bluuebunny/crossref_metadata_2025 huggingface dataset:
Zebrafish Thsd7a is a neural protein required for angiogenic patterning during development
Authors: Wang Chieh‐Huei , Chen I‐Hui , Kuo Meng‐Wei , Su Pei‐Tsu , Lai Zih‐Yin , Wang Chian‐Huei , Huang Wei‐Chang , Hoffman Jana , Kuo Calvin J. , You May‐Su , Chuang Yung‐Jen
Published: April 2011

Angiogenesis is a highly organized process under the control of guidance cues that direct endothelial cell (EC) migration. Recently, many molecules that were initially described as regulators of neural guidance were subsequently shown to also direct EC migration. Here, we report a novel protein, thrombospondin type I domain containing 7A (Thsd7a), that is a neural molecule required for directed EC migration during embryonic angiogenesis in zebrafish. Thsd7a is a vertebrate conserved protein. Zebrafish thsd7a transcript was detected along the ventral edge of the neural tube in the developing zebrafish embryos, correlating with the growth path of angiogenic intersegmental vessels (ISVs). Morpholino‐knockdown of Thsd7a caused a lateral deviation of angiogenic ECs below the thsd7a‐expressing sites, resulting in aberrant ISV patterning. Collectively, our study shows that zebrafish Thsd7a is a neural protein required for ISV angiogenesis, and suggests an important role of Thsd7a in the neurovascular interaction during zebrafish development. Developmental Dynamics 240:1412–1421, 2011. © 2011 Wiley‐Liss, Inc.
Rab3d is required for Xenopus anterior neurulation by regulating noggin secretion
Authors: Kim Hyunjoon , Han Jin‐Kwan
Published: April 2011

Rab3d is a member of the Ras‐related small GTPase family of secretory Rab, Rab3. In this study, we showed that Xenopus Rab3d is expressed specifically in the anterior border of the neural plate when the neural plate converges and folds to initiate neural tube formation. Morpholino‐mediated knockdown of Rab3d resulted in neurulation defects both in neural plate convergence and folding. Interestingly, perturbation of BMP signaling rescued neurulation defects of Rab3d morphants, suggesting that Rab3d inhibits BMP signaling during neurulation. By secretion assay in the Xenopus animal cap, we found that Rab3d specifically regulates secretion of a BMP antagonist, Noggin, but not Chordin and Wnts. We also found that Rab3d is co‐localized with Noggin and that this interaction is dependent on the GTP/GDP cycle of Rab3d. Collectively, these findings suggest that Rab3d‐mediated secretion regulation of a BMP antagonist, Noggin, is one of the mechanisms of BMP antagonism during Xenopus anterior neurulation. Developmental Dynamics 240:1430–1439, 2011. © 2011 Wiley‐Liss, Inc.
Mandometer treatment not superior to treatment as usual for anorexia nervosa
Authors: van Elburg Annemarie A. , Hillebrand Jacquelien J.G. , Huyser Chaim , Snoek Maartje , Kas Martien J.H. , Hoek Hans W. , Adan Roger A.H.
Published: April 2011

Objective:

A comparison of the efficacy of a novel treatment method for anorexia nervosa (AN), the Mandometer treatment (MT), with treatment as usual (TAU).

Method:

During treatment data were collected to determine weight recovery and outcome as assessed by the Morgan Russell Outcome Assessment Schedule (MROAS).

Results:

After treatment 63% of the MT group and 85% of the TAU group had reached a normal weight level and both MT and TAU showed a good outcome on the MROAS (75 and 71%, respectively). After two years more MT than TAU patients were still in treatment and more MT patients had relapsed.

Discussion:

The outcome for both treatments in our study were similar and comparable with, if not better than outcome data of other AN studies. MT is not superior to TAU in outcome results and in relapse rate during the first two years following admission for AN treatment. © 2011 by Wiley Periodicals, Inc. (Int J Eat Disord 2012)
Establishing thresholds for unusually large binge eating episodes
Authors: Arikian Aimee , Peterson Carol B. , Swanson Sonja A. , Berg Kelly C. , Chartier Lisa , Durkin Nora , Crow Scott J.
Published: April 2011

Objective:

This study examined group differences in ratings of amounts of food at the threshold of what is considered “unusually large” to develop empirically derived definitions of binge eating criteria for bulimia nervosa and binge eating disorder.

Method:

Groups included undergraduate students, community members, and participants from an eating disorder (ED) longitudinal study. Data were collected via self‐report questionnaires.

Results:

Ordinal logistic regression indicated that males reported a higher threshold for amounts of food compared to females. Overweight participants from the student and ED samples, but not from the community sample, reported higher thresholds. The presence of binge eating and fear of weight gain were also associated with higher thresholds.

Discussion:

These findings provide evidence that gender, social context, BMI, and eating disorder status are important considerations in determining what is an unusually large amount of food. Future diagnostic guidelines should consider the importance of these factors when defining binge eating. © 2011 by Wiley Periodicals, Inc. (Int J Eat Disord 2012)
InP‐based InGaAsSbN quantum well laser diodes in the 2‐μm wavelength region
Authors: Kawamura Yuichi
Published: April 2011

InGaAsSbN quantum well (QW) laser diodes on InP in the 2‐μm wavelength region were grown by molecular beam epitaxy (MBE). It was found that an increase in Sb content improved the properties of InGaAsSbN QW laser diodes. We observed electroluminescence at 4.51 μm at room temperature for InAsSbN SQ laser diodes, and laser operation at 2.31 μm at 190 K. Annealing effects were also studied. © 2011 Wiley Periodicals, Inc. Electron Comm Jpn, 94(5): 33–38, 2011; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ecj.10195
Brain activity while reading sentences with kanji characters expressing emotions: an fMRI study on kanji characters expressing “laughter” and “tears”
Authors: Yuasa Masahide , Saito Keiichi , Mukawa Naoki
Published: April 2011

In this paper, we describe the brain activity associated with kanji characters expressing emotion, which are placed at the end of a sentence. Japanese use special kanji characters in brackets at the end of sentences in text messages, such as those sent through e‐mail and messaging tools. Such kanji characters have the function of expressing the sender's emotions (such as amusement, laughter, sadness, tears), like emoticons. This is a very simple and effective way to convey the sender's emotions and thoughts to the recipient. In this research, we investigate the effects of emotive kanji characters by using an fMRI study. The experimental results show that both the right and left inferior frontal gyri, which have been implicated in verbal and nonverbal information, were activated. We found that sentences with an emotive kanji character were detected as containing both verbal and nonverbal information, and that sentences with emotive kanji characters enrich communication between the sender and the recipient. © 2011 Wiley Periodicals, Inc. Electron Comm Jpn, 94(5): 1–8, 2011; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ecj.10332
Diatom ecological response to altered hydrological forcing of a shallow lake on the Yangtze floodplain, SE China
Authors: Liu Qian , Yang Xiangdong , Anderson N. John , Liu Enfeng , Dong Xuhui
Published: April 2011

The Yangtze floodplain is characterized by numerous large (surface area > 1 km2; ∼25% are > 10 km2) and shallow lakes (maximum depth mainly < 5 m). Floodplain lakes are inherently dynamic and important sites for biogeochemical cycling, biodiversity as well as human resources. Importantly, the degree of hydrological connectivity between lakes and river channels is affected by climate, geomorphic processes as well as cultural disturbance of the catchment. This study investigated the long‐term (∼200 years) interaction between a shallow floodplain lake (Taibai Lake; area 25 km2, mean depth 3·2 m) and the Yangtze River using high‐resolution multi‐proxy analysis (diatoms, geochemistry, and grain size) of a 210Pb‐dated sediment core. Diatom assemblages in Taibai Lake exhibited a strong temporal succession and were successively dominated by Aulacoseira granulata (planktonic), Gyrosigma acuminatum (periphytic), and the facultatively planktonic Nitzschia palea over the past 200 years. Eutrophication as inferred by diatom inferred‐total phosphorous (DI‐TP), however, only started around 1990 with TP concentration increasing from 65 to 95 µg L−1. Prior to 1950 DI‐TP was constant and detrended correspondence analysis axis 1 sample scores (of the diatom assemblages) were not correlated with DI‐TP concentration suggesting that there were other stressors driving changes in the diatom assemblage besides nutrients. We used sediment grain size as a proxy for hydrological connectivity; median grain size is strongly correlated with the abundance of A. granulata (R2 = 0·67). A comparison of the diatom stratigraphy with physical and geochemical proxies suggested that Taibai Lake shifted from a riverine‐influenced, turbid algae‐macrophyte mixed state to a clearwater macrophyte‐dominated state around 1950 AD, primarily due to the changes in the hydrological regime of the floodplain resulting from land reclamation and building of reservoirs. After 1990 AD, the lake ecosystem deteriorated following continuous input of nutrients from agriculture and aquaculture, shifting to a hyper‐eutrophic algae‐dominated state. These results indicate the dynamic nature of floodplain ecosystems and the complexity of multiple stressors affecting them over decadal timescales and the long‐term interaction between anthropogenic and natural forcing processes. Copyright © 2011 John Wiley & Sons, Ltd.
The role of precipitation variability on the ecohydrology of grasslands
Authors: Petrie M. D. , Brunsell N. A.
Published: April 2011

Precipitation event timing and magnitude are important drivers of ecosystem processes and are instrumental in creating landscape heterogeneity. Ecosystems respond to precipitation and other driving variables at different spatial and temporal scales, which complicates understanding of the relationships that govern ecosystem conditions. To better characterize the ecosystem response, we present a low‐dimensional framework for simulating the influence of precipitation event timing and magnitude on grassland ecosystems, with particular focus on characterizing the temporal sensitivity of water and carbon fluxes to climate forcings and the feedback of water and carbon on soil moisture availability. Results show variation in daily through seasonal sensitivity of ecosystem water and carbon fluxes and identifies the way these sensitivities change at daily to annual timescales to shape long‐term ecosystem states. This provides for a better understanding of the nonlinearities inherent to ecosystem interactions during the growing season and provides assessment of the extent that precipitation variance has on grassland functioning and heterogeneity. Copyright © 2011 John Wiley & Sons, Ltd.
DNA damage and nucleotide excision repair capacity in healthy individuals
Authors: Slyskova Jana , Naccarati Alessio , Polakova Veronika , Pardini Barbara , Vodickova Ludmila , Stetina Rudolf , Schmuczerova Jana , Smerhovsky Zdenek , Lipska Ludmila , Vodicka Pavel
Published: April 2011

Interindividual differences in DNA repair capacity (DRC) represent an important source of variability in genome integrity and thus influence health risk. In the last decade, DRC measurement has attracted attention as a potential biomarker in cancer prediction. Aim of the present exploratory study was to characterize the variability in DNA damage and DRC on 100 healthy individuals and to identify biological, lifestyle, or genetic factors modulating these parameters. The ultimate goal was to obtain reference data from cancer‐free population, which may constitute background for further investigations on cancer patients. The endogenous DNA damage was measured as a level of DNA single‐strand breaks and DRC, specific for nucleotide excision repair (NER), was evaluated using modified comet assay, following the challenge of peripheral blood mononuclear cells with benzo[a]pyrene diolepoxide. Additionally, genetic polymorphisms in NER genes (XPA, XPC, XPD, and XPG) were assessed. We have observed a substantial interindividual variability for both examined parameters. DNA damage was significantly affected by gender and alcohol consumption (P = 0.003 and P = 0.012, respectively), whereas DRC was associated with family history of cancer (P = 0.012). The stratification according to common variants in NER genes showed that DNA damage was significantly modulated by the presence of the variant T allele of XPC Ala499Val polymorphism (P = 0.01), while DRC was modulated by the presence of the A allele of XPA G23A polymorphism (P = 0.048). Our results indicate the range of endogenous DNA single‐strand breaks and capacity of NER in healthy volunteers as well as the role of potentially relevant confounders. Environ. Mol. Mutagen. 2011. © 2011 Wiley‐Liss, Inc.
A laboratory treatability study for pilot‐scale soil washing of Cr, Cu, Ni, and Zn contaminated soils
Authors: Lin Ya‐Ting , Chien Yi‐Chi , Liang Chenju
Published: April 2011

As part of this study, laboratory‐ and pilot‐scale washing of soils contaminated with Cr, Cu, Ni, and Zn were performed. The soil washing agents used included strong acids (hydrochloric acid (HCl) and sulfuric acid (H2SO4)) and chelating agents (ethylenediaminetetraacetic acid calcium disodium salt (EDTA) and citric acid (CA)). A positive correlation was observed between the removal efficiency of the washing process and the concentration of the washing solution. Moreover, the effect of H2SO4 on metal removal with respect to concentration variations was more pronounced in the batch studies due mainly to acid dissolution of the heavy metals. Using H2SO4 concentrations of between 300 and 1000 mM, the removal efficiencies achieved when targeting Cr, Cu, Ni, Zn and the total metal content were 41–42, 38–68, 23–25, 47–53, and 42–55%. The removal efficiencies recorded during the engineering pilot scale washing of the field soils using H2SO4 are comparable to those obtained in the batch study. © 2011 American Institute of Chemical Engineers Environ Prog, 2011
Empirical correlation of PGA, spectral accelerations and spectrum intensities from active shallow crustal earthquakes
Authors: Bradley Brendon A.
Published: April 2011

Empirical correlation equations between peak ground acceleration, spectral acceleration, spectrum intensity, and acceleration spectrum intensity are developed. The correlation equations are developed for shallow crustal earthquakes using the Next Generation Attenuation (NGA) ground motion database, and four of the NGA ground motion prediction equations (GMPEs). A particularly novel aspect of the present study is the explicit consideration of epistemic uncertainty in the correlation equations due to both the adopted ground motion database and GMPEs. The resulting correlation equations enable the joint consideration of these four ground motion intensity measures in ground motion selection using frameworks such as the generalized conditional intensity measure approach. Copyright © 2011 John Wiley & Sons, Ltd.
Biaxial testing of unbonded post‐tensioned rocking bridge piers with external replacable dissipaters
Authors: Marriott Dion , Pampanin Stefano , Palermo Alessandro
Published: April 2011

The biaxial response of two bridge piers is experimentally investigated. A post‐tensioned precast bridge pier with external replaceable mild‐steel dissipaters is tested under biaxial loading. The performance of the post‐tensioned bridge pier is compared with a conventionally reinforced monolithic bridge pier. The experimental biaxial response is then compared with previous uniaxial experimental testing of identical bridge piers to understand the influence of biaxial loading, specifically concerning post‐tensioned rocking sections. A 3‐dimensional moment–curvature and moment–rotation analysis program is created to generate the monotonic section response of a conventional and post‐tensioned bridge pier. After comparing the accuracy of the section analysis program to the experimental testing of the monolithic pier, the program is validated against the experimental testing of the post‐tensioned bridge pier. This section analysis program is then used in the calibration of a macro‐model to capture the entire cyclic response of the post‐tensioned bridge pier. The macro‐model adopts multiple linear‐elastic compression‐only springs at the rocking interface, combined with non‐linear inelastic springs for each of the mild‐steel dissipaters and returns encouraging results at both local and global levels.

The paper concludes with a number of biaxial moment‐interaction design charts for monolithic and post‐tensioned bridge piers as a function of mechanical and geometric section properties. The design charts define the biaxial yield surface at nominal yield and at the design section capacity defined by one of three material limit states. Copyright © 2011 John Wiley & Sons, Ltd.
Personalised caregiver support: effectiveness of psychosocial interventions in subgroups of caregivers of people with dementia
Authors: Van Mierlo Lisa D. , Meiland Franka J. M. , Van der Roest Henriëtte G. , Dröes Rose‐Marie
Published: April 2011

Objective

Insight into the characteristics of caregivers for whom psychosocial interventions are effective is important for care practice. Until now no systematic reviews were conducted into the effectiveness of psychosocial interventions for caregiver subgroups.

Methods

To gain insight into this relationship between caregiver subgroups and intervention outcomes, a first review study was done. This study reviews the personal characteristics of caregivers of people with dementia for whom psychosocial interventions were effective.

Results

Electronic databases and key articles were searched for reviews on psychosocial interventions for caregivers studies published between January 1990 and February 2008. Based on these reviews, twenty‐six studies met the inclusion criteria (i.e. having positive outcomes described in subgroups). Most positive effects were found in caregivers of people with a diagnosis of ‘dementia not otherwise specified’ and in the subgroup of female caregivers. Examples of outcomes were decreased depression and improved self‐efficacy.

Conclusions

This study gives a first overview of successful psychosocial interventions in subgroups of caregivers of people with dementia. It makes clear that until now, relatively little research has been done into subgroups of these caregivers. It also suggests that more research is needed to better understand which psychosocial interventions are effective for specific subgroups of caregivers of people with dementia. Copyright © 2011 John Wiley & Sons, Ltd.
Resting‐state networks in awake five‐ to eight‐year old children
Authors: de Bie Henrica M.A. , Boersma Maria , Adriaanse Sofie , Veltman Dick J. , Wink Alle Meije , Roosendaal Stefan D. , Barkhof Frederik , Stam Cornelis J. , Oostrom Kim J. , Delemarre‐van de Waal Henriette A. , Sanz‐Arigita Ernesto J.
Published: April 2011

During the first 6–7 years of life children undergo a period of major neurocognitive development. Higher‐order cognitive functions such as executive control of attention, encoding and retrieving of stored information and goal‐directed behavior are present but less developed compared to older individuals. There is only very limited information from functional magnetic resonance imaging (fMRI) studies about the level of organization of functional networks in children in the early school period. In this study we perform continuous resting‐state functional connectivity MRI in 5‐ to 8‐year‐old children in an awake state to identify and characterize resting‐state networks (RSNs). Temporal concatenation independent component analysis (ICA) approach was applied to analyze the data. We identified 14 components consisting of regions known to be involved in visual and auditory processing, motor function, attention control, memory, and the default mode network (DMN). Most networks, in particular those supporting basic motor function and sensory related processing, had a robust functional organization similar to mature adult patterns. In contrast, the DMN and other RSNs involved in higher‐order cognitive functions had immature characteristics, revealing incomplete and fragmented patterns indicating less developed functional connectivity. We therefore conclude that the DMN and other RSNs involved in higher order cognitive functioning are detectable, yet in an immature state, at an age when these cognitive abilities are mastered. Hum Brain Mapp, 2011. © 2011 Wiley‐Liss, Inc.
Second malignancies after childhood noncentral nervous system solid cancer: Results from 13 cancer registries
Authors: Maule Milena , Scélo Ghislaine , Pastore Guido , Brennan Paul , Hemminki Kari , Olsen Jorgen H. , Tracey Elizabeth , Pukkala Eero , Weiderpass Elisabete , Brewster David H. , Tamaro Sharon , Chia Kee‐Seng , Pompe‐Kirn Vera , Kliewer Erich V. , Tonita Jon M. , Martos Carmen , Jonasson Jon G. , Merletti Franco , Boffetta Paolo
Published: April 2011

Children diagnosed with noncentral nervous system solid cancers (NCNSSC) experience several adverse late effects, including second malignant neoplasm. The aim of our study was to assess the risk of specific second malignancies after a childhood NCNSSC. Diagnosis and follow‐up data on 10,988 cases of NCNSSC in children (0–14 years) were obtained from 13 registries. Standardized incidence ratios (SIRs) with 95% confidence intervals (CI) and cumulative incidence of second malignancies were computed. We observed 175 second malignant neoplasms, yielding a SIR of 4.6, 95% CI: 3.9–5.3. When considering second cancers with at least 10 occurrences, highest relative risks were found for second malignant bone tumors (SIR = 26.4, 16.6–40.0), soft tissue sarcomas (SIR = 14.1, 6.7–25.8) and myeloid leukemia (SIR = 12.7, 6.3–22.8). Significant increased risks for all malignancies combined were observed after sympathetic nervous system tumors (SIR = 11.4, 5.2–21.6), retinoblastomas (SIR = 7.3, 5.4–9.8), renal tumors (SIR = 5.7, 3.8–8.0), malignant bone tumors (SIR = 5.6, 3.7–8.2), soft tissue sarcomas (SIR = 4.7, 3.2–6.8), germ‐cell, trophoblastic and other gonadal neoplasms (SIR = 2.5, 1.1–4.9), carcinomas and other malignant epithelial neoplasms (SIR = 2.2, 1.4–3.3). The highest risk of a second malignancy of any type occurred 5 to 9 years after NCNSSC (SIR = 9.9, 6.8–13.9). The cumulative incidence of second malignancies 10 years after the first neoplasm was eight times higher among NCNSSC survivors than in the general population, with the absolute difference between observed and expected cumulative incidence still increasing after 50 years of follow‐up. Children who survived a NCNSSC experience a large increased risk of developing a new malignancy, even many years after their initial diagnosis.
Evaluation of predictive models in daily practice for the identification of patients with Lynch syndrome
Authors: Tresallet Christophe , Brouquet Antoine , Julié Catherine , Beauchet Alain , Vallot Céline , Ménégaux Fabrice , Mitry Emmanuel , Radvanyi François , Malafosse Robert , Rougier Philippe , Nordlinger Bernard , Laurent‐Puig Pierre , Boileau Catherine , Emile Jean‐François , Muti Christine , Penna Christophe , Hofmann‐Radvanyi Hélène
Published: April 2011

The optimal strategy for identifying patients with Lynch syndrome among patients with newly diagnosed colorectal cancer (CRC) is still debated. Several predictive models (e.g., MMRpredict, PREMM1,2 and MMRpro) combining personal and familial data have recently been developed to quantify the risk that a given patient with CRC carries a Lynch syndrome‐causing mutation. Their clinical applicability to patients with CRC from the general population requires evaluation. We studied a consecutive series of 214 patients with newly diagnosed CRC characterized for tumor microsatellite instability (MSI), somatic BRAF mutation, MLH1 promoter methylation and mismatch repair (MMR) gene germline mutation status. The performances of the models for identifying MMR mutation carriers (8/214, 3.7%) were evaluated and compared to the revised Bethesda guidelines and a molecular strategy based on MSI testing in all patients followed by the exclusion of MSI‐positive sporadic cases from mutational testing by screening for BRAF mutation and MLH1 promoter methylation. The sensitivities of the three models, at the lowest thresholds proposed, were identical (75%), with similar numbers of probands eligible for further MSI testing (almost half the patients). In our dataset, the prediction models gave no better discrimination than the revised Bethesda guidelines. Both approaches failed to identify two of the eight mutation carriers (the same two patients, aged 67 and 81 years, both with no family history). Thus, like the revised Bethesda guidelines, predictive models did not identify all patients with Lynch syndrome in our series of consecutive CRC. Our results support systematic screening for MMR deficiency in all new CRC cases.
A biparatopic anti‐EGFR nanobody efficiently inhibits solid tumour growth
Authors: Roovers Rob C. , Vosjan Maria J.W.D. , Laeremans Toon , el Khoulati Rachid , de Bruin Renée C.G. , Ferguson Kathryn M. , Verkleij Arie J. , van Dongen Guus A.M.S. , van Bergen en Henegouwen Paul M.P.
Published: April 2011

The epidermal growth factor receptor (EGFR) has been shown to be a valid cancer target for antibody‐based therapy. At present, several anti‐EGFR monoclonal antibodies have been successfully used, such as cetuximab and matuzumab. X‐ray crystallography data show that these antibodies bind to different epitopes on the ecto‐domain of EGFR, providing a rationale for the combined use of these two antibody specificities. We have previously reported on the successful isolation of antagonistic anti‐EGFR nanobodies. In our study, we aimed to improve the efficacy of these molecules by combining nanobodies with specificities similar to both cetuximab and matuzumab into a single biparatopic molecule. Carefully designed phage nanobody selections resulted in two sets of nanobodies that specifically blocked the binding of either matuzumab or cetuximab to EGFR and that did not compete for each others' binding. A combination of nanobodies from both epitope groups into the biparatopic nanobody CONAN‐1 was shown to block EGFR activation more efficiently than monovalent or bivalent (monospecific) nanobodies. In addition, this biparatopic nanobody potently inhibited EGF‐dependent cell proliferation. Importantly, in an in vivo model of athymic mice bearing A431 xenografts, CONAN‐1 inhibited tumour outgrowth with an almost similar potency as the whole mAb cetuximab, despite the fact that CONAN‐1 is devoid of an Fc portion that could mediate immune effector functions. Compared to therapy using bivalent, monospecific nanobodies, CONAN‐1 was clearly more potent in tumour growth inhibition. These results show that the rational design of biparatopic nanobody‐based anticancer therapeutics may yield potent lead molecules for further development.
Intestinal inflammation induces genotoxicity to extraintestinal tissues and cell types in mice
Authors: Westbrook Aya M. , Wei Bo , Braun Jonathan , Schiestl Robert H.
Published: April 2011

Chronic intestinal inflammation leads to increased risk of colorectal and small intestinal cancers and is also associated with extraintestinal manifestations such as lymphomas, other solid cancers and autoimmune disorders. We have previously found that acute and chronic intestinal inflammation causes DNA damage to circulating peripheral leukocytes, manifesting a systemic effect in genetically and chemically induced models of intestinal inflammation. Our study addresses the scope of tissue targets and genotoxic damage induced by inflammation‐associated genotoxicity. Using several experimental models of intestinal inflammation, we analyzed various types of DNA damage in leukocyte subpopulations of the blood, spleen, mesenteric and peripheral lymph nodes and in intestinal epithelial cells, hepatocytes and the brain. Genotoxicity in the form of DNA single‐ and double‐stranded breaks accompanied by oxidative base damage was found in leukocyte subpopulations of the blood, diverse lymphoid organs, intestinal epithelial cells and hepatocytes. The brain did not demonstrate significant levels of DNA double‐stranded breaks as measured by γ‐H2AX immunostaining. CD4+ and CD8+ T‐cells were most sensitive to DNA damage versus other cell types in the peripheral blood. In vivo measurements and in vitro modeling suggested that genotoxicity was induced by increased levels of systemically circulating proinflammatory cytokines. Moreover, genotoxicity involved increased damage rather than reduced repair, as it is not associated with decreased expression of the DNA double‐strand break recognition and repair protein, ataxia telangiectasia mutated. These findings suggest that levels of intestinal inflammation contribute to the remote tissue burden of genotoxicity, with potential effects on nonintestinal diseases and cancer.
Analysis of the cellular uptake and nuclear delivery of insulin‐like growth factor binding protein‐3 in human osteosarcoma cells
Authors: Micutkova Lucia , Hermann Martin , Offterdinger Martin , Hess Michael W. , Matscheski Andrea , Pircher Haymo , Mück Christoph , Ebner Hannes‐Leonhard , Laich Andreas , Ferrando‐May Elisa , Zwerschke Werner , Huber Lukas A. , Jansen‐Dürr Pidder
Published: April 2011

Insulin‐like growth factor (IGF) binding protein‐3 (IGFBP‐3) regulates cell proliferation and survival by extracellular interaction and inactivation of the growth factor IGF‐I. Beyond that, IGF‐independent actions mediated by intracellular IGFBP‐3 including nuclear‐IGFBP‐3, have also been described. We here show, using both confocal and electron microscopy and cell fractionation, that the extracellular addition of IGFBP‐3 to living cells results in rapid uptake and nuclear delivery of IGFBP‐3, by yet partly unknown mechanisms. IGFBP‐3 is internalized through a dynamin‐dependent pathway, traffics through endocytic compartments and is finally delivered into the nucleus. We observed docking of IGFBP‐3 containing structures to the nuclear envelope and found IGFBP‐3 containing dot‐like structures to permeate the nuclear envelope. In summary, our findings establish the pathway by which this tumor suppressor protein is delivered from extracellular space to the nucleus.
Reported behavior of eating anything at anytime and risk of colorectal cancer in women
Authors: Bao Ying , Nimptsch Katharina , Chan Andrew T. , Ng Kimmie , Meyerhardt Jeffrey A. , Willett Walter C. , Giovannucci Edward , Fuchs Charles S.
Published: April 2011

Although numerous studies have assessed the effect of foods and nutrients on colorectal carcinogenesis, few studies have investigated human eating behavior in relation to risk of colorectal cancer. In our study, we assessed whether the reported behavior of eating anything at anytime influenced colorectal cancer risk and related plasma biomarkers. We prospectively followed up 55,540 women in the Nurses' Health Study who were aged 48–73 years, had no history of cancer, ulcerative colitis or diabetes and responded to the item “I eat anything I want, anytime I want” in the 1994 questionnaire. We also analyzed blood samples for 1,994 women, which were collected in 1989–1990. During 12 years of follow‐up, 552 colorectal cancer cases were documented. After adjusting for age, smoking, body mass index, physical activity, red and processed meat and other known risk factors for colorectal cancer, women who reported eating anything at anytime experienced an increased risk of colorectal cancer (relative risk = 1.28, 95% confidence interval = 1.06–1.56) compared to those who did not report this behavior. In addition, reporting eating anything at anytime was associated with higher fasting plasma levels of insulin (p = 0.04) and C‐peptide (p = 0.05). In conclusion, reports of eating anything at anytime are associated with an increased risk of colorectal cancer in this large prospective cohort study, independent of other potential risk factors for colorectal cancer.
An alternative measure of intergenerational income mobility based on a random coefficient model
Authors: Murtazashvili Irina
Published: April 2011

We propose an alternative measure of the degree to which income status is transmitted from one generation to another. Our indicator of intergenerational income mobility is based on a random coefficient model, which allows for variation in intergenerational mobility across families due to multiplicative unobserved family‐specific characteristics. This alternative measure suggests that intergenerational income persistence is typically stronger than when intergenerational income mobility is measured using the standard elasticity of sons' income with respect to fathers' income. Copyright © 2011 John Wiley & Sons, Ltd.
Chromatin interaction networks and higher order architectures of eukaryotic genomes
Authors: Singh Sandhu Kuljeet , Li Guoliang , Sung Wing‐Kin , Ruan Yijun
Published: April 2011

Eukaryotic genome is, not only linearly but also spatially, organized into non‐random architecture. Though the linear organization of genes and their epigenetic descriptors are well characterized, the relevance of their spatial organization is beginning to unfold only recently. It is increasingly being recognized that physical interactions among distant genomic elements could serve as an important mean to eukaryotic genome regulation. With the advent of proximity ligation based techniques coupled with next generation sequencing, it is now possible to explore whole genome chromatin interactions at high resolution. Emerging data on genome‐wide chromatin interactions suggest that distantly located genes are not independent entities and instead cross‐talk with each other in an extensive manner, supporting the notion of “chromatin interaction networks”. Moreover, the data also advance the field to “3‐dimensional (3D) chromatin structure and dynamics”, which would enable molecular biologists to explore the spatiotemporal regulation of genome. In this article, we introduce a stepwise topological transformation of genome from 1‐dimension (1D, linear) to 2‐dimension (2D, networks) to 3‐dimension (3D, architecture) and discuss how such transformations could advance our understanding of genome biology. J. Cell. Biochem. 112: 2218–2221, 2011. © 2011 Wiley‐Liss, Inc.
Fisetin induces Nrf2‐mediated HO‐1 expression through PKC‐δ and p38 in human umbilical vein endothelial cells
Authors: Lee Seung Eun , Jeong Seong Il , Yang Hana , Park Cheung‐Seog , Jin Young‐Ho , Park Yong Seek
Published: April 2011

Fisetin is a natural flavonoid from fruits and vegetables that exhibits antioxidant, neurotrophic, anti‐inflammatory, and anti‐cancer effects in various disease models. Up‐regulation of heme oxygenase‐1 (HO‐1) expression protects against oxidative stress‐induced cell death, and therefore, plays a crucial role in cytoprotection in a variety of pathological models. In the present study, we investigated the effect of fisetin on the up‐regulation of HO‐1 in human umbilical vein endothelial cells (HUVECs). Small interfering RNA and pharmacological inhibitors of PKC‐δ and p38 MAPK attenuated HO‐1 induction in fisetin‐stimulated HUVECs. Fisetin treatment resulted in significantly increased NF‐E2‐related factor 2 (Nrf2) nuclear translocation, and antioxidant response element (ARE)‐luciferase activity, leading to up‐regulation of HO‐1 expression. In addition, fisetin pretreatment reduced hydrogen peroxide (H2O2)‐induced cell death, and this effect was reversed by ZnPP, an inhibitor of HO‐1. In summary, these findings suggest that induction of HO‐1 expression via Nrf2 activation may contribute to the cytoprotection exerted by fisetin against H2O2‐induced oxidative stress in HUVECs. J. Cell. Biochem. 112: 2352–2360, 2011. © 2011 Wiley‐Liss, Inc.
β‐globin matrix attachment region improves stable genomic expression of the Sleeping beauty transposon
Authors: Sjeklocha Lucas , Chen Yixin , Daly Meghan C. , Steer Clifford J. , Kren Betsy T.
Published: April 2011

The liver is an attractive target for gene therapy due to its extensive capability for protein production and the numerous diseases resulting from a loss of gene function it normally provides. The Sleeping Beauty Transposon (SB‐Tn)1 system is a non‐viral vector capable of delivering and mediating therapeutic transgene(s) insertion into the host genome for long‐term expression. A current challenge for this system is the low efficiency of integration of the transgene. In this study we use a human hepatoma cell line (HuH‐7) and primary human blood outgrowth endothelial cells (BOECs) to test vectors containing DNA elements to enhance transposition without integrating themselves. We employed the human β‐globin matrix attachment region (MAR) and the Simian virus 40 (SV40) nuclear translocation signal to increase the percent of HuH‐7 cells persistently expressing a GFP::Zeo reporter construct by ∼50% for each element; while combining both did not show an additive effect. Interestingly, both elements together displayed an additive effect on the number of insertion sites, and in BOECs the SV40 alone appeared to have an inhibitory effect on transposition. In long‐term cultures the loss of plasmid DNA, transposase expression and mapping of insertion sites demonstrated bona fide transposition without episomal expression. These results show that addition of the β‐globin MAR and potentially other elements to the backbone of SB‐Tn system can enhance transposition and expression of therapeutic transgenes. These findings may have a significant influence on the use of SB transgene delivery to liver for the treatment of a wide variety of disorders. J. Cell. Biochem. 112: 2361–2375, 2011. © 2011 Wiley‐Liss, Inc.
Fanconi anemia D2 protein is an apoptotic target mediated by caspases
Authors: Park Su‐Jung , Beck Brian D. , Saadatzadeh M. Reza , Haneline Laura S. , Clapp D. Wade , Lee Suk‐Hee
Published: April 2011

FANCD2, a key factor in the FANC‐BRCA1 pathway is monoubiquitinated and targeted to discrete nuclear foci following DNA damage. Since monoubiquitination of FANCD2 is a crucial indicator for cellular response to DNA damage, we monitored the fate of FANCD2 and its monoubiquitination following DNA damage. Disappearance of FANCD2 protein was induced following DNA damage in a dose‐dependent manner, which correlated with degradation of BRCA1 and poly‐ADP ribose polymerase (PARP), known targets for caspase‐mediated apoptosis. Disappearance of FANCD2 was not affected by a proteasome inhibitor but was blocked by a caspase inhibitor. DNA damage‐induced disappearance of FANCD2 was also observed in cells lacking FANCA, suggesting that disappearance of FANCD2 does not depend on FANC‐BRCA1 pathway and FANCD2 monoubiquitination. In keeping with this, cells treated with TNF‐α, an apoptotic stimulus without causing any DNA damage, also induced disappearance of FANCD2 without monoubiquitination. Together, our data suggest that FANCD2 is a target for caspase‐mediated apoptotic pathway, which may be an early indicator for apoptotic cell death. J. Cell. Biochem. 112: 2383–2391, 2011. © 2011 Wiley‐Liss, Inc.
Motive‐oriented therapeutic relationship in brief psychodynamic intervention for patients with depression and personality disorders
Authors: Kramer Ueli , Rosciano Alessandra , Pavlovic Mirjana , Berthoud Laurent , Despland Jean‐Nicolas , de Roten Yves , Caspar Franz
Published: April 2011

Motive‐Oriented Therapeutic Relationship (MOTR, also called Complementary Therapeutic Relationship) has already shown itself to be related to therapeutic outcome in several studies. The present study aims to test MOTR in a 4‐session Brief Psychodynamic Intervention for patients presenting with major depressive disorder (MDD) and comorbid personality disorder (PD). In total, N = 20 patients were selected; n = 10 had MDD, n = 10 had MDD with comorbid PD. The first therapy session was videotaped and analyzed by means of Plan Analysis and the MOTR scale. Results suggest a differential effect on outcome: only the nonverbal component of MOTR is related to symptomatic change in patients presenting with MDD and comorbid PD; no such effect was found for patients with MDD alone. These results are discussed in line with the generalization and refinement of the conclusions of previous findings on the MOTR. © 2011 Wiley Periodicals, Inc. J Clin Psychol 67:1–11, 2011.
P‐glycoprotein mediates resistance to A3 adenosine receptor agonist 2‐chloro‐N6‐(3‐iodobenzyl)‐adenosine‐5′‐n‐methyluronamide in human leukemia cells
Authors: Mlejnek Petr , Dolezel Petr , Kosztyu Petr
Published: April 2011

We studied effects of 2‐chloro‐N6‐(3‐iodobenzyl)‐adenosine‐5′‐N‐methyluronamide (Cl‐IB‐MECA) on apoptosis induction in the K562/Dox cell line, which overexpressed P‐glycoprotein (P‐gp, ABCB1, MDR1). We found that the K562/Dox cell line was significantly more resistant to Cl‐IB‐MECA than the maternal cell line K562, which did not express P‐gp. Although both cell lines expressed the A3 adenosine receptor (A3AR), cytotoxic effects of Cl‐IB‐MECA were not prevented by its selective antagonist MRS1523 (3‐propyl‐6‐ethyl‐5‐[(ethylthio)carbonyl]‐2 phenyl‐4‐propyl‐3‐pyridine carboxylate). Analysis of cell extracts revealed that the intracellular level of Cl‐IB‐MECA was significantly lower in the K562/Dox cell line than in the maternal cell line K562. The downregulation of P‐gp expression using shRNA targeting ABCB1 gene led to increased intracellular level of Cl‐IB‐MECA and restored cell sensitivity to this drug. Similarly, valspodar (PSC‐833), a specific inhibitor of P‐gp, restored sensitivity of the K562/Dox cell line to Cl‐IB‐MECA with concomitant increase of intracellular level of Cl‐IB‐MECA in the resistant cell line, while it affected cytotoxicity of Cl‐IB‐MECA in the sensitive cell line only marginally. An enzyme based assay provided evidence for interaction of P‐gp with Cl‐IB‐MECA. We further observed that cytotoxic effects of Cl‐IB‐MECA could be augmented by activation of extrinsic cell death pathway by Apo‐2L (TRAIL) but not FasL or TNF‐α. Our results revealed that Cl‐IB‐MECA induced an increase in expression of TRAIL receptors in K562 cells, which could sensitize cells to apoptosis induction via an extrinsic cell death pathway. Importantly, these effects were inversely related to P‐gp expression. In addition, MRS1523 did not affect Cl‐IB‐MECA induced expression of TRAIL receptors. J. Cell. Physiol. 227: 676–685, 2012. © 2011 Wiley Periodicals, Inc.
Human β‐defensins differently affect proliferation, differentiation, and mineralization of osteoblast‐like MG63 cells
Authors: Kraus D. , Deschner J. , Jäger A. , Wenghoefer M. , Bayer S. , Jepsen S. , Allam J. P. , Novak N. , Meyer R. , Winter J.
Published: April 2011

Purpose of this study was to investigate whether human β‐defensins (hBDs) affect maturation and proliferation of osteoblast‐like MG63 cells in vitro. Osteoblast‐like MG63 cells were stimulated with hBD‐1, ‐2, and ‐3 under control conditions and with hBD‐2 during experimental inflammation (induced by interleukin‐1β, tumor necrosis factor‐α, toll‐like receptor‐2 and ‐4 agonists). Expression of different osteogenic markers and hBDs were analyzed by real‐time PCR, immunohistochemistry, and enzyme‐linked immunosorbent assay. In addition, alkaline phosphatase (ALP) enzyme activity and biomineralization as markers for differentiation were monitored. All tested hBDs were expressed on mRNA and protein level in MG63 cells. Only stimulation with hBD‐2 elevated the proliferation rate. hBD‐2 and hBD‐3 positively affected the differentiation of osteoblast‐like cells provided by increased transcript levels of osteogenic markers, up‐regulated ALP enzyme activity and enhanced mineralized nodule formation. All pro‐inflammatory stimuli enhanced interleukin‐6 and hBD‐2 expression and down‐regulated markers of osteoblastic differentiation. In accordance, inflammation increased transcript level of Notch‐1 (an inhibitor of osteoblastic differentiation). hBD‐2 was not able to revert effects of inflammation on differentiation. In bone cells human β‐defensins exhibit further functions than antimicrobial peptide activity. These include stimulation of proliferation and differentiation. Differentiation arrest due to inflammation could not be overcome by hBD‐2 alone. J. Cell. Physiol. 227: 994–1003, 2012. © 2011 Wiley Periodicals, Inc.
Enhanced lipid—but not carbohydrate—supported mitochondrial respiration in skeletal muscle of PGC‐1α overexpressing mice
Authors: Hoeks Joris , Arany Zolt , Phielix Esther , Moonen‐Kornips Esther , Hesselink Matthijs K.C. , Schrauwen Patrick
Published: April 2011

Skeletal muscle mitochondrial dysfunction has been linked to several disease states as well as the process of aging. A possible factor involved is the peroxisome proliferator‐activated receptor (PPAR) γ co‐activator 1α (PGC‐1α), a major player in the regulation of skeletal muscle mitochondrial metabolism. However, it is currently unknown whether PGC‐1α, besides stimulating mitochondrial proliferation, also affects the functional capacity per mitochondrion. Therefore, we here tested whether PGC‐1α overexpression, besides increasing mitochondrial content, also leads to intrinsic mitochondrial adaptations. Skeletal muscle mitochondria from 10 male, muscle‐specific PGC‐1α overexpressing mice (PGC‐1αTg) and 8 wild‐type (WT) mice were isolated. Equal mitochondrial quantities were then analyzed for their oxidative capacity by high‐resolution respirometry, fuelled by a carbohydrate‐derived (pyruvate) and a lipid (palmitoyl‐CoA plus carnitine) substrate. Additionally, mitochondria were tested for reactive oxygen species (superoxide) production and fatty acid (FA)‐induced uncoupling. PGC‐1αTg mitochondria were characterized by an improved intrinsic mitochondrial fat oxidative capacity as evidenced by pronounced increase in ADP‐stimulated respiration (P < 0.001) and maximal uncoupled respiration (P < 0.001) upon palmitoyl‐CoA plus carnitine. Interestingly, intrinsic mitochondrial capacity on a carbohydrate‐derived substrate tended to be reduced. Furthermore, the sensitivity to FA‐induced uncoupling was diminished in PGC‐1αTg mitochondria (P = 0.02) and this was accompanied by a blunted reduction in mitochondrial ROS production upon FAs in PGC‐1αTg versus WT mitochondria (P = 0.04). Uncoupling protein 3 (UCP3) levels were markedly reduced in PGC‐1αTg mitochondria (P < 0.001). Taken together, in addition to stimulating mitochondrial proliferation in skeletal muscle, we show here that overexpression of PGC‐1α leads to intrinsic mitochondrial adaptations that seem restricted to fat metabolism. J. Cell. Physiol. 227: 1026–1033, 2012. © 2011 Wiley Periodicals, Inc.