bluuebunny/crossref_metadata_2025 huggingface dataset:
MHC class II molecules activate NFAT and the ERK group of MAPK through distinct signaling pathways in B cells
Authors: Haylett Romney S. , Koch Norbert , Rink Lothar
Published: June 2009

MHC class II (MHC‐II) molecules are capable of transducing signals with the help of associated molecules. Although the search to find associated molecules over the past few years has been fruitful, it remains clear that not all signaling components and their mechanisms of action have been identified. In this study, we investigated calcium and MAPK signaling pathways using the BJAB and Raji human B cell lines. We demonstrate that calcium mobilization is an isotype‐independent event that triggers the dephosphorylation of NFAT. We also show that BCR activation followed by MHC‐II ligation increases the activation of NFAT. This signaling pathway differs from MHC‐II‐mediated MAP activation, where MEK1/2 and ERK1/2 phosphorylation are isotype‐specific events, which correspond to the induction of c‐Fos and formation of AP‐1. Future studies should elucidate the intertwined, intricate signaling cascades triggered by BCR and MHC‐II leading to humoral immune responses.
IL‐15 is critical for the maintenance and innate functions of self‐specific CD8+ T cells
Authors: Itsumi Momoe , Yoshikai Yasunobu , Yamada Hisakata
Published: June 2009

IL‐15 is a pleiotropic cytokine involved in host defense as well as autoimmunity. IL‐15‐deficient mice show a decrease of memory phenotype (MP) CD8+ T cells, which develop naturally in naïve mice and whose origin is unclear. It has been shown that self‐specific CD8+ T cells developed in male H‐Y antigen‐specific TCR transgenic mice share many similarities with naturally occurring MP CD8+ T cells in normal mice. In this study, we found that H‐Y antigen‐specific CD8+ T cells in male but not female mice decreased when they were crossed with IL‐15‐deficient mice, mainly due to impaired peripheral maintenance. The self‐specific TCR transgenic CD8+ T cells developed in IL‐15‐deficient mice showed altered surface phenotypes and reduced effector functions ex vivo. Bystander activation of the self‐specific CD8+ T cells was induced in vivo during infection with Listeria monocytogenes, in which proliferation but not IFN‐γ production was IL‐15‐dependent. These results indicated important roles for IL‐15 in the maintenance and functions of self‐specific CD8+ T cells, which may be included in the naturally occurring MP CD8+ T‐cell population in naïve normal mice and participate in innate host defense responses.
Neonates harbour highly active γδ T cells with selective impairments in preterm infants
Authors: Gibbons Deena L. , Haque Syeda F. Y. , Silberzahn Tobias , Hamilton Katherine , Langford Cordelia , Ellis Peter , Carr Robert , Hayday Adrian C.
Published: June 2009

Acknowledgement of the breadth of T‐cell pleiotropy has provoked increasing interest in the degree to which functional responsiveness is elicited by environmental cues versus differentiation. This is particularly relevant for young animals requiring rapid responses to acute environmental exposure. In young mice, γδ T cells are disproportionately important for immuno‐protection. To examine the situation in humans, we compared populations and clones of T cells from term and preterm babies, and adults. By comparison with αβ T cells, neonate‐derived γδ cells show stronger, pleiotropic functional responsiveness, and lack signatory deficits in IFN‐γ production. Emphasising the acquisition of functional competence in utero, IFN‐γ was produced by γδ cells sampled from premature births, and, although one month's post‐partum environmental exposure invariably increased their TNF‐α production, it had no consistent effect on IFN‐γ or IL‐2. In sum, γδ cells seem well positioned at birth to contribute to immuno‐protection and immuno‐regulation, possibly compensating for selective immaturity in the αβ compartment. With regard to the susceptibilities of preterm babies to viral infection, γδ cells from preterm neonates were commonly impaired in Toll‐like receptor‐3 and ‐7 expression and compared with cells from term babies failed to optimise cytokine production in response to coincident TCR and TLR agonists.
Type I IFN regulate DC turnover in vivo
Authors: Mattei Fabrizio , Bracci Laura , Tough David F. , Belardelli Filippo , Schiavoni Giovanna
Published: June 2009

DC are the most potent antigen‐presenting cells that recognise signs of infection and serve as the main activators of naïve T cells. We have previously shown that type I IFN (IFN‐I) are produced by DC and can act in an autocrine manner to activate DC. In the present study, we have investigated the role of IFN‐I in regulating the turnover and lifespan of DC. We found that DC, especially the CD8α+ subset, from type I IFN receptor knock out (IFNAR KO) mice, display a reduced turnover rate when compared with DC from WT mice, as revealed by BrdU labelling kinetics. In vitro, IFNAR KO BM precursor cells cultured in the presence of GM‐CSF generated CD11c+ DC less efficiently than WT BM, and the IFNAR KO DC that arose displayed reduced migratory ability. Interestingly, splenic DC from IFNAR KO mice exhibited a higher survival rate in short‐term culture compared with control DC. Exposure to IFN‐I in vivo markedly increased the turnover rate of splenic DC, particularly CD8α+ DC, which was preceded by a transient induction of apoptosis. In accordance with this, IFN‐I stimulated the apoptosis of splenic DC in vitro. Overall, our data indicate that IFN‐I are important regulators of DC turnover in vivo and suggest that these cytokines may exert this function through the modulation of multiple processes involving DC apoptosis, proliferation and migration.
A Th17‐like developmental process leads to CD8+ Tc17 cells with reduced cytotoxic activity
Authors: Huber Magdalena , Heink Sylvia , Grothe Henrike , Guralnik Anna , Reinhard Katharina , Elflein Karin , Hünig Thomas , Mittrücker Hans‐Willi , Brüstle Anne , Kamradt Thomas , Lohoff Michael
Published: June 2009

Activation of naive CD8+ T cells with antigen in the absence of skewing cytokines triggers their differentiation into effector CTL, which induces death of target cells. We show that CD8+ T cells activated in the presence of the cytokines IL‐6 or IL‐21 plus TGF‐β similar to CD4+ T cells, develop into IL‐17‐producing (Tc17) cells. These cells display greatly suppressed cytotoxic function along with low levels of the CTL markers: T‐box transcription factor Eomesodermin, granzyme B and IFN‐γ. Instead, these cells express hallmark molecules of Th17 program including retinoic acid receptor‐related orphan receptor (ROR)γt, RORα, IL‐21 and IL‐23R. The expression of the type 17 master regulator RORγt is causally linked to Tc17 generation, because its overexpression stimulates production of IL‐17 in the presence of IL‐6 or IL‐21. Both, upregulation of the type 17 program as well as suppression of CTL differentiation are STAT3 dependent. Furthermore, Tc17 cells producing IL‐17 but not granzyme B are also detectable in EAE, a mouse model for multiple sclerosis. Our data point to the existence of mutually exclusive CTL and Tc17 developmental pathways in vitro and in vivo.
Assessing rabbit and chicken tissue susceptibility to oxidation through the ferrous oxidation‐xylenol orange method
Authors: Tres Alba , Nuchi Carla Daniela , Bou Ricard , Codony Rafael , Guardiola Francesc
Published: June 2009

We used an induced version of the FOX method to assess the oxidative stability of meats. Formerly, this induced version only measured the lipid hydroperoxide (LHP) value once the ferrous oxidation‐xylenol orange (FOX) reaction had reached a plateau. However, samples could have similar final LHP values that were reached in different ways. Thus, there may be variations in the samples' susceptibility to oxidation that are not detected by a final measurement of the LHP value. If the LHP value is measured at different points in the FOX reaction, it might be possible to calculate parameters such as induction time, oxidation rate, maximum LHP value, time of maximum LHP value and area under the curve. Such parameters might provide deeper insight into the evolution of oxidation in each sample than a final measurement of the LHP value. However, the accuracy of the measurement of these parameters could depend on the number of LHP measurements that can be taken during the FOX reaction. This improvement in the FOX method for assessing sample susceptibility to oxidation was applied to meats and other tissues such as liver.
Enzymatic reduction of polyunsaturated lysophosphati‐dylcholine hydroperoxides by glutathione peroxidase‐1
Authors: Huang Long Shuang , Kim Mee Ree , Sok Dai‐Eun
Published: June 2009

Some lipid peroxides are known to be converted to their corresponding alcohols in cells containing glutathione peroxidase (GPx). In this respect, we examined the enzymatic conversion of lysophosphatidylcholine (lysoPC) hydroperoxides to hydroxyl derivatives using RBL‐2H3 cells and erythrocyte GPx‐1. First, the incubation of RBL‐2H3 cells with arachidonoyl lysoPC led to the formation of a major product, with maximal UV absorbance at 234 nm and m/z [M+H]+ at 560.2, corresponding to monohydroxyeicosatetraenoyl lysoPC. Similarly, linoleoyl lysoPC was also converted to its hydroxyl derivative in RBL‐2H3 cells. Separately, lysoPC hydroperoxide, generated from soybean lipoxygenase 1‐catalyzed oxygenation of linoleoyl lysoPC, arachidonoyl lysoPC or docosahexaenoyl lysoPC, was converted by GPx‐1 to the corresponding hydroxyl derivatives. When the kinetic values were determined, the Km values (3.1–32.3 µM) of the polyunsaturated lysoPC hydroperoxides increased with decreasing number of double bonds, in contrast to a similar value of Vm among them. Moreover, the catalytic efficiency of docosahexaenoyl lysoPC hydroperoxide was much greater than that of H2O2 as substrate of GPx‐1. In related experiments, where phosphatidylcholine hydroperoxides were incubated with phospholipase A2 and GPx‐1, the complete conversion of phosphatidylcholine hydroperoxides to hydroxyl derivatives was confirmed by LC/MS. Taken together, it is proposed that GPx‐1‐type enzymes may participate in the conversion of polyunsaturated lysoPC hydroperoxides to hydroxyl derivatives in cell systems.
Unfavourable family characteristics and their associations with childhood obesity: A cross‐sectional study
Authors: Moens Ellen , Braet Caroline , Bosmans Guy , Rosseel Yves
Published: June 2009

Objective

This cross‐sectional study explores the influence of multiple familial factors on children's weight status and the interaction between parenting stress and unfavourable family characteristics.

Methods

A total of 197 families with children between 6 and 14 years participated in this study. Of this group, 97 families had a child with normal weight and 100 families had a child with overweight. Parents reported on seven family factors (maternal BMI, number of children, family structure, socioeconomic position, life events, parental psychopathology and parenting stress).

Results

Families with overweight children experience more parenting stress. A regression analysis revealed that familial factors explain 27% in the variance in child's weight status. The hypothesis that a combination of familial factors will be more able to explain child's adiposity could not be confirmed.

Conclusions

Familial factors have moderate ability to predict children's weight status. There is a need to identify other familial mechanisms taking into account developmental and temporal evolutions over the past decade. Copyright © 2009 John Wiley & Sons, Ltd and Eating Disorders Association.
The uniform fuzzy index of power system security
Authors: Halilčević Suad Smail , Gubina Ferdinand , Gubina Andrej Ferdo
Published: June 2009

The paper presents a new approach to assessment of the power system security. Using fuzzy membership functions of power system elements, it continuously quantifies the security state of a power system, as opposed to conventional methods which use off‐line screening for the most vulnerable system states. It introduces global fuzzy security index (GFSI) of the power system using system's variables characterized by fuzzy sets of a trapezoidal form. GFSI is calculated by multiplying the security membership grade (SMG) values of the power system's segments that exhibit the lowest SMG values. The power system security levels are traced continually through time using real data of power flow and state estimation calculations as well as measurements of variables inaccessible by the load flow analysis. The GFSI enables the system operator to identify the insecure state and then continuously monitor the distance of the power system's actual state and the insecure one. Application of the algorithm is illustrated using the data of Bosnian power system. Copyright © 2009 John Wiley & Sons, Ltd.
An adaptive distance relaying strategy based on global network simulation
Authors: Sadr V. Gohari , Kouhsari SH. M.
Published: June 2009

In this paper, a new method based on Global Network Simulation (GNS) approach for adaptive distance relaying is presented. The GNS approach uses Diakoptics and Large Change Sensitivity (LCS) concepts to perform the interconnected power systems analysis globally. The proposed method employs the decentralized nature of GNS short circuit analysis for calculation of relay settings of each sub‐network independently in the federal environment. Updating the relay settings of each utility in every power system conditions adaptively as well as meeting individual utilities' adopted coordination philosophies are great achievements of presented approach. No computational errors encountered in the proposed method since the applied concepts eliminates the usual needs for equivalent network or reduced models. The proposed approach is well fitted for nowadays restructured power industry requirements. The performance of the presented approach is examined using the IEEE 14 bus as a small tangible test system and a real version of huge interconnected network for practical purposes. The results compared with conventional approach. Copyright © 2009 John Wiley & Sons, Ltd.
Suppressing white‐noise in partial discharge measurements part 2: the optimal de‐noising scheme
Authors: Xie Yanbin , Tang Ju , Zhang Xiaoxing
Published: June 2009

Suppressing white noise in partial discharge (PD) measurements is a very challenging task. Complex Daubechies wavelet (CDW) transform is proved to be an effective method of noise rejection because of its shift‐invariance and available of phase information. The major challenge of noise rejection based on CDW transform is the determination of the optimal mother CDW, complex threshold and combined information. In this paper, a new method of determination of the optimal de‐noising scheme is proposed to solve this problem. The optimal mother CDW is determined by comparing the shift‐invariance among CDW2 to CDW12. Combined information and complex threshold are determined by calculating the waveform similarity between original signals and de‐noised signals as well as peak‐signal‐to‐noise ratio (PSNR) of de‐noised signals. On‐site applications of extracting PD signals from noisy background by the optimal de‐noising scheme based on CDW are illustrated. The on‐site experimental results show that the optimal de‐noising scheme is an effective way to suppress white noise in PD measurement. It preserves more energy of original signals and enables the waveform distortion small after de‐noising. Copyright © 2009 John Wiley & Sons, Ltd.
Characterization and gene expression profiling in glioma cell lines with deletion of chromosome 19 before and after microcell‐mediated restoration of normal human chromosome 19
Authors: Drucker Kristen L. , Kitange Gaspar J. , Kollmeyer Thomas M. , Law Mark E. , Passe Sandra , Rynearson Amanda L. , Blair Hilary , Soderberg Cheryl L. , Morlan Bruce W. , Ballman Karla V. , Giannini Caterina , Jenkins Robert B.
Published: June 2009

Nearly 10% of human gliomas are oligodendrogliomas. Deletion of chromosome arm 19q, often in conjunction with deletion of 1p, has been observed in 65–80% of these tumors. This has suggested the presence of a tumor suppressor gene located on the 19q arm. Chromosome 19 deletion is also of interest due to the better prognosis of patients with deletion, including longer survival and better response to chemotherapy, compared with patients without deletion. Two glioma cell lines with deletion of 19q were used for chromosome 19 microcell‐mediated transfer, to assess the effect of replacing the deleted segment. Complementation with chromosome 19 significantly reduced the growth rate of the hybrid cells compared with the parental cell lines. Affymetrix U133 Plus 2.0 Gene Chip analysis was performed to measure and compare the expression of the chromosome 19 genes in the chromosome 19 hybrid cell lines to the parental cell line. Probes were considered significantly different when a P value <0.01 was seen in all of the cell line comparisons. Of 345 probes within the commonly deleted 19q region, seven genes (APOE, RCN3, FLJ10781, SAE1, STRN4, CCDC8, and BCL2L12) were identified as potential candidate genes. RT‐PCR analysis of primary tumor specimens showed that several genes had significant differences when stratified by tumor morphology or deletion status. This suggests that one or more of these candidates may play a role in glioma formation or progression. © 2009 Wiley‐Liss, Inc.
Palaeoenvironmental context of the Late‐glacial woolly mammoth (Mammuthus primigenius) discoveries at Condover, Shropshire, UK
Authors: Allen J. R. M. , Scourse J. D. , Hall A. R. , Coope G. R.
Published: June 2009

In 1986/1987 the remains of several mammoths, Mammuthus primigenius (Blumenbach), were discovered on the spoil heap of an actively working gravel pit at Condover, Shropshire, England. The discovery of the remains posed two questions that could be addressed by analyses of biological proxies. First, as none of the bones was found in situ it was necessary to confirm the stratum in which the remains occurred. Second, what was the environment in which these animals lived and died? A range of biological indicators was used to address these questions, including pollen, spore and algal, plant macrofossil, invertebrate, anuran and biological mineral analyses. Multivariate statistical analyses of palynological and Pediastrum data, along with evidence from the Coleopteran assemblages, support the attribution of the mammoth bones to a unit of dark grey clayey sandy silt, although they may have lived at the time of the overlying green detritus mud. The palaeobiological data supports the correlation of these sediments to the Devensian Late‐glacial. The mammoths entered this basin at the start of the Late‐glacial Interstadial (Greenland Interstadial 1e) (ca. 14 830—3930 cal. year BP; 12 300 ± 110 14C year BP) and became mired in soft cohesive sediments. Palaeotemperature reconstructions, based on the Coleopteran assemblages, from the time when the mammoths actually became mired, show that the climate was temperate with mean July temperatures between 15 and 19°C and mean January temperatures between −13 and +6°C. Biological indicators from the sediments encasing the mammoths indicate that the landscape surrounding the basin was treeless and dry, contrasting with rich vegetation within the basin itself that had possibly attracted the mammoths to the site. Evidence of sedimentary disturbance suggests that the mammoths caused large‐scale bioturbation of the deposits making palaeoenvironmental interpretations difficult. Fossils of terrestrial blowflies, carcass and dung beetles show that some of the decaying corpses must have lain exposed on the land surface for sufficient time for the soft parts to have rotted away and skin and bones to have become desiccated before many of them sank into the dark grey clayey sandy silt. Copyright © 2009 John Wiley & Sons, Ltd.
Late‐glacial mammoth skeletons (Mammuthusprimigenius) from Condover (Shropshire, UK): anatomy, pathology, taphonomy and chronological significance
Authors: Lister Adrian M.
Published: June 2009

The Condover mammoths, discovered by chance in 1986, are a remarkably well‐preserved assemblage of partial skeletons unique in western and central Europe. The skeletons were preserved in a kettle‐hole infill and recoveredex situ, requiring careful anatomical reconstruction. This revealed the skeleton of a 28‐year‐old adult male woolly mammoth (Mammuthus primigenius), largely complete except for the cranium, the partial skeletons of four or five juveniles in the age range 3–6 years, plus sparse remains of a subadult individual. The adult skeleton bears several traces of pathology, particularly a badly fractured but re‐healed scapula. The presence of blowfly puparia within bone cavities, together with other environmental data and a consideration of mammoth biology, allow a detailed reconstruction of the taphonomy of the skeletons, which appear to have become mired within the kettle‐hole. The discovery of complete skeletons from a stratified, dated context contributes strong evidence for the survival of mammoths in Britain and western Europe into the Devensian Late‐glacial ca. 14.5–14.0 ka cal BP, within Greenland Interstadial 1. Copyright © 2009 John Wiley & Sons, Ltd.
Late‐glacial remains of woolly mammoth (Mammuthus primigenius) from Shropshire, UK: stratigraphy, sedimentology and geochronology of the Condover site
Authors: Scourse J. D. , Coope G. R. , Allen J. R. M. , Lister A. M. , Housley R. A. , Hedges R. E. M. , Jones A. S. G. , Watkins R.
Published: June 2009

In 1986 remains of an adult woolly mammoth, Mammuthus primigenius (Blumenbach), were discovered at Norton Farm Pit, Condover, south of Shrewsbury, UK. Preliminary stratigraphical investigations indicated that this individual dated to the Devensian Late‐glacial Interstadial, then the first evidence for survival of mammoth in Britain following the Last Glacial Maximum. Initial radiocarbon analysis confirmed this interpretation. Subsequent excavations in 1987/1988 recovered the remains of a further three juvenile mammoth individuals. All of these remains were found in the spoil heaps of overburden (ex situ) and their true stratigraphical context had to be reconstructed from the remnants surviving in the Pit. The 1987/1988 excavations enabled stratigraphical investigation of the site and submission of samples for radiocarbon (14C) dating, including the use of ultrafiltration pretreatment for bone samples, with the aims of reconstructing the geological and palaeoenvironmental evolution of the site and the sedimentary context of the unstratified mammoth remains. These results are presented here. This investigation indicates that the woolly mammoth remains at Condover derive from a dead‐ice landscape dominated by eskers, kames and kettle‐hole basins, and that the sedimentary sequence in which the mammoth remains were found forms the infilling of a kettle‐hole basin. The sedimentary infilling and formation of the kettle‐hole basin through ice block melt‐induced subsidence were syngenetic. 14C determinations indicate that basin infill was initiated prior to Greenland Interstadial 1, and probably in Greenland Stadial 2 i.e. before 14.7 ka BP and that it continued until the early Holocene, around 8 ka BP. The sedimentological and 14C data indicate that the unstratified mammoth remains can be attributed to a dark grey clayey sandy silt (Unit C1), which accumulated during the earlier part of Greenland Interstadial 1 (14 to 14.5 ka BP) within an actively subsiding slow‐flowing, beaded, fluvial network characterized by channels and pools/lakes, and with relatively shallow marginal slopes. The sedimentary architecture indicates survival of the buried ice block into Greenland Interstadial 1 and final melting only towards the end of the Interstadial at ca. 12.65 ka BP. Copyright © 2009 John Wiley & Sons, Ltd.
Maintaining retinal astrocytes normalizes revascularization and prevents vascular pathology associated with oxygen‐induced retinopathy
Authors: Dorrell Michael I. , Aguilar Edith , Jacobson Ruth , Trauger Sunia A. , Friedlander Jeffrey , Siuzdak Gary , Friedlander Martin
Published: June 2009

Astrocytes are well known modulators of normal developmental retinal vascularization. However, relatively little is known about the role of glial cells during pathological retinal neovascularization (NV), a leading contributor to vision loss in industrialized nations. We demonstrate that the loss of astrocytes and microglia directly correlates with the development of pathological NV in a mouse model of oxygen‐induced retinopathy (OIR). These two distinct glial cell populations were found to have cooperative survival effects in vitro and in vivo. The intravitreal injection of myeloid progenitor cells, astrocytes, or astrocyte‐conditioned media rescued endogenous astrocytes from degeneration that normally occurs within the hypoxic, vaso‐obliterated retina following return to normoxia. Protection of the retinal astrocytes and microglia was directly correlated with accelerated revascularization of the normal retinal plexuses and reduction of pathological intravitreal NV normally associated with OIR. Using astrocyte‐conditioned media, several factors were identified that may contribute to the observed astrocytic protection and subsequent normalization of the retinal vasculature, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Injection of VEGF or bFGF at specific doses rescued the retinas from developing OIR‐associated pathology, an effect that was also preceded by protection of endogenous glia from hypoxia‐induced degeneration. Together, these data suggest that vascular‐associated glia are also required for normalized revascularization of the hypoxic retina. Methods developed to target and protect glial cells may provide a novel strategy by which normalized revascularization can be promoted and the consequences of abnormal NV in retinal vascular diseases can be prevented. © 2009 Wiley‐Liss, Inc.
Expression of antigen processing and presenting molecules by Schwann cells in inflammatory neuropathies
Authors: Meyer Zu Horste Gerd , Heidenreich Holger , Lehmann Helmar C. , Ferrone Soldano , Hartung Hans‐Peter , Wiendl Heinz , Kieseier Bernd C.
Published: June 2009

Schwann cells are the myelinating glia cells of the peripheral nervous system (PNS) and can become targets of an autoimmune response in inflammatory neuropathies like the Guillain‐Barré syndrome (GBS). Professional antigen presenting cells (APCs) are known to promote autoimmune responses in target tissues by presenting self‐antigens. Other cell types could participate in local autoimmune responses by acting as nonprofessional APCs. Using a combined approach of immunocytochemistry, immunohistochemistry, and flow cytometry analysis we demonstrate that human Schwann cells express the antigen processing and presenting machinery (APM) in vitro and in vivo. Moreover, cultured human Schwann cells increase the expression of proteasome subunit delta (Y), antigen peptide transporter TAP2, and HLA Class I and HLA Class II complexes in an inflammatory environment. In correlation with this observation, Schwann cells in sural nerve biopsies from GBS patients show increased expression of antigen processing and presenting molecules. Furthermore, cultured human Schwann cells can proteolytically digest fluorescently‐labeled nonmammalian antigen ovalbumin. Taken together, our data suggest antigen processing and presentation as a possible function of Schwann cells that may contribute to (auto)immune responses within peripheral nerves. © 2009 Wiley‐Liss, Inc.
Hydrogen sulfide‐releasing NSAIDs attenuate neuroinflammation induced by microglial and astrocytic activation
Authors: Lee Moonhee , Sparatore Anna , Del Soldato Piero , Mcgeer Edith , McGeer Patrick L.
Published: June 2009

Endogenously generated hydrogen sulfide (H2S) may have multiple functions in brain. It has been shown that H2S attenuates the expression of pro‐inflammatory cytokines by lipopolysaccharide (LPS)‐activated microglia. Here we demonstrate a neuroprotective effect of NaSH and three H2S‐releasing compounds, ADT‐OH, S‐diclofenac, and S‐aspirin. When activated by LPS and γ‐interferon, human microglia and THP‐1 cells release materials that are toxic to human neuroblastoma SH‐SY5Y cells. These phenomena also occur with γ‐interferon‐stimulated human astroglia and U118 cells. When these cell types are pretreated with aspirin, diclofenac, NASH, or ADT‐OH, the supernatants are significantly less toxic. When they are treated with the NSAID‐H2S hybrid molecules S‐diclofenac and S‐aspirin, which are here referred to as S‐NSAIDs, there is a significant enhancement of the protection. The effect is concentration and incubation time dependent. Such pretreatment also reduces the release of the proinflammatory mediators TNFα, IL‐6, and nitric oxide. The H2S‐releasing compounds are without effect when applied directly to SH‐SY5Y cells. These data suggest that hybrid H2S releasing compounds have significant antiinflammatory properties and may be candidates for treating neurodegenerative disorders that have a prominent neuroinflammatory component such as Alzheimer disease and Parkinson disease. © 2009 Wiley‐Liss, Inc.
Involvement of cathepsin B in the processing and secretion of interleukin‐1β in chromogranin A‐stimulated microglia
Authors: Terada Kayo , Yamada Jun , Hayashi Yoshinori , Wu Zhou , Uchiyama Yasuo , Peters Christoph , Nakanishi Hiroshi
Published: June 2009

Cathepsin B (CB) is a cysteine lysosomal protease implicated in a number of inflammatory diseases. Although it is now evident that caspase‐1, an essential enzyme for maturation of interleukin‐1β (IL‐1β), can be activated through the inflammasome, there is still evidence suggesting the existence of lysosomal‐proinflammatory caspase pathways. In the present study, a marked induction of pro‐IL‐1β, its processing to the mature form and secretion were observed in the primary cultured microglia prepared from wild‐type mice after stimulation with chromogranin A (CGA). Although pro‐IL‐1β also markedly increased in microglia prepared from CB‐deficient mice, CB‐deficiency abrogated the pro‐IL‐1β processing. CA‐074Me, a specific inhibitor for CB, inhibited the pro‐IL‐1β maturation and its release from microglia. Furthermore, the caspase‐1 activation was also inhibited by CA‐074Me and E‐64d, a broad cysteine protease inhibitor. After treatment with CGA, CB was markedly induced at both protein and mRNA levels. The induced pro‐CB was rapidly processed to its mature form. The immunoreactivity for CB co‐localized with both that for caspase‐1 and the cleaved IL‐1β, in the acidic enlarged lysosomes. Inconsistent with these in vitro observations, the immunoreactivity for the cleaved IL‐1β was markedly observed in microglia of the hippocampus from aged wild‐type but not CB‐deficient mice. These observations strongly suggest that CB plays a key role in the pro‐IL‐1β maturationthrough the caspase‐1 activation in enlarged lysosomes ofCGA‐treated microglia. Therefore, either pharmacological or genetic inhibition of CB may provide therapeutic intervention in inflammation‐associated neurological diseases. © 2009 Wiley‐Liss, Inc.
Gatekeeping versus direct‐access when patient information matters
Authors: González Paula
Published: June 2009

We develop a principal‐agent model in which the health authority acts as a principal for both a patient and a general practitioner (GP). The goal of the paper is to weigh the merits of gatekeeping versus non‐gatekeeping approaches to health care when patient self‐health information and patient pressure on GPs to provide referrals for specialized care are considered. We find that, when GPs incentives matter, a non‐gatekeeping system is preferable only when (i) patient pressure to refer is sufficiently high and (ii) the quality of the patient's self‐health information is neither highly inaccurate (in which case the patient's self‐referral will be very inefficient) nor highly accurate (in which case the GP's agency problem will be very costly). Copyright © 2009 John Wiley & Sons, Ltd.
Do regional primary‐care organisations influence primary‐care performance? A dynamic panel estimation
Authors: Scott Anthony , Coote William
Published: June 2009

The role of regional primary‐care organizations (PCOs) in health‐care systems is not well understood. This is the first study to attempt to isolate the effect of regional PCOs on primary‐care performance. We examine Divisions of General Practice in Australia, which were established in 1992. A unique Division‐level panel data set is used to examine the effect of Divisions, and their activities, on various aspects of primary‐care performance. Dynamic panel estimation is used to account for state dependence and the endogeneity of Divisions' activities. The results show that Divisions were more likely to have influenced general practice infrastructure than clinical performance in diabetes, asthma and cervical screening. The effect of specific Division activities, such as providing support for practice nurses and IT support, was not directly related to changes in the level of general practice performance. Specific support in the areas of diabetes and asthma was associated with general practice performance, but this was due to reverse causality and the effect of unobservable factors, rather than the direct effect of Divisions. Copyright © 2009 John Wiley & Sons, Ltd.
Duloxetine in obese binge eater outpatients: preliminary results from a 12‐week open trial
Authors: Leombruni Paolo , Lavagnino Luca , Gastaldi Filippo , Vasile Alessia , Fassino Secondo
Published: June 2009

Objective

Attempts have been made to find appropriate drug regimens to treat binge eating disorder (BED). Several reports have examined the use of selective serotonin reuptake inhibitors (SSRIs) or mood stabilizers; both serotonin and noradrenalin reuptake inhibitors (SNRIs) have been reported to be useful for binge eating, but the available data are limited. We evaluated the efficacy of duloxetine, an SNRI, in 45 obese patients who reported binge eating.

Methods

Forty‐five patients with BED or binge eating with sub‐threshold symptoms (s‐BED) with high eating impulsivity, received duloxetine 60–120 mg/day for 12 weeks.

Results

A significant reduction in number of binges/week was observed in BED patients; statistical analyses performed on the whole sample revealed significant reductions in scores on the binge eating scale (BES) and the Beck depression inventory (BDI), weight, body mass index (BMI), clinical global impression, and the bulimia scale of the eating disorder inventory‐2. The reduction in BES and BDI scores was not statistically different between BED and s‐BED subjects.

Conclusions

Although preliminary, results from this open trial suggest that duloxetine may be a successful option to reduce binge eating and depressive symptoms in both obese BED and s‐BED outpatients. Copyright © 2009 John Wiley & Sons, Ltd.
Spatial analysis of instream nitrogen loads and factors controlling nitrogen delivery to streams in the southeastern United States using spatially referenced regression on watershed attributes (SPARROW) and regional classification frameworks
Authors: Hoos Anne B. , McMahon Gerard
Published: June 2009

Understanding how nitrogen transport across the landscape varies with landscape characteristics is important for developing sound nitrogen management policies. We used a spatially referenced regression analysis (SPARROW) to examine landscape characteristics influencing delivery of nitrogen from sources in a watershed to stream channels. Modelled landscape delivery ratio varies widely (by a factor of 4) among watersheds in the southeastern United States—higher in the western part (Tennessee, Alabama, and Mississippi) than in the eastern part, and the average value for the region is lower compared to other parts of the nation. When we model landscape delivery ratio as a continuous function of local‐scale landscape characteristics, we estimate a spatial pattern that varies as a function of soil and climate characteristics but exhibits spatial structure in residuals (observed load minus predicted load). The spatial pattern of modelled landscape delivery ratio and the spatial pattern of residuals coincide spatially with Level III ecoregions and also with hydrologic landscape regions. Subsequent incorporation into the model of these frameworks as regional scale variables improves estimation of landscape delivery ratio, evidenced by reduced spatial bias in residuals, and suggests that cross‐scale processes affect nitrogen attenuation on the landscape. The model‐fitted coefficient values are logically consistent with the hypothesis that broad‐scale classifications of hydrologic response help to explain differential rates of nitrogen attenuation, controlling for local‐scale landscape characteristics. Negative model coefficients for hydrologic landscape regions where the primary flow path is shallow ground water suggest that a lower fraction of nitrogen mass will be delivered to streams; this relation is reversed for regions where the primary flow path is overland flow. Published in 2009 by John Wiley & Sons, Ltd.
No one true path: uncovering the interplay between geography, institutions, and fractionalization in economic development
Authors: Tan Chih Ming
Published: June 2009

Do institutions rule when explaining cross‐country divergence? By employing regression tree analysis to uncover the existence and nature of multiple development clubs and growth regimes, this paper finds that to a large extent they do. However, the role of ethnic fractionalization cannot be dismissed. The findings suggest that sufficiently high‐quality institutions may be necessary for the negative impact on development from high levels of ethnic fractionalization to be mitigated. Interestingly, I find no role for geographic factors—neither those associated with climate nor physical isolation—in explaining divergence. There is also no evidence to suggest a role for religious fractionalization. Copyright © 2009 John Wiley & Sons, Ltd.
Phosphoproteome sequence analysis and significance: Mining association patterns around phosphorylation sites utilizing MAPRes
Authors: Ahmad Ishtiaq , Mehmood Abid , Khurshid Ahmed , Qazi Wajahat M. , Hoessli Daniel C. , Walker‐Nasir Evelyne , Shakoori Abdul Rauf , Nasir‐ud‐Din
Published: June 2009

Phosphorylation, one of the most common protein post‐translational modifications (PTMs) on hydroxyl groups of S/T/Y is catalyzed by kinases and involves the presence or absence of certain amino acid residues in the vicinity of the phosphorylation sites. Using MAPRes, we have analyzed the substrate proteins of Phospho.ELM 7.0 and found that there are both general and specific requirements for the presence or absence of particular amino acids in the vicinity of phosphorylated S/T/Y for both of the phosphorylation data, whether or not kinase information was taken into account. Patterns extracted by MAPRes for kinase‐specific data have been utilized to find the consensus sequence motifs for various kinases required to catalyze the process of phosphorylation on S/T/Y. These consensus sequences for different kinase groups, families, and individual members are consistent with those described earlier with some novel consensus reported for the first time. A comparison study for the patterns mined by MAPRes with the results of existing prediction methods was performed by searching for these patterns in the vicinity of phosphorylation sites predicted by different available method. This comparison resulted in 87–98% conformity with the results of the predictions by available methods. Additionally, the patterns mined by MAPRes for substrate sites included 61 kinases, the highest number analyzed so far. J. Cell. Biochem. 108: 64–74, 2009. © 2009 Wiley‐Liss, Inc.
Osteoprotegerin production by breast cancer cells is suppressed by dexamethasone and confers resistance against TRAIL‐induced apoptosis
Authors: Rachner Tilman D. , Benad Peggy , Rauner Martina , Goettsch Claudia , Singh Shiv K. , Schoppet Michael , Hofbauer Lorenz C.
Published: June 2009

Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF‐κB ligand (RANKL) and TNF‐related apoptosis‐inducing ligand (TRAIL). While RANKL is essential for osteoclastogenesis and facilitates breast cancer migration into bone, TRAIL promotes breast cancer apoptosis. We analyzed the expression of OPG and TRAIL and its modulation in estrogen receptor‐positive MCF‐7 cells and receptor‐negative MDA‐MB‐231 cells. In both cells, OPG mRNA levels and protein secretion were dose‐ and time‐dependently enhanced by interleukin (IL)‐1β and suppressed by dexamethasone. In contrast to MCF‐7 cells, MDA‐MB‐231 abundantly expressed TRAIL mRNA, which was enhanced by IL‐1β and inhibited by dexamethasone. TRAIL activated pro‐apoptotic caspase‐3, ‐7, and poly‐ADP‐ribose polymerase and decreased cell numbers of MDA‐MB‐231, but had no effect on MCF‐7 cells. Gene silencing siRNA directed against OPG resulted in a 31% higher apoptotic rate compared to non‐target siRNA‐treated MDA‐MB‐231 cells. Furthermore, TRAIL induced significantly less apoptosis in cells cultured in conditioned media (containing OPG) compared to cells exposed to TRAIL in fresh medium lacking OPG (P < 0.01) and these protective effects were reversed by blocking OPG with its specific ligand RANKL (P < 0.05). The association between cancer cell survival and OPG production by MDA‐MB‐231 cells was further supported by the finding, that modulation of OPG secretion using IL‐1β or dexamethasone prior to TRAIL exposure resulted in decreased and increased rate of apoptosis, respectively (P < 0.05). Thus, OPG secretion by breast cancer cells is modulated by cytokines and dexamethasone, and may represent a critical resistance mechanism that protects against TRAIL‐induced apoptosis. J. Cell. Biochem. 108: 106–116, 2009. © 2009 Wiley‐Liss, Inc.
Differentiation of synovial CD‐105+ human mesenchymal stem cells into chondrocyte‐like cells through spheroid formation
Authors: Arufe M.C. , De la Fuente A. , Fuentes‐Boquete I. , De Toro Francisco J. , Blanco Francisco J.
Published: June 2009

Mesenchymal stem cells (MSCs) have the capacity to differentiate into several cell lineages, some of which can generate bone, cartilage, or adipose tissue. The presence of MSCs in the synovial membrane was recently reported. Data from comparative studies of MSCs derived from various mesenchymal tissues suggest that MSCs from synovial membranes have a superior chondrogenesis capacity. Previous chondrogenic differentiation studies have used the total population of MSCs, including cells with several MSC markers, such as CD44, CD90, CD105, or CD73. However the chondrogenic capacity of an individual population of MSCs has not been examined. Our aim was to study the chondrogenic capacity of the cellular MSC subset, CD105+, derived from synovial membrane tissues of patients with osteoarthritis (OA) and normal donors. The tissues were digested with a cocktail of collagenase/dispase and the isolated MSCs were seeded into plates. The subpopulation of CD105+‐MSCs was separated using a magnetic separator. The MSCs were then differentiated towards chondrocyte‐like cells using a specific medium to promote spheroid formation. Spheroids were collected after 14, 28, and 46 days in chondrogenic medium and stained with hematoxylin, eosin, Safranin O or Alcian blue to evaluate the extracellular matrix. Immunohistochemistry was performed to study collagen types I (COLI) and II (COLII) and aggrecan expression. Phenotypic characterization of the isolated CD105+‐MSCs shows that these cells are also positive for CD90 and CD44, but negatives for CD34 and CD45. In addition, this cellular subset expressed Sox‐9. Spheroids appeared after 7 days in culture in the presence of chondrogenic medium. Our studies show no differences between MSCs obtained from OA and normal synovial membranes during chondrogenesis. The morphological analysis of spheroids revealed characteristics typical of chondrocyte cells. The intensity of Safranin O, Alcian blue and aggrecan staining was positive and constant throughout the culture period. However, the intensity of COL2 staining was higher at 28 days (84.29 ± 0.1 U) than at 46 days (61.28 ± 01 U), while COL1 staining was not detected in any samples analyzed. These results were confirmed by reverse transcriptase‐polymerase chain reaction assays. We conclude that the cellular subset of CD105+‐MSCs has chondrogenic capacity. The study also show the similar chondrogenic capacity of CD105+‐MSCs cultured from normal and OA synovial membranes. J. Cell. Biochem. 108: 145–155, 2009. © 2009 Wiley‐Liss, Inc.
Sustained epidermal growth factor receptor levels and activation by tethered ligand binding enhances osteogenic differentiation of multi‐potent marrow stromal cells
Authors: Platt Manu O. , Roman Arian J. , Wells Alan , Lauffenburger Douglas A. , Griffith Linda G.
Published: June 2009

Epidermal growth factor receptor (EGFR)‐mediated signaling helps regulate bone development and healing through its effects on osteogenic cells. Here, we show how EGFR activity and osteogenic differentiation responses in primary human bone marrow‐derived multipotent stromal cells (MSCs) are influenced by presenting covalently tethered epidermal growth factor (tEGF) on the culture substratum, a presentation mode that reduces EGFR internalization and restricts signaling to the cell surface. In both absence and presence of tEGF, MSCs increase expression levels of EGFR and its heterodimerization partner HER2 during the course of osteogenic differentiation. tEGF substrata increased levels of phosphorylated EGFR and phosphorylated extracellular regulated kinase (ERK) compared to control substrata, and these elevations were associated with a twofold enhancement of MSC alkaline phosphatase activity at day 7 and matrix mineralization at day 21. Surprisingly, addition of soluble EGF (sEGF) to cells cultured on tEGF substrata reduces osteogenic differentiation, even though EGFR signaling is more strongly activated in acute, short‐term manner by sEGF treatment than by tEGF treatment. A striking concomitant result of the sEGF effects is near‐complete downregulation of EGFR and HER2, demonstrating that the tEGF/EGFR interaction is dynamically reversible even though temporally sustained. Taken together, our results show that enhanced MSC osteogenic differentiation corresponds to a sustained combination of receptor expression and ligand presentation, both of which are maintained by tEGF. J. Cell. Physiol. 221: 306–317, 2009. © 2009 Wiley‐Liss, Inc.
Riedl's burden and the body plan: selection, constraint, and deep time
Authors: Schoch Rainer R.
Published: June 2009

Rupert Riedl's concept of burden forms a causal hypothesis on organismic integration and evolutionary constraints. Defined as the hierarchically nested interdependence of characters within the organism, burden was seen as (1) defining and conserving body plans and (2) constraining and directing evolutionary trajectories. A review of the components of the burden concept reveals important consistencies with the modern tenets of evo‐devo. This concept differs from the current consensus of evolutionary theory in that it (1) grants evolution less options for changing tightly integrated, “locked‐in” characters and (2) in deducing from this an ever decreasing freedom for evolution, with cyclism and typostrophism as resulting macroevolutionary phenomena. Despite these differences, I show that the burden concept was consistent with most major tenets of the Modern Synthesis, and Riedl attempted to explain patterns of large‐scale evolutionary trends exclusively by microevolutionary (gradualistic) processes. The burden concept is fruitful and unique in its focus on hierarchically nested constraints and resembles the hierarchical architecture of gene regulatory networks. However, such networks are more high‐dimensional and most of their components appear to be easier to evolve than Riedl's burden. Yet in combination with evolvability, a modified concept of burden might contribute substantially to the understanding of organismic integration and the long‐term evolution of body plans. J. Exp. Zool. (Mol. Dev. Evol.) 314B:1–10, 2010. © 2009 Wiley‐Liss, Inc.