bluuebunny/crossref_metadata_2025_split huggingface dataset:
A journey of hope: lessons learned from studies on rare diseases and orphan drugs
Authors: WÄSTFELT M. , FADEEL B. , HENTER J.‐I. 
Published: June 2006

Abstract.Rare diseases are frequently life‐threatening or chronically debilitating and the impact on the quality of life of affected patients and their family members is thus significant. However, drug development for these conditions has been limited by a lack of understanding of the underlying mechanisms of disease and the relative unavailability of subjects for clinical trials, as well as the prohibitive cost of investing in a novel pharmaceutical agent with poor market potential. Nevertheless, the introduction of Orphan Drug legislations has provided important incentives for the development of orphan drugs (i.e. drugs that have been abandoned or ‘orphaned’ by major drug companies). Moreover, recent studies on rare diseases, including inherited immunodeficiencies and metabolic disorders, have served not only to alleviate the plight of patients with rare diseases, but also yielded valuable information on biological processes of relevance for other, more common conditions. These lessons, along with the crucial importance of cooperation between academic institutions, pharmaceutical companies, patient advocacy groups and society in the elucidation of rare diseases, are highlighted in the present review.
Binding of the low‐density lipoprotein by streptococcal collagen‐like protein Scl1 of Streptococcus pyogenes
Authors: Han Runlin , Caswell Clayton C. , Lukomska Ewa , Keene Douglas R. , Pawlowski Marcin , Bujnicki Janusz M. , Kim Jiyeun K. , Lukomski Slawomir 
Published: June 2006

SummarySeveral bacterial genera express proteins that contain collagen‐like regions, which are associated with variable (V) non‐collagenous regions. The streptococcal collagen‐like proteins, Scl1 and Scl2, of group A Streptococcus (GAS) are members of this ‘prokaryotic collagen’ family, and they too contain an amino‐terminal non‐collagenous V region of unknown function. Here, we use recombinant rScl constructs, derived from several Scl1 and Scl2 variants, and affinity chromatography to identify Scl ligands present in human plasma. First, we show that Scl1, but not Scl2, proteins from different GAS serotypes bind the same ligand identified as apolipoprotein B (ApoB100), which is a major component of the low‐density lipoprotein (LDL). Scl1 binding to purified ApoB100 and LDL is specific and concentration‐dependent. Furthermore, the non‐collagenous V region of the Scl1 protein is responsible for LDL/ApoB100 binding because only those rScls, constructed by domain swapping, which contain the V region from Scl1 proteins, were able to bind to ApoB100 and LDL ligands, and this binding was inhibited by antibodies directed against the Scl1‐V region. Electron microscopy images of Scl1–LDL complexes showed that the globular V domain of Scl1 interacted with spherical particles of LDL. Importantly, live M28‐type GAS cells absorbed plasma LDL on the cell surface and this binding depended on the surface expression of the Scl1.28, but not Scl2.28, protein. Phylogenetic analysis showed that the non‐collagenous globular domains of Scl1 and Scl2 evolved independently to form separate lineages, which differ in amino acid sequence, and these differences may account for the variations in binding patterns of Scl1 and Scl2 proteins. Present studies provide insight into the structure‐function relationship of the Scl proteins and also underline the importance of lipoprotein binding by GAS.
Ornithine lipid is required for optimal steady‐state amounts of c‐type cytochromes in Rhodobacter capsulatus
Authors: Aygun‐Sunar Semra , Mandaci Sevnur , Koch Hans‐George , Murray Ian V. J. , Goldfine Howard , Daldal Fevzi 
Published: June 2006

SummaryThe c‐type cytochromes are haemoproteins that are subunits or physiological partners of electron transport chain components, like the cytochrome bc1 complex or the cbb3‐type cytochrome c oxidase. Their haem moieties are covalently attached to the corresponding apocytochromes via a complex post‐translational maturation process. During our studies of cytochrome biogenesis, we uncovered a novel class of mutants that are unable to produce ornithine lipid and that lack several c‐type cytochromes. Molecular analyses of these mutants led us to the ornithine lipid biosynthesis genes of Rhodobacter capsulatus. Herein, we have characterized these mutants, and established the chemical structure of this non‐phosphorus membrane lipid from R. capsulatus. Ornithine lipids are known to induce potent host immune responses, including B‐lymphocyte mitogenicity, adjuvanticity and macrophage activation. Yet, despite their widespread occurrence in Eubacteria, and the diverse biological effects they elicit in mammals, their physiological role in bacterial cells remained hitherto poorly defined. Our findings now indicate that under certain bacterial growth conditions ornithine lipids are crucial for optimal steady‐state amounts of some extracytoplasmic proteins, including several c‐type cytochromes, and attribute them a novel and important biological function.
Unique conjugation mechanism in mycelial streptomycetes: a DNA‐binding ATPase translocates unprocessed plasmid DNA at the hyphal tip
Authors: Reuther Jens , Gekeler Cordula , Tiffert Yvonne , Wohlleben Wolfgang , Muth Günther 
Published: June 2006

SummaryA single plasmid‐encoded protein, the septal DNA translocator TraB, is sufficient to promote conjugal plasmid transfer in mycelial streptomycetes. To analyse the molecular mechanism of conjugation the closely related TraB proteins from plasmids pSG5 of Streptomyces ghanaensis and pSVH1 of Streptomyces venezuelae were characterized. TraB of pSG5 was expressed as a fusion protein with eGFP and found to be localized at the hyphal tips of Streptomyces lividans by fluorescence microscopy, which strongly indicates that conjugation takes place at the tips of the mating mycelium. The TraB protein of pSVH1 was heterologously expressed in S. lividans with an N‐terminal strep‐tagII and purified as a soluble protein to near homogeneity. The purified protein was shown to hydrolyse ATP and to bind to a 50 bp non‐coding pSVH1 sequence containing a 14 bp direct repeat. The protein–DNA complex was too large to enter an agarose gel, indicating that multimers of TraB were bound to the DNA. Denaturation of the protein–DNA complex released unprocessed plasmid DNA demonstrating that the TraB protein does not possess nicking activity. Our experimental data provide evidence that conjugal DNA transfer in streptomycetes is mediated by the septal DNA translocator TraB, an plasmid‐encoded ATPase that interacts non‐covalently with DNA and translocates an unprocessed double‐stranded DNA molecule at the hyphal tip into the recipient.
Identification of Nostoc punctiforme akinete‐expressed genes using differential display
Authors: Argueta Claudia , Yuksek Kamile , Patel Ronak , Summers Michael L. 
Published: June 2006

SummaryAkinetes are spore‐like resting cells formed by certain filamentous cyanobacteria that have increased resistance to environmental stress. They can be found at low frequencies in dense cultures experiencing low light or phosphate limitation, but also form at high frequencies in a zwf mutant strain of Nostoc punctiforme following dark incubation in the presence of fructose. The wild‐type strain is capable of facultative heterotrophic growth under these conditions and does not form akinetes. To identify genes associated with akinete development, differential display was used to amplify and compare cDNA from a wild‐type and zwf mutant strain of N. punctiforme following a switch to dark heterotrophic conditions. Screening of candidate genes by reverse transcriptase real‐time quantitative PCR and subsequent testing for akinete‐specific expression using GFP transcriptional reporter plasmids lead to the identification of three novel akinete‐expressed genes. The genes identified from the screening encoded for proteins homologous to an aminopeptidase (aapN), a zinc protease (hap) and an ATP‐binding cassette (ABC)‐type transporter (aet). Expression of hap was also increased in developing hormogonia, a transient type of differentiated filament capable of gliding motility. Transcriptional start sites for akinete‐expressed genes were determined using random amplification of cDNA ends (RACE), and promoter regions were compared with orthologues in other filamentous cyanobacteria to identify putative regulatory sequences.
Quantifying rates of coastal progradation from sediment volume using GPR and OSL: the Holocene fill of Guichen Bay, south‐east South Australia
Authors: BRISTOW C. S. , PUCILLO K. 
Published: June 2006

AbstractGuichen Bay on the south‐east coast of South Australia faces west towards the prevailing westerly winds of the Southern Ocean. The bay is backed by a 4 km wide Holocene beach‐ridge plain with more than 100 beach ridges. The morphology of the Guichen Bay strandplain complex shows changes in the width, length, height and orientation of beach ridges. A combination of geomorphological interpretation, shallow geophysics and existing geochronology is used to interpret the Holocene fill of Guichen Bay. Six sets of beach ridges are identified from the interpretation of orthorectified aerial photographs. The ridge sets are distinguished on the basis of beach‐ridge orientation and continuity. A 2·25 km ground‐penetrating radar (GPR) profile across the beach ridges reveals the sedimentary structures and stratigraphic units. The beach ridges visible in the surface topography are a succession of stabilized foredunes that overlie progradational foreshore and upper shoreface sediments. The beach progrades show multiple truncation surfaces interpreted as storm events. The GPR profile shows that there are many more erosion surfaces in the subsurface than beach ridges on the surface. The width and dip of preserved beach progrades imaged by GPR shows that the shoreface has steepened from around 2·9° to around 7·5°. The changes in beach slope are attributed to increasing wave energy associated with beach progradation into deeper water as Guichen Bay was infilled. At the same time, the thickness of the preserved beach progrades increases slightly as the beach prograded into deeper water. Using the surface area of the ridge sets measured from the orthophotography, and the average thickness of upper shoreface, foreshore and coastal dune sands interpreted from the GPR profile, the volume of Holocene sediments within three of the six sets of beach‐ridge accretion has been calculated. Combining optically stimulated luminescence (OSL) ages and volume calculations, rates of sediment accumulation for Ridge Sets 3, 4 and 5 have been estimated. Linear rates of beach‐ridge progradation appear to decrease in the mid‐Holocene. However, the rates of sediment accumulation calculated from beach volumes have remained remarkably consistent through the mid‐ to late Holocene. This suggests that sediment supply to the beach has been constant and that the decrease in the rate of progradation is due to increasing accommodation space as the beach progrades into deeper water. Changes in beach‐ridge morphology and orientation reflect environmental factors such as changes in wave climate and wind regime.
Anomalous geochemical provenance and weathering history of Plio‐Pleistocene glaciomarine fjord strata, Bardin Bluffs Formation, East Antarctica
Authors: PASSCHIER SANDRA , WHITEHEAD JASON M. 
Published: June 2006

AbstractMajor and trace element chemical analyses of the Plio‐Pleistocene Bardin Bluffs Formation, on the margin of a major ice‐stream of the East Antarctic Ice Sheet, yield an anomalous chemically altered sediment composition. The Bardin Bluffs Formation of the Pagodroma Group is one of the key deposits on the Antarctic continent recording glaciomarine sedimentation under open marine fjord conditions as recently as the Plio‐Pleistocene. In modern fjords occupied by outlet glaciers of ice sheets, the composition of fine‐grained terrigenous sediments approaches that of unweathered rock types exposed upstream. In the Bardin Bluffs Formation, average abundances of stable elements (Ti, Al, Zr) approach average upper crustal compositions and the element ratios are consistent with sediments with a cratonic source, implying glacial dispersal from a large shield area through the Lambert Glacier drainage system. Interestingly, the chemical index of alteration (CIA) of these sediments has values similar to those of average shales formed under conditions of chemical weathering. The sediments are particularly depleted in silicate Ca, which has been observed elsewhere in glacial muds sourced from pre‐glacial saprolites. The anomalous chemistry of the Bardin Bluffs Formation can be explained by a sequence of events, involving chemical weathering prior to glacial expansion and erosion. The presence of a remnant 1·5 m deep late Neogene weathering profile at the base of the Bardin Bluffs sequence corroborates this conclusion. Supply of large quantities of chemically weathered materials to Antarctic marginal basins requires at least partial deglaciation of the continent and was previously regarded as uncharacteristic for late Neogene Antarctica.
Characterization of a new xyloglucan endotransglucosylase/hydrolase (XTH) from ripening tomato fruit and implications for the diverse modes of enzymic action
Authors: Saladié Montserrat , Rose Jocelyn K. C. , Cosgrove Daniel J. , Catalá Carmen 
Published: June 2006

SummaryXyloglucan endotransglucosylase/hydrolases (XTHs) are cell wall‐modifying enzymes that align within three or four distinct phylogenetic subgroups. One explanation for this grouping is association with different enzymic modes of action, as XTHs can have xyloglucan endotransglucosylase (XET) or endohydrolase (XEH) activities. While Group 1 and 2 XTHs predominantly exhibit XET activity, to date the activity of only one member of Group 3 has been reported: nasturtium TmXH1, which has a highly specialized function and hydrolyses seed‐storage xyloglucan rather than modifying cell wall structure. Tomato fruit ripening was selected as a model to test the hypothesis that preferential XEH activity might be a defining characteristic of Group 3 XTHs, which would be expressed during processes where net xyloglucan depolymerization occurs. Database searches identified 25 tomato XTHs, and one gene (SlXTH5) was of particular interest as it aligned within Group 3 and was expressed abundantly during ripening. Recombinant SlXTH5 protein acted primarily as a transglucosylase in vitro and depolymerized xyloglucan more rapidly in the presence than in the absence of xyloglucan oligosaccharides (XGOs), indicative of XET activity. Thus, there is no correlation between the XTH phylogenetic grouping and the preferential enzymic activities (XET or XEH) of the proteins in those groups. Similar analyses of SlXTH2, a Group 2 tomato XTH, and nasturtium seed TmXTH1 revealed a spectrum of modes of action, suggesting that all XTHs have the capacity to function in both modes. The biomechanical properties of plant walls were unaffected by incubation with SlXTH5, with or without XGOs, suggesting that XTHs do not represent primary cell wall‐loosening agents. The possible roles of SlXTH5 in vivo are discussed.
Genetical metabolomics of flavonoid biosynthesis in Populus: a case study
Authors: Morreel Kris , Goeminne Geert , Storme Véronique , Sterck Lieven , Ralph John , Coppieters Wouter , Breyne Peter , Steenackers Marijke , Georges Michel , Messens Eric , Boerjan Wout 
Published: June 2006

SummaryGenetical metabolomics [metabolite profiling combined with quantitative trait locus (QTL) analysis] has been proposed as a new tool to identify loci that control metabolite abundances. This concept was evaluated in a case study with the model tree Populus. Using HPLC, the peak abundances were analyzed of 15 closely related flavonoids present in apical tissues of two full‐sib poplar families, Populus deltoides cv. S9‐2 × P. nigra cv. Ghoy and P. deltoides cv. S9‐2 × P. trichocarpa cv. V24, and correlation and QTL analysis were used to detect flux control points in flavonoid biosynthesis. Four robust metabolite quantitative trait loci (mQTL), associated with rate‐limiting steps in flavonoid biosynthesis, were mapped. Each mQTL was involved in the flux control to one or two flavonoids. Based on the identities of the affected metabolites and the flavonoid pathway structure, a tentative function was assigned to three of these mQTL, and the corresponding candidate genes were mapped. The data indicate that the combination of metabolite profiling with QTL analysis is a valuable tool to identify control points in a complex metabolic pathway of closely related compounds.
Partially edited RNAs are intermediates of RNA editing in plant mitochondria
Authors: Verbitskiy Daniil , Takenaka Mizuki , Neuwirt Julia , Van Der Merwe Johannes A. , Brennicke Axel 
Published: June 2006

SummaryRNA editing in flowering plant mitochondria addresses several hundred specific C nucleotides in individual sequence contexts in mRNAs and tRNAs. Many of the in vivo steady state RNAs are edited at some sites but not at others. It is still unclear whether such incompletely edited RNAs can either be completed or are aborted. To learn more about the dynamics of the substrate recognition process, we investigated in vitro RNA editing at a locus in the atp4 mRNA where three editing sites are clustered within four nucleotides. A single cis‐element of about 20 nucleotides serves in the recognition of at least two sites. Competition with this sequence element suppresses in vitro editing. Surprisingly, unedited and edited competitors are equally effective. Experiments with partially pre‐edited substrates indicate that indeed the editing status of a substrate RNA does not affect the binding affinity of the specificity factor(s). RNA molecules in which all editing sites are substituted by either A or G still compete, confirming that editing site recognition can occur independently of the actual editing site. These results show that incompletely edited mRNAs can be substrates for further rounds of RNA editing, resolving a long debated question.
Modulation of allergic immune responses by mucosal application of recombinant lactic acid bacteria producing the major birch pollen allergen Bet v 1
Authors: Daniel C. , Repa A. , Wild C. , Pollak A. , Pot B. , Breiteneder H. , Wiedermann U. , Mercenier A. 
Published: June 2006

Background:  Probiotic lactic acid bacteria (LAB) are able to modulate the host immune system and clinical trials have demonstrated that specific strains have the capacity to reduce allergic symptoms. Therefore, we aimed to evaluate the potential of recombinant LAB producing the major birch pollen allergen Bet v 1 for mucosal vaccination against birch pollen allergy.Methods:  Recombinant Bet v 1‐producing Lactobacillus plantarum and Lactococcus lactis strains were constructed. Their immunogenicity was compared with purified Bet v 1 by subcutaneous immunization of mice. Intranasal application of the live recombinant strains was performed to test their immunomodulatory potency in a mouse model of birch pollen allergy.Results:  Bet v 1 produced by the LAB was recognized by monoclonal anti‐Bet v 1 and IgE antibodies from birch pollen‐allergic patients. Systemic immunization with the recombinant strains induced significantly lower IgG1/IgG2a ratios compared with purified Bet v 1. Intranasal pretreatment led to reduced allergen‐specific IgE vs enhanced IgG2a levels and reduced interleukin (IL)‐5 production of splenocytes in vitro, indicating a shift towards non‐allergic T‐helper‐1 (Th1) responses. Airway inflammation, i.e. eosinophils and IL‐5 in lung lavages, was reduced using either Bet v 1‐producing or control strains. Allergen‐specific secretory IgA responses were enhanced in lungs and intestines after pretreatment with only the Bet v 1‐producing strains.Conclusions:  Mucosal vaccination with live recombinant LAB, leading to a shift towards non‐allergic immune responses along with enhanced allergen‐specific mucosal IgA levels offers a promising approach to prevent systemic and local allergic immune responses.
Are risk factors of childhood asthma predicting disease persistence in early adulthood different in the developing world?
Authors: Sekerel B. E. , Civelek E. , Karabulut E. , Yildirim S. , Tuncer A. , Adalioglu G. 
Published: June 2006

Background:  Predictive factors of childhood asthma for favorable prognosis may differ between populations where a variety of genetic and environmental factors are present.Objectives:  To document the factors predicting disease persistence in early adulthood in Turkey.Methods:  An outpatient cohort (n = 115) with a mean follow‐up duration of 11.4 ± 0.2 years was evaluated. Complete remission was defined as no asthma symptoms, no use of controller medication, no airflow limitation and no airway hyper‐responsiveness, and clinical remission as no symptoms and no use of controller medication, within the past year.Results:  The mean ages during referral and at the final visit were 5.8 ± 0.2 and 17.1 ± 0.2 years, respectively. Thirty‐one (27%) were in complete remission, and a further 30 (26%) in clinical remission. In multivariate logistic models, diminished airflow [forced expiratory volume in 1 s (FEV1) <80%vs≥80%] at the initial lung function test predicted current diminished airflow (8.422; 2.202–32.206) (odds ratio; 95% confidence interval), and presence of obstructive pattern (FEV1/forced vital capacity (FVC) <80%vs≥80%) predicted current obstructive pattern (29.333; 3.022–284.724). Furthermore, female gender appeared to predict persistence of asthma symptoms (3.330; 1.250–8.333) and absence of clinical remission (2.398; 1.038–5.254); eosinophilia predicted persistence of symptoms (4.271; 1.080–16.889) and presence of airway hyper‐responsiveness (3.723; 1.129–12.278).Conclusions:  Diminished airflow, female gender and eosinophilia appear to predict an adverse outcome of childhood asthma, supporting the concept that variability may exist between populations.