bluuebunny/crossref_metadata_2025 huggingface dataset:
Pain and clinical findings in the low back: A study of industrial employees with 5‐, 10‐, and 28‐year follow‐ups
Authors: Kääriä Sanna‐Mari , Mälkiä Esko A. , Luukkonen Ritva A. , Leino‐Arjas Päivi I.
Published: January 2010

Little is known about the relationships of clinical findings in the low back with low back pain (LBP) in the normal working population. We studied whether physiotherapist's findings in the low back were associated with local and radiating LBP among a cohort (n = 902) of employees in the engineering industry. A systematic non‐proportional sample was drawn in strata by age, gender, and occupational class. The non‐proportionality aimed at increasing sample size in smaller strata. Physiotherapists performed the straight‐leg raising test (SRL), and made assessments of the fingertip‐to‐floor distance and pain in palpation of the lumbar interspinous spaces. The variables on pain at the interspinous spaces and the SRL tests were entered in cluster analysis. Three clusters emerged: no, minor, and severe clinical findings. In logistic regression analysis at baseline, limited forward flexion and the clinical findings cluster variable were associated with local and, particularly, radiating LBP. Follow‐ups of the occurrence of local and radiating LBP at 5, 10, and 28 years from baseline were made. At the 5‐year follow‐up among subjects with no radiating LBP at baseline, the OR of radiating LBP for the clusters of minor and severe clinical findings compared to no findings were 2.7 (95% CI 1.4–5.1) and 3.8 (2.0–6.9), respectively, adjusted for age, gender, and occupational class. At the 10‐year follow‐up, the latter cluster predicted new reports of radiating LBP (1.9; 1.0–3.1) and of local LBP (4.1; 1.9–9.0, among subjects with no local LBP at baseline), similarly adjusted. No associations between limited forward flexion and new cases of LBP were observed. Thus, membership in clusters with different levels of findings in simple clinical measurements predicted new reports of radiating LBP, in particular, among employees. The generalizability of the results may be limited due to the characteristics of the sampling.
Autophagy‐mediated antigen processing in CD4+ T cell tolerance and immunity
Authors: Klein Ludger , Münz Christian , Lünemann Jan D.
Published: January 2010

Macroautophagy, a homeostatic process that shuttles cytoplasmic constituents into endosomal and lysosomal compartments, has recently been shown to deliver antigens for presentation on major histocompatibility complex (MHC) class II. Autophagy‐mediated antigen processing in thymic epithelial cells has been suggested to be involved in the generation of a self‐MHC restricted and self‐tolerant CD4+ T cell repertoire. Furthermore, there is accumulating evidence that the up‐regulation of autophagy by pattern‐recognition receptor signaling represents an innate defense mechanism against intracellular pathogens. Thus, through linking pathogen breakdown with the presentation of pathogen‐derived autophagy substrates on MHC class II, autophagy serves a dual function at the interface of the innate and the adaptive immune response.
Enhancement of natural and acquired immunity byLactobacillus rhamnosus(HN001),Lactobacillus acidophilus(HN017) andBifidobacterium lactis(HN019)
Authors: Gill H. S. , Rutherfurd K. J. , Prasad J. , Gopal P. K.
Published: January 2010

In order to study the mechanism by which increasing unsaturation of dietary fat lowers HDL-cholesterol levels, we studied various measures of HDL metabolism in hamsters fed with fats with different degrees of saturation. Hamsters were fed on a cholesterol-enriched (1 g/kg) semipurified diet containing 200 g/kg of maize oil, olive oil, or palm oil for 9 weeks. Increasing saturation of dietary fat resulted in increasing concentrations of total plasma cholesterol (4·29 (SD 0·51), 5·30 (sd 0·67) and 5·58 (sd 0·76) mmol/l respectively,n12) and HDL-cholesterol (3·31 (sd 0·50), 3·91 (sd 0·12) and 3·97 (sd 0·43) mmol/l) and these concentrations were significantly higher (P< 0·05) in the palm-oil and olive-oil-fed hamsters compared with the maize-oil group. Total plasma triacylglycerol levels also increased with increasing fat saturation (1·01 (sd 0·59), 1·56 (sd 0·65) and 2·75 (sd 1·03) mmol/l) and were significantly higher (P< 0·05) in the palm-oil group compared with the olive-oil and maize-oil-fed hamsters. The three diets did not have differential effects on plasma activity levels of lecithin: cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP). Levels of phospholipid transfer protein (PLTP) tended to be higher with increasing fat saturation but this effect was not significant. The capacity of liver membranes to bind human HDL3was significantly higher (P< 0·05) in the hamsters fed with maize oil (810 (sd 100) ng HDL3protein/mg membrane protein,n4) compared with those fed on palm oil (655 (sd 56) ng/mg), whereas the olive-oil group had intermediate values (674 (sd 26) ng/mg). The affinity of HDL3for the binding sites was not affected by the type of dietary fat. Hepatic lipase (EC3.1.1.3) activity, measured in liver homogenates, increased with increasing fat saturation. We conclude that dietary maize oil, when compared with either olive oil or palm oil, may lower HDL-cholesterol concentrations by enhancing HDL binding to liver membranes.
Spatial Effects in Dyadic Data
Authors: Neumayer Eric , Plümper Thomas
Published: January 2010

Political units often spatially depend in their policy choices on other units. This also holds in dyadic settings where, as in much of international relations research, analysis focuses on the interaction or relation between a pair or dyad of two political units. Yet, with few exceptions, social scientists have analyzed contagion in monadic datasets only, consisting of individual political units. This article categorizes all possible forms of spatial effect modeling in both undirected and directed dyadic data, where it is possible to distinguish the source and the target of interaction (for example, exporter/importer, aggressor/victim, and so on). This approach enables scholars to formulate and test novel mechanisms of contagion, thus ideally paving the way for studies analyzing spatial dependence between dyads of political units. To illustrate the modeling flexibility gained from an understanding of the full set of specification options for spatial effects in dyadic data, we examine the diffusion of bilateral investment treaties between developed and developing countries, building and extending on Elkins, Guzman, and Simmons's 2006 study. However, we come to different conclusions about the channels through which bilateral investment treaties diffuse. Rather than a capital-importing country being influenced by the total number of BITs signed by other capital importers, as modeled in their original article, we find that a capital-importing country is more likely to sign a BIT with a capital exporter only if other competing capital importers have signed BITs with this very same capital exporter. Similarly, other capital exporters' BITs with a specific capital importer influence an exporter's incentive to agree on a BIT with the very same capital importer.
Do Democracies Make Inferior Counterinsurgents? Reassessing Democracy's Impact on War Outcomes and Duration
Authors: Lyall Jason
Published: January 2010

A core proposition from decades of research on internal wars asserts that democracies, with their casualty-averse publics, accountable leaders, and free media, are uniquely prone to losing counterinsurgency (COIN) wars. Yet one should question this finding, for two reasons. First, existing studies overwhelmingly adopt no-variance research designs that only examine democracies, leaving them unable to assess their performance relative to autocracies. Second, these studies do not control for confounding factors that bias causal estimates. Democracies, for example, typically fight wars of choice as external occupiers, while most autocracies face homegrown insurgencies, a function in part of divergent levels of state capacity possessed by democratic and autocratic combatants. This study corrects for both problems using a new dataset of insurgencies (1800–2005) and matching to test whether democracies experience significantly higher rates of defeat and shorter wars. No relationship between democracy and war outcomes or duration is found once regime type is varied and inferential threats are addressed.
Americans Disunited: Americans United for World Organization and the Triumph of Internationalism
Authors: JOHNSTONE ANDREW
Published: January 2010

Created in 1944, Americans United for World Organization was a private internationalist organization promoting US entry into the United Nations, and although it has been overlooked by historians it deserves re-evaluation. This is less a result of its contributions to the public and congressional debates over UN ratification, and more closely related to the internal ideological and bureaucratic divisions that afflicted the organization from its very beginning. Americans United for World Organization was in fact anything but united, and it foreshadowed the divisions of the internationalist movement in the early years of the Cold War.
“The New Americans”: The Creation of a Typology of Vietnamese-American Identity in Children's Literature
Authors: CHATTARJI SUBARNO
Published: January 2010

The influx of Vietnamese refugees, “boat people,” and immigrants into the United States after April 1975 has led to the establishment of a significant Vietnamese-American community. There is a body of literature written for children and young adults that creates and delineates this new community within the topography of a welcoming and immigrant-friendly USA. This paper will examine the meanings and implications of the appellation “Vietnamese-American” as defined within a body of nonfiction children's literature. It will highlight how these texts negotiate questions related to refugee status, immigration, identity and belonging, contributing in many instances to a bland re-creation of a formerly oppressed but now coherent and increasingly prosperous and Americanized people. The children's literature plays an important role in defining the relatively new community to itself and to mainstream America. In its dissemination of truisms about Confucian heritages and stereotypes of “model minorities” the literature reveals as much about American ideological desires as it does about “the new Americans.”
Affective Narratives: Harlem and the Lower East Side
Authors: ROTTENBERG CATHERINE
Published: January 2010

This paper begins by juxtaposing contemporary discourses on Harlem and the Lower East Side, arguing that the processes of iconization of these two neighborhoods have been very different. Whereas the iconicity of Harlem has always been shot through with ambivalence, the Lower East Side has come to signify a relatively unambivalent sacred space for US Jewry. The second part of the essay then traces the representations of Harlem and the Lower East Side back to early twentieth-century African American and Jewish American novels, claiming that critically analyzing the theme of ambivalence in these texts – and, more specifically, how ambivalence manifests itself differently within each literary tradition – is key to understanding not only why Harlem and the Lower East Side have undergone parallel but divergent processes of iconization, but also the way Jews and blacks have been positioned and have attempted to position themselves in relation to dominant white US society.
Depression and cancer mortality: a meta-analysis
Authors: Pinquart M. , Duberstein P. R.
Published: January 2010

Background

The goal of the present study was to analyze associations between depression and mortality of cancer patients and to test whether these associations would vary by study characteristics.

Method

Meta-analysis was used for integrating the results of 105 samples derived from 76 prospective studies.

Results

Depression diagnosis and higher levels of depressive symptoms predicted elevated mortality. This was true in studies that assessed depression before cancer diagnosis as well as in studies that assessed depression following cancer diagnosis. Associations between depression and mortality persisted after controlling for confounding medical variables. The depression–mortality association was weaker in studies that had longer intervals between assessments of depression and mortality, in younger samples and in studies that used the Beck Depression Inventory as compared with other depression scales.

Conclusions

Screening for depression should be routinely conducted in the cancer treatment setting. Referrals to mental health specialists should be considered. Research is needed on whether the treatment of depression could, beyond enhancing quality of life, extend survival of depressed cancer patients.
Reconciling reason and religion: a response to Peels
Authors: ZAMULINSKI BRIAN
Published: January 2010

In ‘The ethics of belief and Christian faith as commitment to assumptions’, Rik Peels attacks the views that I advanced in ‘Christianity and the ethics of belief’. Here, I rebut his criticisms of the claim that it is wrong to believe without sufficient evidence, of the contention that Christians are committed to that claim, and of the notion of that faith is not belief but commitment to assumptions in the hope of salvation. My original conclusions still stand.
A critique of religious fictionalism
Authors: CORDRY BENJAMIN S.
Published: January 2010

Andrew Eshleman has argued that atheists can believe in God by being fully engaged members of religious communities and using religious discourse in a non-realist way. He calls this position ‘fictionalism’ because the atheist takes up religion as a useful fiction. In this paper I critique fictionalism along two lines: that it is problematic to successfully be a fictionalist and that fictionalism is unjustified. Reflection on fictionalism will point to some wider problems with religious anti-realism.
Jonathan Edwards's ontology: a critique of Sang Hyun Lee's dispositional account of Edwardsian metaphysics
Authors: CRISP OLIVER D.
Published: January 2010

Sang Hyun Lee's account of Jonathan Edwards's ontology has become the benchmark of many recent discussions of Edwards's thought. In this paper, I argue that this Lee interpretation is flawed in several crucial respects. In place of Lee's understanding of Edwards I offer an account of Edwards's work according to which Edwards is an idealist-occasionalist, but not an advocate of a purely dispositional ontology of creation.
How left behind are rural parents of migrant children? Evidence from Thailand
Authors: KNODEL JOHN , KESPICHAYAWATTANA JIRAPORN , SAENGTIENCHAI CHANPEN , WIWATWANICH SUVINEE
Published: January 2010

The consequences of adult children's migration from rural areas for older parents who remain behind are keenly debated. While the mass media and international advocacy organisations favour an ‘alarmist’ view of desertion, the academic literature makes more sanguine assessments using the ‘household strategy’ and ‘modified extended family’ perspectives. We examine the relationship between the migration of adult children and various dimensions of older parents' wellbeing in Thailand using evidence from a survey that focused on the issues. The results provide little support for the alarmist view, but instead suggest that parents and adult children adapt to the social and economic changes associated with development in ways not necessarily detrimental to intergenerational relations. The migration of children, especially to urban areas, often benefits parents' material support while the recent spread of cell phones has radically increased their ability to maintain social contact. Nevertheless, changing living arrangements through increased migration and the smaller family sizes of the youngest age groups of older people pose serious challenges for aspects of filial support, especially at advanced ages when chronic illness and frailty require long-term personal care. Dealing with this emerging situation in a context of social, economic and technological change is among the most critical issues facing those concerned with the implications of rapid population ageing in Thailand and elsewhere.
10. The spread of bacterial infection, the problem of herd immunity Topley WWC, Wilson GS. J Hyg 1923; 21: 243–249
Authors: FINE PAUL
Published: January 2010

This paper [1] is a milestone in the literature on infectious diseases. To put it in context, we recall that the late 19th century saw the construction of the germ theory, and its ultimate acceptance by the medical profession. The massive research effort led by Pasteur and Koch and their followers demonstrated a variety of infectious agents, catalogued their properties, and traced their pathogenesis in infected hosts. An understanding of the behaviour of infections in populations came only later, in the early 20th century, exemplified in the work of Ross on malaria [2], which was extrapolated to all infections in his ‘theory of happenings’ [3], and of Hamer on measles [4]. But there remained a tension between those who viewed infections from the perspective of the laboratory, with its emphasis upon biological properties, and those who viewed disease from the perspective of population statistics [5], which lent itself to more abstract and mathematical descriptions of epidemiological patterns. Fierce battles were waged between these disciplines, as between Almroth Wright and Karl Pearson on the subject of typhoid vaccination [6, 7].
Analyse subjektiver und objektiver Auswirkungen von Regeländerungen im Stabhochsprung
Authors: Lobinger Babett , Hohmann Tanja , Nicklisch Andreas
Published: January 2010

Zusammenfassung. Die Auswirkungen von Regeländerungen auf das subjektive Erleben von Sportlerinnen und Sportlern sind wenig untersucht. Im Rahmen einer Interviewstudie wurden 12 deutsche Stabhochspringerinnen und -springer zu den umfassenden Regeländerungen ihrer Disziplin im vorolympischen Jahr 2003 befragt. Die subjektiven Eindrücke der Athletinnen und Athleten wurden anschließend mit objektiven Daten verglichen. Die Ergebnisse zeigen, dass Anpassungsleistungen im Bereich der Bewegungsvorstellung sowie der Bewegungsausführung und taktischen Wettkampfgestaltung erfolgten, aber einige Sportlerinnen und Sportler dennoch den Eindruck hatten, dass sich die Regeländerungen negativ auf ihre Leistungen auswirkten. Die objektiven Daten zeigen weder die befürchteten Leistungseinbußen, noch lassen sich Zusammenhänge zwischen dem subjektiven Zeitdruck aufgrund der verkürzten Versuchszeiten und den tatsächlichen Ablaufzeiten finden. Aufbauend auf den Ergebnissen und deren kritischer Diskussion werden Empfehlungen für die Praxis gegeben.
Tidal triggering of earthquakes precursory to the recent Sumatra megathrust earthquakes of 26 December 2004 (Mw 9.0), 28 March 2005 (Mw 8.6), and 12 September 2007 (Mw 8.5)
Authors: Tanaka Sachiko
Published: January 2010

I observed tidal triggering of earthquakes precursory to the three giant earthquakes occurring off Sumatra on 26 December 2004 (Mw 9.0), 28 March 2005 (Mw 8.6), and 12 September 2007 (Mw 8.5). I measured the correlation between the Earth tide and earthquake occurrence in and around the focal regions of these megathrust earthquakes. The result of statistical analysis indicates that a high correlation appeared for several to ten years preceding the occurrence of the large earthquakes. The correlation vanished after the main events. The frequency distribution of tidal phase angles in the pre‐event period exhibited a peak near the angle where the tidal shear stress is at its maximum to accelerate the fault slip. This implies that the high correlation observed in the pre‐seismic stage is not a stochastic chance but is likely a physical consequence of the tidal stress change.
A density‐temperature description of the outer electron radiation belt during geomagnetic storms
Authors: Denton Michael H. , Borovsky Joseph E. , Cayton Thomas E.
Published: January 2010

Bi‐Maxwellian fits are made to energetic‐electron flux measurements from seven satellites in geosynchronous orbit, yielding a number density (n) and temperature (T) description of the outer electron radiation belt. For 54.5 spacecraft years of measurements the median value of n is 3.7 × 10−4 cm−3, and the median value of T is 148 keV. General statistical properties of n, T, and the 1.1–1.5 MeV flux F are investigated, including local‐time and solar‐cycle dependencies. Using superposed‐epoch analysis where the zero epoch is convection onset, the evolution of the outer electron radiation belt through high‐speed‐stream‐driven storms is investigated. The number‐density decay during the calm before the storm, relativistic‐electron dropouts and recoveries, and the heating of the outer electron radiation belt during storms are analyzed. Using four different “triggers” (sudden storm commencement (SSC), southward interplanetary magnetic field (IMF) portions of coronal mass ejection (CME) sheaths, southward‐IMF portions of magnetic clouds, and minimum Dst) a selection of CME‐driven storms are analyzed with superposed‐epoch techniques. For CME‐driven storms, only a very modest density decay prior to storm onset is found. In addition, the compression of the outer electron radiation belt at the time of SSC is analyzed, the number‐density increase and temperature decrease during storm main phase are characterized, and the increase in density and temperature during storm recovery phase is determined. During the different phases of storms, changes in the flux are sometimes in response to changes in the temperature, sometimes to changes in the number density, and sometimes to changes in both. Differences are found between the density‐temperature and flux descriptions, and it is concluded that more information is available using the density‐temperature description.
Maintenance of tropical tropopause layer cirrus
Authors: Dinh T. P. , Durran D. R. , Ackerman T. P.
Published: January 2010

A two‐dimensional cloud resolving model with explicit bin microphysics is used to study the maintenance of tropical tropopause layer (TTL) cirrus. Numerical simulations using this model show that a TTL cirrus with a maximum radiative heating rate of 3 K/day is able to self‐maintain for as long as 2 days if it contains ice crystals whose initial mean radius is smaller than about 5 μm. The key to the maintenance of the cloud is the circulation thermally forced by the cloud radiative heating. When the cloud layer is at ice saturation and temperature decreases with height, advection of water vapor by the thermally forced circulation results in water vapor flux convergence in the cloud. This leads to growth of ice crystals despite the diabatic warming produced by the radiative heating. The source of water vapor for the growth of ice crystals is outside the cloud lateral edge, which is outside the vertical column that contains the initial cloud. The conversion of water vapor into ice in the simulated TTL cirrus indicates its potential to dehydrate the surrounding environment. This dehydration mechanism does not involve adiabatic cooling associated with external large‐scale uplift.
Characterizing polar atmospheres and their effect on Rayleigh‐scattering optical depth
Authors: Tomasi Claudio , Petkov Boyan , Stone Robert S. , Benedetti Elena , Vitale Vito , Lupi Angelo , Mazzola Mauro , Lanconelli Christian , Herber Andreas , von Hoyningen‐Huene Wolfgang
Published: January 2010

A large set of radiosoundings was analyzed to study the dependence of Rayleigh‐scattering optical depth (ROD) on pressure and temperature features of the polar clear‐sky atmosphere. This set consists of 1320 radiosoundings, launched throughout the year at six Arctic sites, and of 940 radiosoundings launched at five Antarctic sites. The vertical profiles of pressure, temperature, and relative humidity given by these radiosoundings were corrected for lag errors and dry biases and then completed up to 120 km altitude, using COSPAR International Reference Atmosphere (CIRA) monthly vertical profiles of pressure and temperature, water vapor mixing ratio data derived from various satellite observations, and standard CO2vertical profile relative to 2007, when the ground‐level concentration was 380 ppmv. Calculations of the volume Rayleigh‐scattering coefficient were made for all the radiosoundings to study its seasonal variations with height due to pressure and temperature changes occurring in the troposphere and stratosphere. It was found that the surface‐level pressure and temperature conditions can account to a large extent for these seasonal effects. Therefore, average spectral evaluations of ROD were made at 88 selected wavelengths from 0.20 to 4.0μm for all the radiosoundings, subdivided into eight latitude/altitude site classes, representing 70°N, 75°N, 80°N, 70°S, 75°S, 80°S, and 90°S latitudes, for which the average ground values of air pressurepaand air temperatureTawere defined. The dependence of ROD on the daily ground‐level values of air pressurepoand air temperatureTomeasured at each site can be accounted for by using an algorithm in which the pressure dependence is given with good approximation by ratio (po/pa), and the temperature linear dependence is expressed by the difference (Ta−To) multiplied by a spectral slope coefficientk(λ) which varies by site classification. This algorithm was estimated to provide values of ROD with accuracy within ±0.5% at the six sea‐level Arctic sites, ±0.5% at the three Antarctic coastal sites, and ±0.7% at the two Antarctic Plateau sites (Dome C and South Pole). When used to analyze the Sun photometer measurements, the present evaluations of ROD are estimated to provide aerosol optical depth values at visible wavelengths with relative errors of 1%–2% at the Arctic sites, 1%–4% at the coastal Antarctic sites, and 3%–13% at the Antarctic Plateau sites, for background aerosol extinction conditions.
Performance polymers from renewable monomers: high molecular weight poly(pentadecalactone) for fiber applications
Authors: de Geus Matthijs , van der Meulen Inge , Goderis Bart , van Hecke Kristof , Dorschu Marko , van der Werff Harm , Koning Cor E. , Heise Andreas
Published: January 2010

Polypendadecalactone has properties comparable to polyethylene. Enzymatic polymerisation affords polymers with high molecular weight, which can be spun into fibres with high crystalline order and strength.
Dimer–dimer stacking interactions are important for nucleic acid binding by the archaeal chromatin protein Alba
Authors: Jelinska Clare , Petrovic-Stojanovska Biljana , Ingledew W. John , White Malcolm F.
Published: January 2010

Archaea use a variety of small basic proteins to package their DNA. One of the most widespread and highly conserved is the Alba (Sso10b) protein. Alba interacts with both DNA and RNA in vitro, and we show in the present study that it binds more tightly to dsDNA (double-stranded DNA) than to either ssDNA (single-stranded DNA) or RNA. The Alba protein is dimeric in solution, and forms distinct ordered complexes with DNA that have been visualized by electron microscopy studies; these studies suggest that, on binding dsDNA, the protein forms extended helical protein fibres. An end-to-end association of consecutive Alba dimers is suggested by the presence of a dimer–dimer interface in crystal structures of Alba from several species, and by the strong conservation of the interface residues, centred on Arg59 and Phe60. In the present study we map perturbation of the polypeptide backbone of Alba upon binding to DNA and RNA by NMR, and demonstrate the central role of Phe60 in forming the dimer–dimer interface. Site-directed spin labelling and pulsed ESR are used to confirm that an end-to-end, dimer–dimer interaction forms in the presence of dsDNA.
Assembly manual for the proteasome regulatory particle: the first draft
Authors: Park Soyeon , Tian Geng , Roelofs Jeroen , Finley Daniel
Published: January 2010

The proteasome is the most complex protease known, with a molecular mass of approx. 3 MDa and 33 distinct subunits. Recent studies reported the discovery of four chaperones that promote the assembly of a 19-subunit subcomplex of the proteasome known as the regulatory particle, or RP. These and other findings define a new and highly unusual macromolecular assembly pathway. The RP mediates substrate selection by the proteasome and injects substrates into the CP (core particle) to be degraded. A heterohexameric ring of ATPases, the Rpt proteins, is critical for RP function. These ATPases abut the CP and their C-terminal tails help to stabilize the RP–CP interface. ATPase heterodimers bound to the chaperone proteins are early intermediates in assembly of the ATPase ring. The four chaperones have the common feature of binding the C-domains of Rpt proteins, apparently a remarkable example of convergent evolution; each chaperone binds a specific Rpt subunit. The C-domains are distinct from the C-terminal tails, but are proximal to them. Some, but probably not all, of the RP chaperones appear to compete with CP for binding of the Rpt proteins, as a result of the proximity of the tails to the C-domain. This competition may underlie the release mechanism for these chaperones. Genetic studies in yeast point to the importance of the interaction between the CP and the Rpt tails in assembly, and a recent biochemical study in mammals suggests that RP assembly takes place on pre-assembled CP. These results do not exclude a parallel CP-independent pathway of assembly. Ongoing work should soon clarify the roles of both the CP and the four chaperones in RP assembly.
A new map to understand deubiquitination
Authors: Katz Elijah J. , Isasa Marta , Crosas Bernat
Published: January 2010

Deubiquitination is a crucial mechanism in ubiquitin-mediated signalling networks. The importance of Dubs (deubiquitinating enzymes) as regulators of diverse cellular processes is becoming ever clearer as new roles are elucidated and new pathways are shown to be affected by this mechanism. Recent work, reviewed in the present paper, provides new perspective on the widening influence of Dubs and a new tool to focus studies of not only Dub interactions, but also potentially many more cellular systems.
SUMO and ubiquitin paths converge
Authors: Denuc Amanda , Marfany Gemma
Published: January 2010

One of the more rapidly expanding fields in cell signalling nowadays is the characterization of proteins conjugated to Ub (ubiquitin) or Ub-like peptides, such as SUMO (small Ub-related modifier). The reversible covalent attachment of these small peptides remodels the target protein, providing new protein–protein interaction interfaces, which can be dynamically regulated given a set of enzymes for conjugation and deconjugation. First, ubiquitination was thought to be merely relegated to the control of protein turnover and degradation, whereas the attachment of SUMO was involved in the regulation of protein activity and function. However, the boundaries between the protein fates related to these tag molecules are becoming more and more fuzzy, as either the differences between mono-, multi- and poly-modifications or the lysine residue used for growth of the poly-chains is being dissected. The Ub and SUMO pathways are no longer separated, and many examples of this cross-talk are found in the literature, involving different cellular processes ranging from DNA repair and genome stability, to the regulation of protein subcellular localization or enzyme activity. Here, we review several cases in which SUMOylation and ubiquitination intersect, showing also that the same protein can be conjugated to SUMO and Ub for antagonistic, synergistic or multiple outcomes, illustrating the intricacy of the cellular signalling networks. Ub and SUMO have met and are now applying for new regulatory roles in the cell.
Properties of natural and artificial proteins displaying multiple ubiquitin-binding domains
Authors: Lopitz-Otsoa Fernando , Rodríguez Manuel S. , Aillet Fabienne
Published: January 2010

Ubiquitylation provides a rapid alternative to control the activity of crucial cellular factors through the remodelling of a target protein. Diverse ubiquitin chains are recognized by domains with affinity for UBDs (ubiquitin-binding domains) present in receptor/effector proteins. Interestingly, some proteins contain more than one UBD and the preservation of this structure in many species suggests an evolutionary advantage for this topology. Here, we review some typical proteins that naturally contain more than one UBD and emphasize how such structures contribute to the mechanism they mediate. Characteristics such as higher affinities for polyubiquitin chains and chain-linkage preferences can be replicated by the TUBEs (tandem ubiquitin-binding entities). Furthermore, TUBEs show two additional properties: protection of ubiquitylated substrates from deubiquitylating enzymes and interference with the action of the proteasome. Consequently, TUBEs behave as ‘ubiquitin traps’ that efficiently capture endogenous ubiquitylated proteins. Interpretations and hypothetical models proposed by different groups to understand the synchronous action of multiple UBDs are discussed herein.
The anaphase-promoting complex/cyclosome (APC/C): cell-cycle-dependent and -independent functions
Authors: Manchado Eusebio , Eguren Manuel , Malumbres Marcos
Published: January 2010

The APC/C (anaphase-promoting complex/cyclosome) is an E3 ubiquitin ligase that targets specific substrates for degradation by the 26S proteasome. APC/C activity depends on two cofactors, namely Cdc20 (cell division cycle 20) and Cdh1, which select the appropriate targets for ubiquitination. It is well established that APC/C is a target of the SAC (spindle assembly checkpoint) during mitosis and has critical roles in controlling the protein levels of major regulators of mitosis and DNA replication. In addition, recent studies have suggested new cell-cycle-independent functions of APC/C in non-mitotic cells and specifically in neuronal structure and function. Given the relevant functions of APC/C in cell proliferation and neuronal physiology, modulating APC/C activity may have beneficial effects in the clinic.
Cyclin A and Nek2A: APC/C–Cdc20 substrates invisible to the mitotic spindle checkpoint
Authors: Zon Wouter van , Wolthuis Rob M.F.
Published: January 2010

Active cyclin B1–Cdk1 (cyclin-dependent kinase 1) keeps cells in mitosis, allowing time for spindle microtubules to capture the chromosomes and for incorrect chromosome-spindle attachments to be repaired. Meanwhile, securin, an inhibitor of separase, secures cohesion between sister chromatids, preventing anaphase onset. The spindle checkpoint is a signalling pathway emerging from improperly attached chromosomes that inhibits Cdc20, the mitotic activator of the APC/C (anaphase-promoting complex/cyclosome) ubiquitin ligase. Blocking Cdc20 stabilizes cyclin B1 and securin to delay mitotic exit and anaphase until all chromosomes reach bipolar spindle attachments. Cells entering mitosis in the absence of a functional spindle checkpoint degrade cyclin B1 and securin right after nuclear-envelope breakdown, in prometaphase. Interestingly, two APC/C substrates, cyclin A and Nek2A, are normally degraded at nuclear-envelope breakdown, even when the spindle checkpoint is active. This indicates that the APC/C is activated early in mitosis, whereas cyclin B1 and securin are protected as long as the spindle checkpoint inhibits Cdc20. Remarkably, destruction of cyclin A and Nek2A also depends on Cdc20. The paradox of Cdc20 being both active and inhibited in prometaphase could be explained if cyclin A and Nek2A are either exceptionally efficient Cdc20 substrates, or if they are equipped with ‘stealth’ mechanisms to effectively escape detection by the spindle checkpoint. In the present paper, we discuss recently emerging models for spindle-checkpoint-independent APC/C–Cdc20 activity, which might even have implications for cancer therapy.
SUMO in the mammalian response to DNA damage
Authors: Morris Joanna R.
Published: January 2010

Modification by SUMOs (small ubiquitin-related modifiers) is largely transient and considered to alter protein function through altered protein–protein interactions. These modifications are significant regulators of the response to DNA damage in eukaryotic model organisms and SUMOylation affects a large number of proteins in mammalian cells, including several proteins involved in the response to genomic lesions [Golebiowski, Matic, Tatham, Cole, Yin, Nakamura, Cox, Barton, Mann and Hay (2009) Sci. Signaling 2, ra24]. Furthermore, recent work [Morris, Boutell, Keppler, Densham, Weekes, Alamshah, Butler, Galanty, Pangon, Kiuchi, Ng and Solomon (2009) Nature 462, 886–890; Galanty, Belotserkovskaya, Coates, Polo, Miller and Jackson (2009) Nature 462, 935–939] has revealed the involvement of the SUMO cascade in the BRCA1 (breast-cancer susceptibility gene 1) pathway response after DNA damage. The present review examines roles described for the SUMO pathway in the way mammalian cells respond to genotoxic stress.
Control of PCNA deubiquitylation in yeast
Authors: Gallego-Sánchez Alfonso , Conde Francisco , Segundo Pedro San , Bueno Avelino
Published: January 2010

Eukaryotes ubiquitylate the replication factor PCNA (proliferating-cell nuclear antigen) so that it tolerates DNA damage. Although, in the last few years, the understanding of the evolutionarily conserved mechanism of ubiquitylation of PCNA, and its crucial role in DNA damage tolerance, has progressed impressively, little is known about the deubiquitylation of this sliding clamp in most organisms. In the present review, we will discuss potential molecular mechanisms regulating PCNA deubiquitylation in yeast.
Ubiquitin-dependent regulation of translesion polymerases
Authors: Chun Abel C.S. , Jin Dong-Yan
Published: January 2010

In response to DNA damage, TLS (translesion synthesis) allows replicative bypass of various DNA lesions, which stall normal replication. TLS is achieved by low-fidelity polymerases harbouring less stringent active sites. In humans, Y-family polymerases together with Polζ (polymerase ζ) are responsible for TLS across different types of damage. Protein–protein interaction contributes significantly to the regulation of TLS. REV1 plays a central role in TLS because it interacts with all other Y-family members and Polζ. Ubiquitin-dependent regulatory mechanisms also play important roles in TLS. Ubiquitin-binding domains have been found in TLS polymerases and they might be required for TLS activity. Mono-ubiquitination of PCNA (proliferating-cell nuclear antigen), the central scaffold of TLS polymerases, is thought to promote TLS. In addition, both non-proteolytic and proteolytic polyubiquitination of PCNA and TLS polymerases has been demonstrated. Owing to their low fidelity, the recruitment of TLS polymerases is strictly restricted to stalled replication forks.
Emerging role of Alzheimer's disease-associated ubiquilin-1 in protein aggregation
Authors: Haapasalo Annakaisa , Viswanathan Jayashree , Bertram Lars , Soininen Hilkka , Tanzi Rudolph E. , Hiltunen Mikko
Published: January 2010

Abnormal protein aggregation and intracellular or extracellular accumulation of misfolded and aggregated proteins are key events in the pathogenesis of different neurodegenerative diseases. Furthermore, endoplasmic reticulum stress and impairment of the ubiquitin–proteasome system probably contribute to neurodegeneration in these diseases. A characteristic feature of AD (Alzheimer's disease) is the abnormal accumulation of Aβ (amyloid β-peptide) in the brain. Evidence shows that the AD-associated PS (presenilin) also forms aggregates under certain conditions and that another AD-associated protein, ubiquilin-1, controls protein aggregation and deposition of aggregated proteins. Here, we review the current knowledge of ubiquilin-1 and PS in protein aggregation and related events that potentially influence neurodegeneration.
Control of NF-κB activation by the COP9 signalosome
Authors: Schweitzer Katrin , Naumann Michael
Published: January 2010

The transcription factor NF-κB (nuclear factor κB) exerts crucial functions in the regulation of innate and adaptive immune responses, wound healing and tissue maintenance and in the development of immune cells. Tight control of NF-κB is essential for an efficient defence against pathogens and environmental stress to protect organisms from inflammatory diseases including cancer. An involvement of the CSN (COP9 signalosome) in the regulation of NF-κB has been discovered recently. The CSN is a conserved multiprotein complex, which mainly functions in the control of proteolysis. Here, we review recent observations indicating important roles of the CSN in the control of NF-κB in innate immunity, as well as T-cell activation and maturation.
Regulation of SNAP-25 trafficking and function by palmitoylation
Authors: Greaves Jennifer , Prescott Gerald R. , Gorleku Oforiwa A. , Chamberlain Luke H.
Published: January 2010

The SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) protein SNAP-25 (25 kDa synaptosome-associated protein) is essential for regulated exocytosis in neuronal and neuroendocrine cells. Whereas the majority of SNARE proteins contain transmembrane domains, SNAP-25 is instead anchored to membranes by the palmitoylation of a central cysteine-rich region. In this review, we discuss the mechanisms of SNAP-25 palmitoylation and how this modification regulates the intracellular trafficking and exocytotic function of this essential protein.
Role of neuronal Ca2+-sensor proteins in Golgi–cell-surface membrane traffic
Authors: Mikhaylova Marina , Reddy Pasham Parameshwar , Kreutz Michael R.
Published: January 2010

The regulated local synthesis of PtdIns4P and PtdIns(4,5)P2 is crucial for TGN (trans-Golgi network)–plasma membrane trafficking. The activity of PI4Kβ (phosphoinositide 4-kinase IIIβ) at the Golgi membrane is a first mandatory step in this process. In addition to PI4Kβ activity, elevated Ca2+ levels are also needed for the exit of vesicles from the TGN. The reason for this Ca2+ requirement is at present unclear. In the present review, we discuss the role of neuronal Ca2+-sensor proteins in the regulation of PI4Kβ and suggest that this regulation might impose a need for elevated Ca2+ levels for a late step of vesicle assembly.
The Sla2p/HIP1/HIP1R family: similar structure, similar function in endocytosis?
Authors: Gottfried Irit , Ehrlich Marcelo , Ashery Uri
Published: January 2010

HIP1 (huntingtin interacting protein 1) has two close relatives: HIP1R (HIP1-related) and yeast Sla2p. All three members of the family have a conserved domain structure, suggesting a common function. Over the past decade, a number of studies have characterized these proteins using a combination of biochemical, imaging, structural and genetic techniques. These studies provide valuable information on binding partners, structure and dynamics of HIP1/HIP1R/Sla2p. In general, all suggest a role in CME (clathrin-mediated endocytosis) for the three proteins, though some differences have emerged. In this mini-review we summarize the current views on the roles of these proteins, while emphasizing the unique attributes of each family member.
Regulation of cyclin D1 gene expression
Authors: Witzel Ini-Isabée , Koh Li Fang , Perkins Neil D.
Published: January 2010

Cyclin D1 is a key regulator of cell proliferation and its expression is subject to both transcriptional and post-transcriptional regulation. In different cellular contexts, different pathways assume a dominant role in regulating its expression, whereas their disregulation can contribute to overexpression of cyclin D1 in tumorigenesis. Here, we discuss the ability of the NF-κB (nuclear factor κB)/IKK [IκB (inhibitor of NF-κB) kinase] pathways to regulate cyclin D1 gene transcription and also consider the newly discovered role of the SNARP (SNIP1/SkIP-associated RNA processing) complex as a co-transcriptional regulator of cyclin D1 RNA stability.
The role of p63 in epidermal morphogenesis and neoplasia
Authors: McDade Simon S. , McCance Dennis J.
Published: January 2010

The p53 family of transcription factors is made up of p53, p63 and p73, which share significant structural homology. In particular, transcriptional complexity and the expression of multiple protein isoforms are an emergent trait of all family members. p63 is the evolutionarily eldest member of the p53 family and the various isoforms have critical roles in the development of stratifying epithelia. Recent results have uncovered additional splice variants, adding to the complexity of the transcriptional architecture of p63. These observations and the emerging extensive interplay between p63 and p53 in development, proliferation and differentiation underline the importance of considering all isoforms and family members in studies of the function of p53 family members.
Coupling genetics and post-genomic approaches to decipher the cellular splicing code at a systems-wide level
Authors: Liu Yilei , Elliott David J.
Published: January 2010

Nuclear RNA processing is a critical stage in eukaryotic gene expression, and is controlled in part by the expression and concentration of nuclear RNA-binding proteins. Different nuclear RNA-binding proteins are differentially expressed in different cells, helping the spliceosome to decode pre-mRNAs into alternatively spliced mRNAs. Recent post-genomic technology has exposed the complexity of nuclear RNA processing, and is starting to reveal the mechanisms and rules through which networks of RNA-binding proteins can regulate multiple parallel pathways. Identification of multiple parallel processing pathways regulated by nuclear RNA-binding proteins is leading to a systems-wide understanding of the rules and consequences of alternative nuclear RNA processing.
The nuclear envelope from basic biology to therapy
Authors: Worman Howard J. , Foisner Roland
Published: January 2010

The nuclear envelope has long been a focus of basic research for a highly specialized group of cell biologists. More recently, an expanding group of scientists and physicians have developed a keen interest in the nuclear envelope since mutations in the genes encoding lamins and associated proteins have been shown to cause a diverse range of human diseases often called laminopathies or nuclear envelopathies. Most of these diseases have tissue-selective phenotypes, suggesting that the nuclear envelope must function in cell-type- and developmental-stage-specific processes such as chromatin organization, regulation of gene expression, controlled nucleocytoplasmic transport and response to stress in metazoans. On 22–23 April 2009, Professor Christopher Hutchison organized the 4th British Nuclear Envelope Disease and Chromatin Organization meeting at the College of St Hild and St Bede at Durham University, sponsored by the Biochemical Society. In attendance were investigators with one common interest, the nuclear envelope, but with diverse expertise and training in animal and plant cell biology, genetics, developmental biology and medicine. We were each honoured to be keynote speakers. This issue of Biochemical Society Transactions contains papers written by some of the presenters at this scientifically exciting meeting, held in a bucolic setting where the food was tasty and the wine flowed freely. Perhaps at the end of this excellent meeting more questions were raised than answered, which will stimulate future research. However, what became clear is that the nuclear envelope is a cellular structure with critical functions in addition to its traditional role as a barrier separating the nuclear and cytoplasmic compartments in interphase eukaryotic cells.