bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stability of toxin gene proportion in red-pigmented populations of the cyanobacterium Planktothrix during 29 years of re-oligotrophication of Lake Zürich
Authors: Ostermaier Veronika , Schanz Ferdinand , Köster Oliver , Kurmayer Rainer 
Published: December 2012

Abstract

Background
Harmful algal blooms deteriorate the services of aquatic ecosystems. They are often formed by cyanobacteria composed of genotypes able to produce a certain toxin, for example, the hepatotoxin microcystin (MC), but also of nontoxic genotypes that either carry mutations in the genes encoding toxin synthesis or that lost those genes during evolution. In general, cyanobacterial blooms are favored by eutrophication. Very little is known about the stability of the toxic/nontoxic genotype composition during trophic change.

Results
Archived samples of preserved phytoplankton on filters from aquatic ecosystems that underwent changes in the trophic state provide a so far unrealized possibility to analyze the response of toxic/nontoxic genotype composition to the environment. During a period of 29 years of re-oligotrophication of the deep, physically stratified Lake Zürich (1980 to 2008), the population of the stratifying cyanobacterium Planktothrix was at a minimum during the most eutrophic years (1980 to 1984), but increased and dominated the phytoplankton during the past two decades. Quantitative polymerase chain reaction revealed that during the whole observation period the proportion of the toxic genotype was strikingly stable, that is, close to 100%. Inactive MC genotypes carrying mutations within the MC synthesis genes never became abundant. Unexpectedly, a nontoxic genotype, which lost its MC genes during evolution, and which could be shown to be dominant under eutrophic conditions in shallow polymictic lakes, also co-occurred in Lake Zürich but was never abundant. As it is most likely that this nontoxic genotype contains relatively weak gas vesicles unable to withstand the high water pressure in deep lakes, it is concluded that regular deep mixing selectively reduced its abundance through the destruction of gas vesicles.

Conclusions
The stability in toxic genotype dominance gives evidence for the adaptation to deep mixing of a genotype that retained the MC gene cluster during evolution. Such a long-term dominance of a toxic genotype draws attention to the need to integrate phylogenetics into ecological research as well as ecosystem management.
Ubiquitination and sumoylation of the HTLV-2 Tax-2B protein regulate its NF-κB activity: a comparative study with the HTLV-1 Tax-1 protein
Authors: Turci Marco , Lodewick Julie , Di Gennaro Gianfranco , Rinaldi Anne Sophie , Marin Oriano , Diani Erica , Sampaio Carla , Bex Françoise , Bertazzoni Umberto , Romanelli Maria Grazia 
Published: December 2012

Abstract

Background
Retroviruses HTLV-1 and HTLV-2 have homologous genomic structures but differ significantly in pathogenicity. HTLV-1 is associated with Adult T cell Leukemia (ATL), whereas infection by HTLV-2 has no association with neoplasia. Transformation of T lymphocytes by HTLV-1 is linked to the capacity of its oncoprotein Tax-1 to alter cell survival and cell cycle control mechanisms. Among these functions, Tax-1-mediated activation of cellular gene expression via the NF-κB pathway depends on Tax-1 post-translational modifications by ubiquitination and sumoylation. The Tax-2 protein of HTLV-2B (Tax-2B) is also modified by ubiquitination and sumoylation and activates the NF-κB pathway to a level similar to that of Tax-1. The present study aims to understand whether ubiquitination and sumoylation modifications are involved in Tax-2B-mediated activation of the NF-κB pathway.

Results
The comparison of Tax-1 and Tax-2B lysine to arginine substitution mutants revealed conserved patterns and levels of ubiquitination with notable difference in the lysine usage for sumoylation. Neither Tax-1 nor Tax-2B ubiquitination and sumoylation deficient mutants could activate the NF-κB pathway and fusion of ubiquitin or SUMO-1 to the C-terminus of the ubiquitination and sumoylation deficient Tax-2B mutant strikingly restored transcriptional activity. In addition, ubiquitinated forms of Tax-2B colocalized with RelA and IKKγ in prominent cytoplasmic structures associated with the Golgi apparatus, whereas colocalization of Tax-2B with the RelA subunit of NF-κB and the transcriptional coactivator p300 in punctate nuclear structures was dependent on Tax-2B sumoylation, as previously observed for Tax-1.

Conclusions
Both Tax-1 and Tax-2 activate the NF-κB pathway via similar mechanisms involving ubiquitination and sumoylation. Therefore, the different transforming potential of HTLV-1 and HTLV-2 is unlikely to be related to different modes of activation of the canonical NF-κB pathway.
A bivalent recombinant protein inactivates HIV-1 by targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2 domains
Authors: Lu Lu , Pan Chungen , Li Yuan , Lu Hong , He Wu , Jiang Shibo 
Published: December 2012

AbstractBackgroundMost currently approved anti-HIV drugs (e.g., reverse transcriptase inhibitors, protease inhibitors and fusion/entry inhibitors) must act inside or on surface of the target cell to inhibit HIV infection, but none can directly inactivate virions away from cells. Although soluble CD4 (sCD4) can inactivate laboratory-adapted HIV-1 strains, it fails to reduce the viral loads in clinical trials because of its low potency against primary isolates and tendency to enhance HIV-1 infection at low concentration. Thus, it is essential to design a better HIV inactivator with improved potency for developing new anti-HIV therapeutics that can actively attack the virus in the circulation before it attaches to and enter into the target cell.ResultsWe engineered a bivalent HIV-1 inactivator, designated 2DLT, by linking the D1D2 domain of CD4 to T1144, the next generation HIV fusion inhibitor, with a 35-mer linker. The D1D2 domain in this soluble 2DLT protein could bind to the CD4-binding site and induce the formation of the gp41 prehairpin fusion-intermediate (PFI), but showed no sCD4-mediated enhancement of HIV-1 infection. The T1144 domain in 2DLT then bound to the exposed PFI, resulting in rapid inactivation of HIV-1 virions in the absence of the target cell. Beside, 2DLT could also inhibit fusion of the virus with the target cell if the virion escapes the first attack of 2DLT.ConclusionThis bivalent molecule can serve as a dual barrier against HIV infection by first inactivating HIV-1 virions away from cells and then blocking HIV-1 entry on the target cell surface, indicating its potential for development as a new class of anti-HIV drug.
Adrenocortical steroid response to ACTH in different phenotypes of non-obese polycystic ovary syndrome
Authors: Cinar Nese , Harmanci Ayla , Aksoy Duygu Yazgan , Aydin Kadriye , Yildiz Bulent Okan 
Published: December 2012

Abstract

Background
Adrenal androgen excess is frequently observed in PCOS. The aim of the study was to determine whether adrenal gland function varies among PCOS phenotypes, women with hyperandrogenism (H) only and healthy women.

Methods
The study included 119 non-obese patients with PCOS (age: 22.2 ± 4.1y, BMI:22.5 ± 3.1 kg/m2), 24 women with H only and 39 age and BMI- matched controls. Among women with PCOS, 50 had H, oligo-anovulation (O), and polycystic ovaries (P) (PHO), 32 had O and H (OH), 23 had P and H (PH), and 14 had P and O (PO). Total testosterone (T), SHBG and DHEAS levels at basal and serum 17-hydroxprogesterone (17-OHP), androstenedione (A4), DHEA and cortisol levels after ACTH stimulation were measured.

Results
T, FAI and DHEAS, and basal and AUC values for 17-OHP and A4 were significantly and similarly higher in PCOS and H groups than controls (p < 0.05 for all) whereas three groups did not differ for basal or AUC values of DHEA and cortisol. Three hyperandrogenic subphenotypes (PHO, OH, and PH) compared to non-hyperandrogenic subphenotype (PO) had significantly and similarly higher T, FAI, DHEAS and AUC values for 17-OHP, A4 and DHEA (p < 0.05). All subphenotypes had similar basal and AUC values for cortisol.

Conclusion
PCOS patients and women with H only have similar and higher basal and stimulated adrenal androgen levels than controls. All three hyperandrogenic subphenotypes of PCOS exhibit similar and higher basal and stimulated adrenal androgen secretion patterns compared to non-hyperandrogenic subphenotype.
Fibroblast growth factor receptor 3 effects on proliferation and telomerase activity in sheep growth plate chondrocytes
Authors: Smith Logan B , Belanger Janelle M , Oberbauer Anita M 
Published: December 2012

Abstract

Background
Fibroblast growth factor receptor 3 (FGFR3) inhibits growth-plate chondrocyte proliferation and limits bone elongation. Gain-of-function FGFR3 mutations cause dwarfism, reduced telomerase activity and shorter telomeres in growth plate chondroyctes suggesting that FGFR3 reduces proliferative capacity, inhibits telomerase, and enhances senescence. Thyroid hormone (T3) plays a role in cellular maturation of growth plate chondrocytes and a known target of T3 is FGFR3. The present study addressed whether reduced FGFR3 expression enhanced telomerase activity, mRNA expression of telomerase reverse transcriptase (TERT) and RNA component of telomerase (TR), and chondrocyte proliferation, and whether the stimulation of FGFR3 by T3 evoked the opposite response.

Results
Sheep growth-plate proliferative zone chondrocytes were cultured and transfected with siRNA to reduce FGFR3 expression; FGFR3 siRNA reduced chondrocyte FGFR3 mRNA and protein resulting in greater proliferation and increased TERT mRNA expression and telomerase activity (p < 0.05). Chondrocytes treated with T3 significantly enhanced FGFR3 mRNA and protein expression and reduced telomerase activity (p < 0.05); TERT and TR were not significantly reduced. The action of T3 at the growth plate may be partially mediated through the FGFR3 pathway.

Conclusions
The results suggest that FGFR3 inhibits chondrocyte proliferation by down-regulating TERT expression and reducing telomerase activity indicating an important role for telomerase in sustaining chondrocyte proliferative capacity during bone elongation.
Plasma lipoprotein-associated phospholipase A2 activity in Alzheimer's disease, amnestic mild cognitive impairment, and cognitively healthy elderly subjects: a cross-sectional study
Authors: Davidson Julie E , Lockhart Andrew , Amos Leslie , Stirnadel-Farrant Heide A , Mooser Vincent , Sollberger Marc , Regeniter Axel , Monsch Andreas U , Irizarry Michael C 
Published: December 2012

Abstract
Introduction
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulating enzyme with pro-inflammatory and oxidative activities associated with cardiovascular disease and ischemic stroke. While high plasma Lp-PLA2 activity was reported as a risk factor for dementia in the Rotterdam study, no association between Lp-PLA2 mass and dementia or Alzheimer's disease (AD) was detected in the Framingham study. The objectives of the current study were to explore the relationship of plasma Lp-PLA2 activity with cognitive diagnoses (AD, amnestic mild cognitive impairment (aMCI), and cognitively healthy subjects), cardiovascular markers, cerebrospinal fluid (CSF) markers of AD, and apolipoprotein E (APOE) genotype.

Methods
Subjects with mild AD (n = 78) and aMCI (n = 59) were recruited from the Memory Clinic, University Hospital, Basel, Switzerland; cognitively healthy subjects (n = 66) were recruited from the community. Subjects underwent standardised medical, neurological, neuropsychological, imaging, genetic, blood and CSF evaluation. Differences in Lp-PLA2 activity between the cognitive diagnosis groups were tested with ANOVA and in multiple linear regression models with adjustment for covariates. Associations between Lp-PLA2 and markers of cardiovascular disease and AD were explored with Spearman's correlation coefficients.

Results
There was no significant difference in plasma Lp-PLA2 activity between AD (197.1 (standard deviation, SD 38.4) nmol/min/ml) and controls (195.4 (SD 41.9)). Gender, statin use and low-density lipoprotein cholesterol (LDL) were independently associated with Lp-PLA2 activity in multiple regression models. Lp-PLA2 activity was correlated with LDL and inversely correlated with high-density lipoprotein (HDL). AD subjects with APOE-ε4 had higher Lp-PLA2 activity (207.9 (SD 41.2)) than AD subjects lacking APOE-ε4 (181.6 (SD 26.0), P = 0.003) although this was attenuated by adjustment for LDL (P = 0.09). No strong correlations were detected for Lp-PLA2 activity and CSF markers of AD.

Conclusion
Plasma Lp-PLA2 was not associated with a diagnosis of AD or aMCI in this cross-sectional study. The main clinical correlates of Lp-PLA2 activity in AD, aMCI and cognitively healthy subjects were variables associated with lipid metabolism.
Meta-analysis identified the TNFA -308G > A promoter polymorphism as a risk factor for disease severity in patients with rheumatoid arthritis
Authors: Toonen Erik JM , Barrera Pilar , Fransen Jaap , de Brouwer Arjan PM , Eijsbouts Agnes M , Miossec Pierre , Marotte Hubert , Scheffer Hans , van Riel Piet LCM , Franke Barbara , Coenen Marieke JH 
Published: December 2012

Abstract
Introduction
The goal of this study is to investigate whether the -308G > A promoter polymorphism in the tumor necrosis factor alpha (TNFA) gene is associated with disease severity and radiologic joint damage in a large cohort of patients with rheumatoid arthritis (RA).

Methods
A long-term observational early RA inception cohort (n = 208) with detailed information about disease activity and radiologic damage after 3, 6 and 9 years of disease was genotyped for the TNFA -308G > A promoter polymorphism (rs1800629). A longitudinal regression analysis was performed to assess the effect of genotype on RA disease severity and joint damage. Subsequently, a meta-analysis, including all publically available data, was performed to further test the association between joint erosions and the TNFA polymorphism. To learn more about the mechanism behind the effect of the polymorphism, RNA isolated from peripheral blood from RA patients (n = 66) was used for TNFA gene expression analysis by quantitative PCR.

Results
Longitudinal regression analysis with correction for gender and disease activity showed a significant difference in total joint damage between GG and GA+AA genotype groups (P = 0.002), which was stable over time. The meta-analysis, which included 2,053 patients, confirmed an association of the genetic variant with the development of erosions (odds ratio 0.78, 95% CI 0.62, 0.98). No significant differences in TNFA gene expression were observed for the different genotypes, confirming earlier findings in healthy individuals.

Conclusions
Our data confirm that the TNFA -308G > A promoter polymorphism is associated with joint damage in patients with RA. This is not mediated by differences in TNFA gene expression between genotypes.
Efficacy and safety of lenalidomide for refractory cutaneous lupus erythematosus
Authors: Cortés-Hernández Josefina , Ávila Gabriela , Vilardell-Tarrés Miquel , Ordi-Ros Josep 
Published: December 2012

Abstract
Introduction
Cutaneous lupus erythematosus (CLE) is a chronic disease characterized by disfigurement and a relapsing course. Thalidomide has proven its efficacy in refractory cutaneous lupus disease, although it is not exempt from significant side effects and frequent relapses after withdrawal. New thalidomide analogues have been developed but lack clinical experience. The aim of this preliminary phase II study was to evaluate the efficacy and safety of lenalidomide in patients with refractory CLE.

Methods
Fifteen patients with refractory cutaneous lupus disease were enrolled in this single-center, open-label, non-comparative pilot trial between January 2009 and December 2010. Oral lenalidomide (5 to 10 mg/day) was administered and tapered according to clinical response. Patients were followed up for a mean of 15 months (range: 7 to 30). Primary efficacy endpoint was the proportion of patients achieving complete response, defined by a Cutaneous Lupus Erythematosus Disease Area and Severity index (CLASI) activity score of 0. Other secondary endpoints included development of side effects, evaluation of cutaneous and systemic flares, and impact on the immunological parameters.

Results
One patient discontinued treatment due to side effects. All remaining patients saw clinical improvement and this was already noticeable after 2 weeks of treatment. Twelve of those patients (86%) achieved complete response but clinical relapse was frequent (75%), usually occurring 2 to 8 weeks after lenalidomide's withdrawal. No influence on systemic disease, immunological parameters or CLASI damage score was observed. Side effects including insomnia, grade 2 neutropenia and gastrointestinal symptoms, were minor (13%). These resolved after withdrawing medication. Neither polyneuropathy nor thrombosis was observed.

Conclusion
Lenalidomide appears to be efficacious and safe in patients with refractory CLE, but clinical relapse is frequent after its withdrawal.

Trial registration
ClinicalTrials.gov: NCT01408199.
Phosphorylation network dynamics in the control of cell cycle transitions
Authors: Fisher Daniel , Krasinska Liliana , Coudreuse Damien , Novák Béla 
Published: December 2012

Summary
Fifteen years ago, it was proposed that the cell cycle in fission yeast can be driven by quantitative changes in the activity of a single protein kinase complex comprising a cyclin – namely cyclin B – and cyclin dependent kinase 1 (Cdk1). When its activity is low, Cdk1 triggers the onset of S phase; when its activity level exceeds a specific threshold, it promotes entry into mitosis. This model has redefined our understanding of the essential functional inputs that organize cell cycle progression, and its main principles now appear to be applicable to all eukaryotic cells. But how does a change in the activity of one kinase generate ordered progression through the cell cycle in order to separate DNA replication from mitosis? To answer this question, we must consider the biochemical processes that underlie the phosphorylation of Cdk1 substrates. In this Commentary, we discuss recent findings that have shed light on how the threshold levels of Cdk1 activity that are required for progression through each phase are determined, how an increase in Cdk activity generates directionality in the cell cycle, and why cell cycle transitions are abrupt rather than gradual. These considerations lead to a general quantitative model of cell cycle control, in which opposing kinase and phosphatase activities have an essential role in ensuring dynamic transitions.
(Un-)Verfügbarkeit. Bonaventuras Stigmata
Authors: Kiening Christian 
Published: December 2012

Abstract
The article traces the construction of the legend surrounding the mystery of Francis of Assisi’s stigmata, which are said to have appeared two years before his death. Central to this analysis, which is underpinned by sign and media theory, is the Legenda maior, a description of the life of Francis, written by Bonaventura four decades later on the basis of older testimonies and legends. The focus is on those strategies which allow the change of events between mediation and immediacy, in that they, on the one hand, are dominated by a concrete, spacial framework and, on the other, by moments of that which is unverfügbar.
Die Verfügbarkeit des Teufels und die Kunst
Authors: Schnyder Mireille 
Published: December 2012

Abstract
The article demonstrates how art and technique in the patristic discourse of antiquity are interpreted as strategies of making things verfügbar and associating them with the devil: this is shown in two image conceptions of Christian-theological discourse which are embodied in an exemplary way, on the one hand, by the idolater and tyrannical world conqueror Ninus and, on the other, by the dominator of demons, Zoroaster (Zarathustra). A central hypothesis is that those image reflections which are shaped following a Christian model are not determined by the interest in their production: they focus on the receptional level on which art can be effective as the object of a specific perception ad malam or ad bonam partem.
St. Erkenwald und die Verfügbarmachung des Unverfügbaren
Authors: Johnston Andrew James 
Published: December 2012

Abstract
This article is concerned with the narrative strategies of staging the miraculous in St. Erkenwald (c. 1400). The text explores the different degrees to which the divide between life and death remains exempt from the grasp of humans. In so doing, St. Erkenwald responds to complex late medieval debates involving historical, political and theological matters.
Die Verfügbarkeit des ewigen Lebens: Selbstopferszenarien in mittelalterlicher Literatur
Authors: Ridder Klaus 
Published: December 2012

Abstract
The article discusses the functions and structures of self-sacrifice in relevant literary representations. The central argument is that self-sacrifice – not only with a view to the culture of the Middle Ages – should, in a twofold sense, make verfügbar that which is not verfügbar: on the one hand, that which in current life is not accessible and, on the other, that which aims beyond the frontier of death. The prototype for self-sacrifice is, to be sure, constituted by the Passion of Christ which provides the model of imitatio as a certain path to salvation; however, since selfdestruction is part of this imitatio, it becomes an illegitimate form of disposing of one’s own life, and this is in conflict with the Christian ethic.
Zeichen lesen im höfischen Roman
Authors: Baisch Martin 
Published: December 2012

Abstract
The category of the Spur – ‘trace’ – (as well as its epistemological and semiotic status in cultural and literary science) is a vexed question. The objective of this article is to attempt to contribute to the clarification of these problems and to widen reflexions on the sign through the category of the Spur. The starting point of this discussion is the scene of the blood drops in the snow in Wolfram von Eschenbach‘s Parzival. The author discusses the narrative mises-en-scène of Spuren and their integration in complex perceptional and interpretational processes. The central argument is that Wolfram‘s poetological strategy aims at making traces verfügbar, while nevertheless keeping them present in their Unverfügbarkeit.
Spielraum im Diesseits. (Un-)Verfügbarkeit der Zeit und des Ichs
Authors: Auteri Laura 
Published: December 2012

Abstract
The article questions the changes which took place in the perception of time and of the self during an epoch of historical transition. Using the example of early modern prose romances (among others Fortunatus, Hug Schapler, Der Goldfaden) it is demonstrated that the category of the linearity of (a life-) time acquires a new meaning and that simultaneously the perception of time starts to detach itself from the cyclical rhythm of nature (and from the liturgical year). In this way, the conceptions of the Verfügbarkeit of time and of life are shifted. The article shows the extent to which the prose romance thematised in different ways the relations which are fraught with tension between the Unverfügbarkeit of a lifetime and the cyclical dimensions of time; in addition it also demonstrates the role which is thus played by self-awareness.
Freiheit, Widerfahrnis und Unverfügbarkeit. Der Wille zum Entgrenzen des Verfügbaren
Authors: Landweer Hilge 
Published: December 2012

Abstract
Central to these considerations is not only the context, but also the differentiation of action, Widerfahrnis [occurrence] and Unverfügbarkeit as a problem of philosophy. While a subjective moment of experiencing is inherent to Widerfahrnis, this is not true of Unverfügbarkeit; here a distinction is to be made between that which is contingently given and that which is absolutely given as unverfügbar. The main hypothesis is that the relationship between Verfügbarkeit and Unverfügbarkeit is determined by asymmetry and that, despite their contraposition, the use of both concepts is mainly motivated by the desire for self-determination.