bluuebunny/crossref_metadata_2025 huggingface dataset:
Right and left modules over the Frobenius skew polynomial ring in theF-finite case
Authors: SHARP RODNEY Y. , YOSHINO YUJI
Published: January 2011

The main purposes of this paper are to establish and exploit the result that, over a complete (Noetherian) local ringRof prime characteristic for which the Frobenius homomorphismfis finite, the appropriate restrictions of the Matlis-duality functor provide an equivalence between the category of left modules over the Frobenius skew polynomial ringR[x,f] that are Artinian asR-modules and the category of rightR[x,f]-modules that are Noetherian asR-modules.
Permanence et variation des unités prosodiques dans le discours et l'interaction
Authors: PORTES CRISTEL , BERTRAND ROXANE
Published: January 2011

Notre objectif est de montrer que les unités définies en laboratoire par la phonologie intonative sont non pas seulement identifiables dans la « parole naturelle », mais-jouent également un rôle discursif et interactionnel. Cependant, en vue de procéder à leur identification, on doit réussir à séparer, dans des données non contrôlées, la structure phonologique des autres types d'information encodés par la prosodie. Cela inclut à la fois des variations prosodiques « orthogonales » et graduelles de registre mélodique et de tempo, relative à la structure informationnelle ou au marquage du discours rapporté, mais aussi les disfluences (inhérentes aux processus de la production de la parole), qui jouent un rôle important dans la négociation de la prise de tours.
Une approche intégrative des relations de l'accentuation au phrasé prosodique du français
Authors: DI CRISTO ALBERT
Published: January 2011

Cet article expose les fondements et la démarche de notre approche des relations de l'accentuation au phrasé prosodique en français. Cette approche s'inscrit dans un cadre théorique général que nous exposons dans la première partie. D'autre part, elle s'appuie sur des principes généraux et sur des principes spécifiques au français que nous présentons dans la seconde partie. Ces principes supervisent des dispositifs de projection accentuelle fonctionnellement motivés (décrits dans la troisième partie) dont l'application conduit à la construction des trois domaines prosodiques qui constituent selon nous le système-noyau du phrasé prosodique du français: l'unité tonale, le syntagme prosodique et l'unité intonative. Ces unités sont illustrées par des exemples empruntés à divers types de corpus.
Modular Orientations of Random and Quasi-Random Regular Graphs
Authors: ALON NOGA , PRAŁAT PAWEŁ
Published: January 2011

Extending an old conjecture of Tutte, Jaeger conjectured in 1988 that for any fixed integer p ≥ 1, the edges of any 4p-edge connected graph can be oriented so that the difference between the outdegree and the indegree of each vertex is divisible by 2p+1. It is known that it suffices to prove this conjecture for (4p+1)-regular, 4p-edge connected graphs. Here we show that there exists a finite p0 such that for every p > p0 the assertion of the conjecture holds for all (4p+1)-regular graphs that satisfy some mild quasi-random properties, namely, the absolute value of each of their non-trivial eigenvalues is at most c1p2/3 and the neighbourhood of each vertex contains at most c2p3/2 edges, where c1, c2 > 0 are two absolute constants. In particular, this implies that for p > p0 the assertion of the conjecture holds asymptotically almost surely for random (4p+1)-regular graphs.
Effect of trichostatin A on fertilization and embryo development during extended culture of mouse oocyte
Authors: Jee Byung Chul , Jo Jun Woo , Lee Jung Ryeol , Suh Chang Suk , Kim Seok Hyun , Moon Shin Yong
Published: January 2011

We performed this study to investigate the effect of histone deacetylase inhibition during extended culture of in vitro matured mouse oocytes. In vitro matured mouse (BDF1) oocytes were cultured in vitro for 6, 12, and 24 h, respectively, and then inseminated. During in vitro culture for 6 and 12 h, two doses of trichostatin A (TSA), a histone deacetylase inhibitor, were added (100 nM and 500 nM) to the culture medium and the oocytes were then inseminated. During the 24-h in vitro culture, two doses of TSA were added (100 nM and 500 nM) to the medium and the oocytes were activated with 10 mM SrCl2. After the 6-h culture, the fertilization rate was similar to that of the control group, but the blastocyst formation rate was significantly decreased. After the 12-h culture, both the fertilization and blastocyst formation rates were significantly decreased. After the 24-h culture, total fertilization failure occurred. In the oocytes cultured for 6 and 12 h, the fertilization and blastocyst formation rates did not differ between the TSA-supplemented and control groups. Although extended culture of the mouse oocytes significantly affected their fertilization and embryo development, TSA supplementation did not overcome their decreased developmental potential.
‘A Little World without the World’: Ecclesiastical Foundation Myths in English Reformation Thought
Authors: Cunningham Jack P.
Published: January 2011

As the English Church began to develop in the sixteenth and seventeenth centuries the question of its origins became highly significant. From the outset the Henrician Reformation had to demonstrate that its claims to national ecclesiastical sovereignty had not been invented by hard-pressed statesmen to extricate the king from an inconvenient deference to the papacy. Thus began an industry that sent scholars delving into the archives in order to recover a historical precedent for independence. Joseph of Arimathea emerged as an early favourite candidate, and King Lucius, Simon Zealot and Aristobulus followed. Then there were the Samotheans, biblical giants that allowed English Reformers to trace their ancestry to Noah. This paper draws on a wide range of contemporary sources in order to explore how the English Reformation struggled with and ultimately failed to provide its Church with a legitimate ancient birth story.
VIA – Intensivtherapeutischer Behandlungsansatz bei Störungen des Sozialverhaltens
Authors: Grasmann Dörte , Stadler Christina
Published: January 2011

Fragestellung: In der Behandlung von Störungen des Sozialverhaltens haben sich verhaltenstherapeutische multimodale Ansätze als effektiv erwiesen. Bislang liegen jedoch kaum Befunde zur Effektivität teilstationärer Behandlungsansätze vor. In diesem Beitrag wird das verhaltenstherapeutische Intensivprogramm zur Reduktion von Aggression (VIA), das ein 10-tägiges Gruppen-Intensivprogramm für Kinder zwischen 8 und 14 Jahren und ein begleitendes Elterntraining umfasst, vorgestellt. Der Studie liegt die Frage zugrunde, inwieweit das VIA-Programm einen effektiven Behandlungsansatz darstellt, um aggressives Verhalten und komorbide Symptome zu reduzieren. Zudem wird der Frage der differenziellen Therapiewirksamkeit nachgegangen. Methodik: Der Untersuchung liegt ein Wartelisten-Gruppen-Design zu Grunde. Neben der varianzanalytischen Überprüfung der Effektivität des VIA-Programms werden Prädiktoren für die Wirksamkeit in einem linearen Regressionsmodell untersucht. Ergebnisse: Insgesamt nahmen 36 Jungen und ihre primären Bezugspersonen an der Untersuchung teil. Die Ergebnisse weisen auf eine signifikante Reduktion der oppositionellen Verhaltensprobleme und der komorbiden ADHS-Symptomatik in der Interventionsgruppe (IG, n = 18) im Vergleich zur Wartegruppe (WG, n = 18) hin. Weiter lassen sich das Alter sowie der Ausprägungsgrad dissozial-aggressiver Verhaltenssymptome als bedeutsame Prädiktoren identifizieren. Schlussfolgerungen: Die Ergebnisse dieser Studie zeigen, dass das intensivtherapeutische VIA-Programm einen effektiven Behandlungsansatz darstellt, um aggressive Verhaltensprobleme und komorbide ADHS-Symptome bei Patienten mit Störungen des Sozialverhaltens zu reduzieren.
Multisystemische Therapie (MST) für Jugendliche mit schweren Störungen des Sozialverhaltens
Authors: Rehberg Walter , Fürstenau Ute , Rhiner Bruno
Published: January 2011

Fragestellung: Das in den USA entwickelte Therapieprogramm der Multisystemischen Therapie (MST) wurde für den deutschsprachigen Raum adaptiert und erstmals bei 70 Jugendlichen angewendet. Es wurde die Frage untersucht, ob von der Anwendung der MST Einsparungseffekte gegenüber anderen Maßnahmen zu erwarten sind. Methodik: Um neben den Prozess- und Ergebnisaspekten der therapeutischen Intervention auch allfällige ökonomische Effekte der MST beurteilen zu können, wurden jene Fachpersonen, die die Jugendlichen in die MST zugewiesen hatten danach befragt, welcher Behandlungsweg ihrer Meinung nach ohne MST wahrscheinlich gewesen wäre. Die Kostenfolgen dieser Behandlungswege wurden ermittelt und den tatsächlichen Kosten der MST gegenübergestellt. Ergebnisse: Die ökonomische Evaluation der Implementierung der MST im deutschsprachigen Raum zeigte ein deutliches Einsparungspotenzial durch diese ambulante Therapieform: Die Fallkosten für die Durchführung der MST lagen um 40 % bis 64 % unter den Kosten für außerfamiliäre Platzierungen, die nach Einschätzung der ZuweiserInnen ohne MST erforderlich gewesen wären. Schlussfolgerungen: Bei der Multisystemischen Therapie handelt es sich nicht nur um ein effektives, sondern auch um ein relativ kostengünstiges Verfahren zu Behandlung von Jugendlichen mit schweren Störungen des Sozialverhaltens.
Theoretical analysis and numerical experiments of variational adjoint approach for refractivity estimation
Authors: Zhao Xiao‐Feng , Huang Si‐Xun , Du Hua‐Dong
Published: January 2011

This paper puts forward possibilities of refractive index profile retrieval using field measurements at an array of radio receivers in terms of variational adjoint approach. The derivation of the adjoint model begins with the parabolic wave equation for a smooth, perfectly conducting surface and horizontal polarization conditions. To deal with the ill‐posed difficulties of the inversion, the regularization ideas are introduced into the establishment of the cost function. Based on steepest descent iterations, the optimal value of refractivity could be retrieved quickly at each point over height. Numerical experiments demonstrate that the method works well for low‐distance signals, while it is not accurate enough for long‐distance propagations. Through curve fitting processing, however, giving a good initial refractivity profile could generally improve the inversions.
Using complex independent component analysis to extract weak returns in MARSIS radar data and their possible relation to a subsurface reflector on Mars
Authors: Zhang Zhenfei , Nielsen Erling
Published: January 2011

Mars Advanced Radar for Subsurface and Ionosphere Sounding (MARSIS) radar signals returned from the surface and subsurface of the northern lowlands of Mars are mostly characterized as a prominent surface pulse followed by a tail of weak signals. We applied the method of blind source separation (BSS) using complex independent component analysis (CICA) to examine if there is any subsurface information hidden in the apparent clutter and noise in the tails. In this paper we describe the application of the method with a case study in a selected region in the western part of Utopia Planitia (88°E–91°E, 45°N–51°N) where an unnamed large (∼160 km in diameter), semifilled crater is located. Applying CICA, we find a particularly significant signal from one of the blind sources. This signal is interpreted as representing a subsurface reflection interface, based on analysis of characteristics of the separated sources and their relation to surface roughness inside and outside the crater. A numerical simulation is conducted to examine the conditions under which the method tends to be effective. We conclude that CICA is helpful for recognizing subsurface signals above the noise level but obscured by clutter and thermal noise, provided the surface is relatively smooth.
Assessment of climate change impacts at the catchment scale with a detailed hydrological model of surface‐subsurface interactions and comparison with a land surface model
Authors: Sulis M. , Paniconi C. , Rivard C. , Harvey R. , Chaumont D.
Published: January 2011

A process‐based model that incorporates hydrodynamic feedbacks between the land surface, soil, and groundwater zones is used to assess the sensitivity of the hydrological response (river discharge, aquifer recharge, and soil water storage) to future climate conditions. The analysis is based on the Intergovernmental Panel on Climate Change Special Report on Emissions Scenario A2 and the des Anglais catchment in southwestern Quebec (Canada). Application of the coupled hydrological model (CATHY) to the study basin revealed significant spatiotemporal variations in the river discharge response to climate change owing to a different partitioning between the overland runoff and base flow components of the hydrograph, with the latter alleviating the marked decrease in discharge during the summer period. A spatial analysis of recharge patterns shows that the greatest variations are expected to occur, throughout the year, in the southern portion of the catchment, where the elevations are highest. Compared to river discharge and aquifer recharge, the soil water storage volumes are less sensitive to climate changes. From a spatial analysis of soil moisture variations it was possible to observe organizational patterns that follow the topographic and pedologic characteristics of the catchment. In addition to these analyses, we also compare predictions obtained with the land surface scheme (CLASS) that is coupled to the regional climate model (CRCM) to those from the detailed catchment model for past and future climate change projections. An examination of the runoff revealed that CLASS produces higher estimates than CATHY of surface and subsurface runoff throughout the annual cycle for both past and future projections. For soil water storage, the two models are in general agreement in terms of the intra‐annual variability of moisture content at shallower soil layers, whereas a larger difference is found for the deepest layer, with CATHY predicting wetter soil conditions over the entire simulation period and moisture fluctuations of much smaller amplitude.
Coral-mucus-associated Vibrio integrons in the Great Barrier Reef: genomic hotspots for environmental adaptation
Authors: Koenig Jeremy E , Bourne David G , Curtis Bruce , Dlutek Marlena , Stokes H W , Doolittle W Ford , Boucher Yan
Published: January 2011

Integron cassette arrays in a dozen cultivars of the most prevalent group of Vibrio isolates obtained from mucus expelled by a scleractinian coral (Pocillopora damicornis) colony living on the Great Barrier Reef were sequenced and compared. Although all cultivars showed >99% identity across recA, pyrH and rpoB genes, no two had more than 10% of their integron-associated gene cassettes in common, and some individuals shared cassettes exclusively with distantly-related members of the genus. Of cassettes shared within the population, a number appear to have been transferred between Vibrio isolates, as assessed by phylogenetic analysis. Prominent among the mucus Vibrio cassettes with potentially inferable functions are acetyltransferases, some with close similarity to known antibiotic-resistance determinants. A subset of these potential resistance cassettes were shared exclusively between the mucus Vibrio cultivars, Vibrio coral pathogens and human pathogens, thus illustrating a direct link between these microbial niches through exchange of integron-associated gene cassettes.
Factors Associated With Early Atherosclerosis and Arterial Calcifications in Young Subjects With a Benign Phenotype of Obesity
Authors: Gilardini Luisa , Pasqualinotto Lucia , Di Matteo Silvia , Caffetto Katherine , Croci Marina , Girola Andrea , Invitti Cecilia
Published: January 2011

We assessed (i) the association between early arterial disease and factors linked to adiposity, dietary habits, and family in a young cohort of 151 obese children and adolescents with less than or equal to one cardiovascular (CV) risk factor, (ii) whether in subjects with carotid calcifications there was an imbalance of calcium‐phosphorus homeostasis. Measurement included: carotid ultrasound, oral glucose tolerance test, anthropometry, body composition, dietary history, white blood cells count, lipids, uric acid, adiponectin, insulin, C‐reactive protein, plasminogen activator inhibitor 1 (PAI‐1), 25‐hydroxyvitamin D, parathyroid hormone (PTH), calcium and phosphorus. Obese children with carotid artery intima media thickness (cIMT) values >75° percentile (0.55 mm), compared to those with lower cIMT, were more obese, more often pubertal and had higher prevalence of family history of CV disease (CVD) (P < 0.05), higher plasma PAI‐1 and uric acid (P < 0.001) and lower adiponectin (P < 0.05) and high‐density lipoprotein (HDL) cholesterol levels (P < 0.05). After adjustment for sex, age, puberty, obesity, and insulin levels, only PAI‐I remained significantly different between the two groups (10.9 (7.2–29.8) vs. 6.2 (4.3–10.6) ng/ml, P < 0.001). Dietary intake did not affect cIMT values. Eight percent of subjects showed nonatherosclerotic carotid calcifications with patchy pattern. These children had a worse lipid profile (P < 0.05) and higher plasma PTH levels (48.6 ± 21.5 vs 38.5 ± 16.9 pg/ml, P < 0.05) that were inversely associated with 25‐hydroxyvitamin D levels (r = 0.245, P < 0.01). Present results suggest that (i) several adiposity‐related factors may play a role in promoting the development of early arterial diseases in young subjects with a benign phenotype of obesity, (ii) a PTH rise resulting from a subclinical imbalance in calcium‐phosphorus homeostasis may affect the biological process of vascular calcifications.
Sleep Apnea, Reproductive Hormones and Quality of Sexual Life in Severely Obese Men
Authors: Hammoud Ahmad O. , Walker James M. , Gibson Mark , Cloward Tom V. , Hunt Steven C. , Kolotkin Ronette L. , Adams Ted D. , Meikle A. Wayne
Published: January 2011

The effect of sleep apnea on the reproductive function of obese men is not entirely elucidated. The objective of this study was to define the effect of sleep apnea on the reproductive hormones and sexual function in obese men. This study included 89 severely obese men with BMI ≥35 kg/m2 considering gastric bypass surgery. Anthropometrics (weight, and BMI), reproductive hormones, and sleep studies were measured. The sexual quality of life was assessed using the Impact of Weight on Quality of Life‐Lite questionnaire (IWQOL‐Lite). The mean age of our patients was 46.9 ± 11.0 years, the mean BMI was 47.8 ± 8.7 kg/m2 and the mean weight was 337.7 ± 62.4 lb. After correction for age and BMI, means of free testosterone per severity group of sleep apnea were as follows: no or mild sleep apnea 74.4 ± 3.8 pg/ml, moderate sleep apnea 68.6 ± 4.2 pg/ml, and severe sleep apnea 60.2 ± 2.92 pg/ml, P = 0.014. All other parameters of sleep apnea including hypopnea index, percent time below a SpO2 of 90%, and percent time below a SpO2 of 80% were also negatively correlated with testosterone levels after correction for age and BMI. BMI and presence of coronary artery disease decreased the sexual quality of life. Sleep apnea was associated with reduced sexual quality of life. In summary, sleep apnea negatively affects testosterone levels independent of BMI. Severely obese men had decreased sexual quality of life.
The Contribution of Visceral Adiposity and Mid‐Thigh Fat‐Rich Muscle to the Metabolic Profile in Postmenopausal Women
Authors: Dubé Marie‐Christine , Lemieux Simone , Piché Marie‐Eve , Corneau Louise , Bergeron Jean , Riou Marie‐Eve , Weisnagel Stanley J.
Published: January 2011

This study explored the relationship between muscle fat infiltration derived from mid‐thigh computed tomography (CT) scan, central fat distribution and insulin sensitivity in postmenopausal women. Mid‐thigh CT scans were used to measure low attenuation muscle surface (LAMS) (0–34 Hounsfield units (HU)), which represented a specific component of fat‐rich muscle. Whole‐body insulin sensitivity (M/I) was evaluated by an euglycemic‐hyperinsulinemic clamp. A group of 103 women aged 57.0 ± 4.4 years was studied. Women with higher levels of LAMS presented higher metabolic risk features, particularly elevated fasting, 2‐h plasma glucose (2hPG) concentrations and diminished M/I (P < 0.05). To further study the contribution of muscle fat infiltration and central adiposity on metabolic parameters, we divided the whole group based on the median of LAMS and visceral adipose tissue (VAT). As expected, the best metabolic profile was found in the Low‐LAMS/Low‐VAT group and the worst in the High‐LAMS/High‐VAT group. Women with Low‐LAMS/High‐VAT presented similar metabolic risks to those with High‐LAMS/High‐VAT. There was no difference between High‐LAMS/Low‐VAT and Low‐LAMS/Low‐VAT, which presents the most healthy metabolic and glycemic profiles as reflected by the lowest levels of cardiovascular disease risk variables. This suggests that High‐LAMS/Low‐VAT is also at low risk of metabolic deteriorations and that High‐LAMS, only in the presence of High‐VAT seems associated with deteriorated risks. Although increased mid‐thigh fat‐rich muscle was related to a deteriorated metabolic profile, VAT appears as a more important contributor to alterations in the metabolic profile in postmenopausal women.
Identification of regions responsible for the open conformation of S100A10 using chimaeric S100A11–S100A10 proteins
Authors: Santamaria-Kisiel Liliana , Shaw Gary S.
Published: January 2011

S100A11 is a dimeric EF-hand calcium-binding protein. Calcium binding to S100A11 results in a large conformational change that uncovers a broad hydrophobic surface used to interact with phospholipid-binding proteins (annexins A1 and A2) and facilitate membrane vesiculation events. In contrast with other S100 proteins, S100A10 is unable to bind calcium due to deletion and substitution of calcium-ligating residues. Despite this, calcium-free S100A10 assumes an ‘open’ conformation that is very similar to S100A11 in its calcium-bound state. To understand how S100A10 is able to adopt an open conformation in the absence of calcium, seven chimaeric proteins were constructed where regions from calcium-binding sites I and II, and helices II–IV in S100A11 were replaced with the corresponding regions of S100A10. The chimaeric proteins having substitutions in calcium-binding site II displayed increased hydrophobic surface exposure as assessed by bis-ANS (4,4′-dianilino-1,1′-binaphthyl-5,5′disulfonic acid, dipotassium salt) fluorescence and phenyl-Sepharose binding in the absence of calcium. This response is similar to that observed for Ca2+–S100A11 and calcium-free S100A10. Further, this substitution resulted in calcium-insensitive binding to annexin A2 for one chimaeric protein. The results indicate that residues within site II are important in stabilizing the open conformation of S100A10 and presentation of its target binding site. In contrast, S100A11 chimaeric proteins with helical substitutions displayed poorer hydrophobic surface exposure and, consequently, unobservable annexin A2 binding. The present study represents a first attempt to systematically understand the molecular basis for the calcium-insensitive open conformation of S100A10.
Entamoeba histolytica secretes two haem-binding proteins to scavenge haem
Authors: Cruz-Castañeda Areli , López-Casamichana Mavil , Olivares-Trejo José J.
Published: January 2011

Entamoeba histolytica is a human pathogen which can grow using different sources of iron such as free iron, lactoferrin, transferrin, ferritin or haemoglobin. In the present study, we found that E. histolytica was also capable of supporting its growth in the presence of haem as the sole iron supply. In addition, when trophozoites were maintained in cultures supplemented with haemoglobin as the only iron source, the haem was released and thus it was introduced into cells. Interestingly, the Ehhmbp26 and Ehhmbp45 proteins could be related to the mechanism of iron acquisition in this protozoan, since they were secreted to the medium under iron-starvation conditions, and presented higher binding affinity for haem than for haemoglobin. In addition, both proteins were unable to bind free iron or transferrin in the presence of haem. Taken together, our results suggest that Ehhmbp26 and Ehhmbp45 could function as haemophores, secreted by this parasite to facilitate the scavenging of haem from the host environment during the infective process.
The phosphoinositide 3-kinase Vps34p is required for pexophagy in Saccharomyces cerevisiae
Authors: Grunau Silke , Lay Dorothee , Mindthoff Sabrina , Platta Harald W. , Girzalsky Wolfgang , Just Wilhelm W. , Erdmann Ralf
Published: January 2011

PIds (phosphoinositides) are phosphorylated derivatives of the membrane phospholipid PtdIns that have emerged as key regulators of many aspects of cellular physiology. We have discovered a PtdIns3P-synthesizing activity in peroxisomes of Saccharomyces cerevisiae and have demonstrated that the lipid kinase Vps34p is already associated with peroxisomes during biogenesis. However, although Vps34 is required, it is not essential for optimal peroxisome biogenesis. The function of Vps34p-containing complex I as well as a subset of PtdIns3P-binding proteins proved to be mandatory for the regulated degradation of peroxisomes. This demonstrates that PtdIns3P-mediated signalling is required for pexophagy.
Targeting chemokine receptors in allergic disease
Authors: Pease James E.
Published: January 2011

The directed migration of cells in response to chemical cues is known as chemoattraction, and plays a key role in the temporal and spatial positioning of cells in lower- and higher-order life forms. Key molecules in this process are the chemotactic cytokines, or chemokines, which, in humans, constitute a family of approx. 40 molecules. Chemokines exert their effects by binding to specific GPCRs (G-protein-coupled receptors) which are present on a wide variety of mature cells and their progenitors, notably leucocytes. The inappropriate or excessive generation of chemokines is a key component of the inflammatory response observed in several clinically important diseases, notably allergic diseases such as asthma. Consequently, much time and effort has been directed towards understanding which chemokine receptors and ligands are important in the allergic response with a view to therapeutic intervention. Such strategies can take several forms, although, as the superfamily of GPCRs has historically proved amenable to blockade by small molecules, the development of specific antagonists has been has been a major focus of several groups. In the present review, I detail the roles of chemokines and their receptors in allergic disease and also highlight current progress in the development of relevant chemokine receptor antagonists.
The endoplasmic reticulum sulfhydryl oxidase Ero1β drives efficient oxidative protein folding with loose regulation
Authors: Wang Lei , Zhu Li , Wang Chih-chen
Published: January 2011

In eukaryotes, disulfide bonds are formed in the endoplasmic reticulum, facilitated by the Ero1 (endoplasmic reticulum oxidoreductin 1) oxidase/PDI (protein disulfide-isomerase) system. Mammals have two ERO1 genes, encoding Ero1α and Ero1β proteins. Ero1β is constitutively expressed in professional secretory tissues and induced during the unfolded protein response. In the present work, we show that recombinant human Ero1β is twice as active as Ero1α in enzymatic assays. Ero1β oxidizes PDI more efficiently than other PDI family members and drives oxidative protein folding preferentially via the active site in the a′ domain of PDI. Our results reveal that Ero1β oxidase activity is regulated by long-range disulfide bonds and that Cys130 plays a critical role in feedback regulation. Compared with Ero1α, however, Ero1β is loosely regulated, consistent with its role as a more active oxidase when massive oxidative power is required.
Target genes of the largest human SWI/SNF complex subunit control cell growth
Authors: Inoue Hiroko , Giannakopoulos Stavros , Parkhurst Christopher N. , Matsumura Tatsushi , Kono Evelyn A. , Furukawa Takako , Tanese Naoko
Published: January 2011

The largest subunit of the mammalian SWI/SNF-A or BAF (BRG1-associated factor) chromatin-remodelling complex is encoded by two related cDNAs hOsa1/BAF250a and hOsa2/BAF250b that are unique to the BAF complex and absent in the related PBAF (Polybromo BAF). hOsa/BAF250 has been shown to interact with transcriptional activators and bind to DNA suggesting that it acts to target the remodelling complex to chromatin. To better understand the functions of hOsa2, we established inducible stable HeLa cell lines over-expressing FLAG–hOsa2 or a derivative lacking the ARID (AT-rich interactive domain) DNA-binding domain. Immunopurification of complexes containing hOsa2 that was followed by mass spectrometry and immunoblotting demonstrated the presence of BRG1 and known BAFs, but not hOsa1 or hBRM. Deletion of the ARID did not compromise the integrity of the complex. Induction of hOsa2 expression caused impaired cell growth and accumulation of cells in the G0/G1 cell cycle phase. Elevated levels of the p53 and p21 proteins were detected in these cells while c-Myc mRNA and protein levels were found to decrease. Chromatin immunoprecipitation and reporter assays suggested that hOsa2 had a direct effect on c-myc and p21 promoter activity. Thus hOsa2 plays an important role in controlling genes regulating the cell cycle.
Myosin regulatory light chains are required to maintain the stability of myosin II and cellular integrity
Authors: Park Inju , Han Cecil , Jin Sora , Lee Boyeon , Choi Heejin , Kwon Jun Tae , Kim Dongwook , Kim Jihye , Lifirsu Ekaterina , Park Woo Jin , Park Zee Yong , Kim Do Han , Cho Chunghee
Published: January 2011

Myosin II is an actin-binding protein composed of MHC (myosin heavy chain) IIs, RLCs (regulatory light chains) and ELCs (essential light chains). Myosin II expressed in non-muscle tissues plays a central role in cell adhesion, migration and division. The regulation of myosin II activity is known to involve the phosphorylation of RLCs, which increases the Mg2+-ATPase activity of MHC IIs. However, less is known about the details of RLC–MHC II interaction or the loss-of-function phenotypes of non-muscle RLCs in mammalian cells. In the present paper, we investigate three highly conserved non-muscle RLCs of the mouse: MYL (myosin light chain) 12A (referred to as MYL12A), MYL12B and MYL9 (MYL12A/12B/9). Proteomic analysis showed that all three are associated with the MHCs MYH9 (NMHC IIA) and MYH10 (NMHC IIB), as well as the ELC MYL6, in NIH 3T3 fibroblasts. We found that knockdown of MYL12A/12B in NIH 3T3 cells results in striking changes in cell morphology and dynamics. Remarkably, the levels of MYH9, MYH10 and MYL6 were reduced significantly in knockdown fibroblasts. Comprehensive interaction analysis disclosed that MYL12A, MYL12B and MYL9 can all interact with a variety of MHC IIs in diverse cell and tissue types, but do so optimally with non-muscle types of MHC II. Taken together, our study provides direct evidence that normal levels of non-muscle RLCs are essential for maintaining the integrity of myosin II, and indicates that the RLCs are critical for cell structure and dynamics.
Novel cross-talk within the IKK family controls innate immunity
Authors: Clark Kristopher , Peggie Mark , Plater Lorna , Sorcek Ronald J. , Young Erick R. R. , Madwed Jeffrey B. , Hough Joanne , McIver Edward G. , Cohen Philip
Published: January 2011

Members of the IKK {IκB [inhibitor of NF-κB (nuclear factor κB)] kinase} family play a central role in innate immunity by inducing NF-κB- and IRF [IFN (interferon) regulatory factor]-dependent gene transcription programmes required for the production of pro-inflammatory cytokines and IFNs. However, the molecular mechanisms that activate these protein kinases and their complement of physiological substrates remain poorly defined. Using MRT67307, a novel inhibitor of IKKϵ/TBK1 (TANK {TRAF [TNF (tumour-necrosis-factor)-receptor-associated factor]-associated NF-κB activator}-binding kinase 1) and BI605906, a novel inhibitor of IKKβ, we demonstrate that two different signalling pathways participate in the activation of the IKK-related protein kinases by ligands that activate the IL-1 (interleukin-1), TLR (Toll-like receptor) 3 and TLR4 receptors. One signalling pathway is mediated by the canonical IKKs, which directly phosphorylate and activate IKKϵ and TBK1, whereas the second pathway appears to culminate in the autocatalytic activation of the IKK-related kinases. In contrast, the TNFα-induced activation of the IKK-related kinases is mediated solely by the canonical IKKs. In turn, the IKK-related kinases phosphorylate the catalytic subunits of the canonical IKKs and their regulatory subunit NEMO (NF-κB essential modulator), which is associated with reduced IKKα/β activity and NF-κB-dependent gene transcription. We also show that the canonical IKKs and the IKK-related kinases not only have unique physiological substrates, such as IκBα, p105, RelA (IKKα and IKKβ) and IRF3 (IKKϵ and TBK1), but also have several substrates in common, including the catalytic and regulatory (NEMO and TANK) subunits of the IKKs themselves. Taken together, our studies reveal that the canonical IKKs and the IKK-related kinases regulate each other by an intricate network involving phosphorylation of their catalytic and regulatory (NEMO and TANK) subunits to balance their activities during innate immunity.
LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice
Authors: Woods Angela , Heslegrave Amanda J. , Muckett Phillip J. , Levene Adam P. , Clements Melanie , Mobberley Margaret , Ryder Timothy A. , Abu-Hayyeh Shadi , Williamson Catherine , Goldin Robert D. , Ashworth Alan , Withers Dominic J. , Carling David
Published: January 2011

LKB1 is a ‘master’ protein kinase implicated in the regulation of metabolism, cell proliferation, cell polarity and tumorigenesis. However, the long-term role of LKB1 in hepatic function is unknown. In the present study, it is shown that hepatic LKB1 plays a key role in liver cellular architecture and metabolism. We report that liver-specific deletion of LKB1 in mice leads to defective canaliculi and bile duct formation, causing impaired bile acid clearance and subsequent accumulation of bile acids in serum and liver. Concomitant with this, it was found that the majority of BSEP (bile salt export pump) was retained in intracellular pools rather than localized to the canalicular membrane in hepatocytes from LLKB1KO (liver-specific Lkb1-knockout) mice. Together, these changes resulted in toxic accumulation of bile salts, reduced liver function and failure to thrive. Additionally, circulating LDL (low-density lipoprotein)-cholesterol and non-esterified cholesterol levels were increased in LLKB1KO mice with an associated alteration in red blood cell morphology and development of hyperbilirubinaemia. These results indicate that LKB1 plays a critical role in bile acid homoeostasis and that lack of LKB1 in the liver results in cholestasis. These findings indicate a novel key role for LKB1 in the development of hepatic morphology and membrane targeting of canalicular proteins.
Smad7: not only a regulator, but also a cross-talk mediator of TGF-β signalling
Authors: Yan Xiaohua , Chen Ye-Guang
Published: January 2011

TGF-β (transforming growth factor-β) is a pleiotropic cytokine regulating diverse cellular processes. It signals through membrane-bound receptors, downstream Smad proteins and/or other signalling mediators. Smad7 has been well established to be a key negative regulator of TGF-β signalling. It antagonizes TGF-β signalling through multiple mechanisms in the cytoplasm and in the nucleus. Smad7 can be transcriptionally induced by TGF-β and other growth factors and serves as an important cross-talk mediator of the TGF-β signalling pathway with other signalling pathways. Accordingly, it plays pivotal roles in embryonic development and adult homoeostasis, and altered expression of Smad7 is often associated with human diseases, such as cancer, tissue fibrosis and inflammatory diseases.
Flexibility of the Ure2 prion domain is important for amyloid fibril formation
Authors: Yu Yong , Wang Hai-Yan , Bai Ming , Perrett Sarah
Published: January 2011

Ure2, the protein determinant of the Saccharomyces cerevisiae prion [URE3], has a natively disordered N-terminal domain that is important for prion formation in vivo and amyloid formation in vitro; the globular C-domain has a glutathione transferase-like fold. In the present study, we swapped the position of the N- and C-terminal regions, with or without an intervening peptide linker, to create the Ure2 variants CLN-Ure2 and CN-Ure2 respectively. The native structural content and stability of the variants were the same as wild-type Ure2, as indicated by enzymatic activity, far-UV CD analysis and equilibrium denaturation. CLN-Ure2 was able to form amyloid-like fibrils, but with a significantly longer lag time than wild-type Ure2; and the two proteins were unable to cross-seed. Under the same conditions, CN-Ure2 showed limited ability to form fibrils, but this was improved after addition of 0.03 M guanidinium chloride. As for wild-type Ure2, allosteric enzyme activity was observed in fibrils of CLN-Ure2 and CN-Ure2, consistent with retention of the native-like dimeric structure of the C-domains within the fibrils. Proteolytically digested fibrils of CLN-Ure2 and CN-Ure2 showed the same residual fibril core morphology as wild-type Ure2. The results suggest that the position of the prion domain affects the ability of Ure2 to form fibrils primarily due to effects on its flexibility.
Counter-regulation in the IKK family
Authors: O'Neill Luke A. J.
Published: January 2011

The human IKK [IκB (inhibitor of NF-κB) kinase] family has four members; they are the central kinases of innate immunity. Two members, IKKα and IKKβ, the so-called canonical members, phosphoryate IκBα, leading to activation of the transcription factor NF-κB (nuclear factor κB), which controls the expression of many immune and inflammatory genes. The IKK-related proteins TBK-1 (TANK-binding kinase 1) and IKKϵ have a different substrate – IRF3 (interferon regulatory factor 3) – which regulates a different set of genes, the products of which include Type I interferons. Toll-like receptors (TLRs) such as the lipopolysaccharide receptor TLR4 or the poly(I:C) receptor TLR3 activate each of the IKKs, but the pro-inflammatory cytokine IL-1 (interleukin 1), which signals in a broadly similar way to the TLRs, has so far been shown to activate only the canonical IKKs. In this issue of the Biochemical Journal, Clark et al. bring new insights into the regulation of IKKs. They demonstrate that IL-1 is in fact able to activate IKKϵ/TBK-1, which occurs via IKKα/IKKβ. The consequence of this is not IRF3 activation, but a negative feedback effect on IKKα/IKKβ. This provides us with yet another regulatory feedback loop in a system already replete with control mechanisms. It attests yet again to the importance of keeping these innate immune pathways in check, since if they proceed uncontrolled, inflammatory diseases can occur. Importantly, this study utilized new and specific inhibitors of these kinases, suggesting that the interpretation of any effects the compound might have in vivo may be complex, since for example the inhibition of IKKϵ/TBK-1 might actually have a pro-inflammatory effect.
A Copula-Based Sample Selection Model of Telecommuting Choice and Frequency
Authors: Sener Ipek N , Bhat Chandra R
Published: January 2011

The objective of this study is to contribute to the telecommuting literature by jointly examining the propensity and frequency of workers to telecommute, using a rich set of individual demographics, work-related and industry characteristics, household demographics, and commute-trip/work-location characteristics. The data are drawn from the Chicago Regional Household Travel Inventory, collected between 2007 and 2008. From a methodological standpoint, the current study adopts a copula approach that allows the testing of several types of dependency structures between the telecommuting choice and frequency behavioral processes. To our knowledge, this is the first formulation and application in the econometric literature of a copula approach for the case of a binary self-selection mechanism with an ordered-response outcome. The results clearly indicate that telecommuting choice and the frequency of telecommuting are governed by quite different underlying behavioral processes. For instance, women are less likely to telecommute relative to men, though there is no statistically significant difference in telecommuting frequency propensity between men and women telecommuters. Similarly, full-time employed individuals (≥30 hours per week) are more likely to have a telecommuting arrangement than those working part-time (<30 hours per week). However, among those who telecommute, full-time employed individuals telecommute less frequently than part-time employed individuals. Further, the results suggest that the analyst risks the danger of incorrect conclusions regarding dependency in the telecommuting choice and frequency behavioral processes, as well as inconsistent and inefficient parameter estimates, by imposing incorrect dependency structures or assuming independence between the two behavioral processes. Overall, the empirical results indicate the important effects of several demographic and work-related variables on telecommuting choice and frequency, with implications for transportation planning and transportation policy analysis.
The Transformation of Transport Policy in Great Britain? ‘New Realism’ and New Labour's Decade of Displacement Activity
Authors: Docherty Iain , Shaw Jon
Published: January 2011

In 1999 Goodwin announced ‘the transformation of transport policy in Great Britain’. His central point was that consensus was emerging among policy makers and academics, based on earlier work, including “Transport: the new realism”, which rejected previous orthodoxy that the supply of road space could and should be continually expanded to match demand. Instead, a combination of investment in public transport, walking and cycling opportunities, and—crucially—demand management, should form the basis of transport policy to address rising vehicle use and associated increases in congestion and pollution/carbon emissions. This thinking formed the basis of the 1997 Labour government's ‘sustainable transport’ policy, but after thirteen years in power ministers had neither transformed policy nor tackled longstanding transport trends. Our main aim in this paper is to revisit the concept of New Realism and reexamine its potential utility as an agent of change in British transport policy. Notwithstanding the outcome of Labour's approach to transport policy, we find that the central tenets of the New Realism remain robust and that the main barriers to change are related to broader political and governance issues which suppress radical policy innovation.
Neighbourhood Destination Accessibility Index: A GIS Tool for Measuring Infrastructure Support for Neighbourhood Physical Activity
Authors: Witten Karen , Pearce Jamie , Day Peter
Published: January 2011

The sharp increase in obesity in recent years has prompted researchers to examine the various pathways through which urban built environments influence population-level physical activity. Walking access to everyday destinations is one such pathway. This paper describes a measure of pedestrian access to neighbourhood destinations. Using eight domains of neighbourhood destinations (education, transport, recreation, social and cultural, food retail, financial, health, and other retail) we developed a GIS-based ‘Neighbourhood Destination Accessibility Index’ (NDAI) for four New Zealand cities. We found that the intensity of neighbourhood destination opportunities varied considerably among cities and between neighbourhoods within cities. Further, access to neighbourhood infrastructural support tends to be better in more socially deprived places. Potential explanations for the sociospatial distribution of neighbourhood destinations in New Zealand cities include historical processes of residential and economic development and infrastructural investment.
Broader or Deeper? Exploring the Most Effective Intervention Profile for Public Small Business Support
Authors: Mole Kevin F , Hart Mark , Roper Stephen , Saal David S
Published: January 2011

Most advanced economies offer publicly financed advice services to start-up firms and SMEs. In England, local or regional Business Links organisations have provided these services, and divided their support into nonintensive one-off contacts providing information or advice and more intensive support involving a diagnostic process and repeated interaction with firms. A key choice for Business Link managers is how to shape their intervention strategies, balancing resources between intensive and nonintensive support. Drawing on resource dependency theory, we develop a typology of intervention strategies for Business Links in England which reflects differences in the breadth and depth of the support provided. We then test the impacts of these alternative intervention models on client companies using both subjective assessments by firms and econometric treatment models that allow for selection bias. Our key empirical result is that Business Links' choice of intervention strategy has a significant effect both on actual and on perceived business outcomes, with our results emphasising the value of depth over breadth. The implication is that where additional resources are available for business support these should be used to deepen the assistance provided rather than extend assistance to a wider group of firms.
Carry-over effects of ewe nutrition and birth rank during the previous pregnancy on the milking performance during the subsequent lactation of Romney ewes
Authors: van der Linden D. S. , Kenyon P. R. , Jenkinson C. M. C. , Peterson S. W. , Blair H. T.
Published: January 2011

This study investigated whether selection for ewe size and nutrition during the previous pregnancy would affect the lactational performance of the ewe and liveweight gain of her lamb(s) in the subsequent year. A subgroup of singleton-bearing Romney ewes were milked once a week, for 7 consecutive weeks. Singleton-bearing ‘light’ ewes that gave birth to twins in the previous year had reduced milk yields from Day 21 of lactation (L21) onwards in the present year compared with those that gave birth to singletons in the previous year. Lambs born to light ewes had reduced liveweight gain from birth to L21 compared with those born to ‘heavy’ ewes. Singleton-bearing ewes in the present year that were fed maintenance and gave birth to twins in the previous year, produced less milk from L21 onwards compared with those that were maintenance-fed and singleton-bearing in the previous year. Singleton lambs born to milked ewes that were fed maintenance and gave birth to twins in the previous year, had lower liveweight gain from birth to L21 in the present year compared with lambs born to ewes fed maintenance and gave birth to singletons in the previous year. In the entire population, lambs born to ewes fed maintenance and that gave birth to twins in the previous year were lighter at L21 than lambs born to ewes fed ad libitum and bearing twins in the previous year. This indicates that if nutrition is suboptimal, or the ewes are lighter in the previous year, those that were twin-bearing are more likely to rear lighter lambs in the present year. Therefore, farmers need to take these points into consideration when devising feeding plans for the present year.