability of dense molecular markers has made possible the use of genomic selection (GS) for plant breeding. However, the evaluation of models for GS in real plant populations is very limited. This article evaluates the performance of parametric and semiparametric models for GS using wheat (Triticum aestivum L.) and maize (Zea mays) data in which different traits were measured in several environmental conditions. The findings, based on extensive cross-validations, indicate that models including marker information had higher predictive ability than pedigree-based models. In the wheat data set, and relative to a pedigree model, gains in predictive ability due to inclusion of markers ranged from 7.7 to 35.7%. Correlation between observed and predictive values in the maize data set achieved values up to 0.79. Estimates of marker effects were different across environmental conditions, indicating that genotype × environment interaction is an important component of genetic variability. These results indicate that GS in plant breeding can be an effective strategy for selecting among lines whose phenotypes have yet to be observed.
A Targeted UAS-RNAi Screen in Drosophila Larvae Identifies Wound Closure Genes Regulating Distinct Cellular Processes
Authors: Lesch Christine , Jo Juyeon , Wu Yujane , Fish Greg S , Galko Michael J
Published: September 2010

Robust mechanisms for tissue repair are critical for survival of multicellular organisms. Efficient cutaneous wound repair requires the migration of cells at the wound edge and farther back within the epidermal sheet, but the genes that control and coordinate these migrations remain obscure. This is in part because a systematic screening approach for in vivo identification and classification of postembryonic wound closure genes has yet to be developed. Here, we performed a proof-of-principle reporter-based in vivo RNAi screen in the Drosophila melanogaster larval epidermis to identify genes required for normal wound closure. Among the candidate genes tested were kinases and transcriptional mediators of the Jun N-terminal kinase (JNK) signaling pathway shown to be required for epithelial sheet migration during development. Also targeted were genes involved in actin cytoskeletal remodeling. Importantly, RNAi knockdown of both canonical and noncanonical members of the JNK pathway caused open wounds, as did several genes involved in actin cytoskeletal remodeling. Our analysis of JNK pathway components reveals redundancy among the upstream activating kinases and distinct roles for the downstream transcription factors DJun and DFos. Quantitative and qualitative morphological classification of the open wound phenotypes and evaluation of JNK activation suggest that multiple cellular processes are required in the migrating epidermal cells, including functions specific to cells at the wound edge and others specific to cells farther back within the epidermal sheet. Together, our results identify a new set of conserved wound closure genes, determine putative functional roles for these genes within the migrating epidermal sheet, and provide a template for a broader in vivo RNAi screen to discover the full complement of genes required for wound closure during larval epidermal wound healing.