bluuebunny/crossref_metadata_2025_split huggingface dataset:
An autoantibody epitope comprising residues R660, Y661, and Y665 in the ADAMTS13 spacer domain identifies a binding site for the A2 domain of VWF
Authors: Pos Wouter , Crawley James T. B. , Fijnheer Rob , Voorberg Jan , Lane David A. , Luken Brenda M. 
Published: December 2009

Abstract
In the majority of patients with acquired thrombotic thrombocytopenic purpura (TTP), antibodies are directed toward the spacer domain of ADAMTS13. We have previously shown that region Y658-Y665 is involved. We now show that replacement of R660, Y661, or Y665 with alanine in ADAMTS13 reduced/abolished the binding of 2 previously isolated human monoclonal antibodies and polyclonal antibodies derived from plasma of 6 patients with acquired TTP. We investigated whether these residues also influenced cleavage of short von Willebrand factor (VWF) fragment substrate VWF115. An ADAMTS13 variant (R660A/Y661A/Y665A, ADAMTS13-RYY) showed a 12-fold reduced catalytic efficiency (kcat/Km) arising from greatly reduced (> 25-fold) binding, demonstrated by surface plasmon resonance. The influence of these residue changes on full-length VWF was determined with denaturing and flow assays. ADAMTS13-RYY had reduced activity in both, with proteolysis of VWF unaffected by autoantibody. Binding of ADAMTS13-RYY mutant to VWF was, however, similar to normal. Our results demonstrate that residues within Y658-Y665 of the ADAMTS13 spacer domain that are targeted by autoantibodies in TTP directly interact with a complementary exosite (E1660-R1668) within the VWF A2 domain. Residues R660, Y661, and Y665 are critical for proteolysis of short VWF substrates, but wider domain interactions also make important contributions to cleavage of full-length VWF.
Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study
Authors: Pott Christiane , Hoster Eva , Delfau-Larue Marie-Helene , Beldjord Kheira , Böttcher Sebastian , Asnafi Vahid , Plonquet Anne , Siebert Reiner , Callet-Bauchu Evelyne , Andersen Niels , van Dongen Jacques J. M. , Klapper Wolfram , Berger Françoise , Ribrag Vincent , van Hoof Achiel L. , Trneny Marek , Walewski Jan , Dreger Peter , Unterhalt Michael , Hiddemann Wolfgang , Kneba Michael , Kluin-Nelemans Hanneke C. , Hermine Olivier , Macintyre Elizabeth , Dreyling Martin 
Published: December 2009

AbstractThe prognostic impact of minimal residual disease (MRD) was analyzed in 259 patients with mantle cell lymphoma (MCL) treated within 2 randomized trials of the European MCL Network (MCL Younger and MCL Elderly trial). After rituximab-based induction treatment, 106 of 190 evaluable patients (56%) achieved a molecular remission (MR) based on blood and/or bone marrow (BM) analysis. MR resulted in a significantly improved response duration (RD; 87% vs 61% patients in remission at 2 years, P = .004) and emerged to be an independent prognostic factor for RD (hazard ratio = 0.4, 95% confidence interval, 0.1-0.9, P = .028). MR was highly predictive for prolonged RD independent of clinical response (complete response [CR], complete response unconfirmed [CRu], partial response [PR]; RD at 2 years: 94% in BM MRD-negative CR/CRu and 100% in BM MRD-negative PR, compared with 71% in BM MRD-positive CR/CRu and 51% in BM MRD-positive PR, P = .002). Sustained MR during the postinduction period was predictive for outcome in MCL Younger after autologous stem cell transplantation (ASCT; RD at 2 years 100% vs 65%, P = .001) and during maintenance in MCL Elderly (RD at 2 years: 76% vs 36%, P = .015). ASCT increased the proportion of patients in MR from 55% before high-dose therapy to 72% thereafter. Sequential MRD monitoring is a powerful predictor for treatment outcome in MCL. These trials are registered at www.clinicaltrials.gov as #NCT00209222 and #NCT00209209.
Slug deficiency enhances self-renewal of hematopoietic stem cells during hematopoietic regeneration
Authors: Sun Yan , Shao Lijian , Bai Hao , Wang Zack Z. , Wu Wen-Shu 
Published: December 2009

AbstractBoth extrinsic and intrinsic mechanisms tightly govern hematopoietic stem cell (HSC) decisions of self-renewal and differentiation. However, transcription factors that can selectively regulate HSC self-renewal division after stress remain to be identified. Slug is an evolutionarily conserved zinc-finger transcription factor that is highly expressed in primitive hematopoietic cells and is critical for the radioprotection of these key cells. We studied the effect of Slug in the regulation of HSCs in Slug-deficient mice under normal and stress conditions using serial functional assays. Here, we show that Slug deficiency does not disturb hematopoiesis or alter HSC homeostasis and differentiation in bone marrow but increases the numbers of primitive hematopoietic cells in the extramedullary spleen site. Deletion of Slug enhances HSC repopulating potential but not its homing and differentiation ability. Furthermore, Slug deficiency increases HSC proliferation and repopulating potential in vivo after myelosuppression and accelerates HSC expansion during in vitro culture. Therefore, we propose that Slug is essential for controlling the transition of HSCs from relative quiescence under steady-state condition to rapid proliferation under stress conditions. Our data suggest that inhibition of Slug in HSCs may present a novel strategy for accelerating hematopoietic recovery, thus providing therapeutic benefits for patients after clinical myelosuppressive treatment.
Gene expression profiling–based dissection of MLL translocated and MLL germline acute lymphoblastic leukemia in infants
Authors: Stam Ronald W. , Schneider Pauline , Hagelstein Jill A. P. , van der Linden Marieke H. , Stumpel Dominique J. P. M. , de Menezes Renee X. , de Lorenzo Paola , Valsecchi Maria G. , Pieters Rob 
Published: December 2009

AbstractAcute lymphoblastic leukemia (ALL) in infants (< 1 year) is characterized by a poor prognosis and a high incidence of MLL translocations. Several studies demonstrated the unique gene expression profile associated with MLL-rearranged ALL, but generally small cohorts were analyzed as uniform patient groups regardless of the type of MLL translocation, whereas the analysis of translocation-negative infant ALL remained unacknowledged. Here we generated and analyzed primary infant ALL expression profiles (n = 73) typified by translocations t(4;11), t(11;19), and t(9;11), or the absence of MLL translocations. Our data show that MLL germline infant ALL specifies a gene expression pattern that is different from both MLL-rearranged infant ALL and pediatric precursor B-ALL. Moreover, we demonstrate that, apart from a fundamental signature shared by all MLL-rearranged infant ALL samples, each type of MLL translocation is associated with a translocation-specific gene expression signature. Finally, we show the existence of 2 distinct subgroups among t(4;11)–positive infant ALL cases characterized by the absence or presence of HOXA expression, and that patients lacking HOXA expression are at extreme high risk of disease relapse. These gene expression profiles should provide important novel insights in the complex biology of MLL-rearranged infant ALL and boost our progress in finding novel therapeutic solutions.
The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT)
Authors: Geisler Christian H. , Kolstad Arne , Laurell Anna , Räty Riikka , Jerkeman Mats , Eriksson Mikael , Nordström Marie , Kimby Eva , Boesen Anne Marie , Nilsson-Ehle Herman , Kuittinen Outi , Lauritzsen Grete F. , Ralfkiær Elisabeth , Ehinger Mats , Sundström Christer , Delabie Jan , Karjalainen-Lindsberg Marja-Liisa , Brown Peter , Elonen Erkki ,   for the Nordic Lymphoma Group
Published: December 2009

Abstract
Mantle cell lymphoma (MCL) has a heterogeneous clinical course. The recently proposed Mantle Cell Lymphoma International Prognostic Index (MIPI) predicted the survival of MCL better than the International Prognostic Index in MCL patients treated with conventional chemotherapy, but its validity in MCL treated with more intensive immunochemotherapy has been questioned. Applied here to 158 patients of the Nordic MCL2 trial of first-line intensive immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation, the MIPI and the simplified MIPI (s-MIPI) predicted survival significantly better (P < .001) than the International Prognostic Index (P > .004). Both the MIPI and the s-MIPI mainly identified 2 risk groups, low and intermediate versus high risk, with the more easily applied s-MIPI being just as powerful as the MIPI. The MIPIB (biological), incorporating Ki-67 expression, identified almost half of the patients as high risk. We suggest that also a simplified MIPIB is feasible. This trial was registered at www.isrctn.org as #ISRCTN 87866680.
Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study
Authors: Taher Ali T. , Musallam Khaled M. , Karimi Mehran , El-Beshlawy Amal , Belhoul Khawla , Daar Shahina , Saned Mohamed-SalahEldin , El-Chafic Abdul-Hamid , Fasulo Maria R. , Cappellini Maria D. 
Published: December 2009

AbstractDespite recent advances in understanding the pathophysiologic mechanisms behind the thalassemia intermedia (TI) phenotype, data on the effects of treatment are deficient. To provide such data, we evaluated 584 TI patients for the associations between patient and disease characteristics, treatment received, and the rate of complications. The most common disease-related complications were osteoporosis, extramedullary hematopoeisis (EMH), hypogonadism, and cholelithiasis, followed by thrombosis, pulmonary hypertension (PHT), abnormal liver function, and leg ulcers. Hypothyroidism, heart failure, and diabetes mellitus were less frequently observed. On multivariate analysis, older age and splenectomy were independently associated with an increased risk of most disease-related complications. Transfusion therapy was protective for thrombosis, EMH, PHT, heart failure, cholelithiasis, and leg ulcers. However, transfusion therapy was associated with an increased risk of endocrinopathy. Iron chelation therapy was in turn protective for endocrinopathy and PHT. Hydroxyurea treatment was associated with an increased risk of hypogonadism yet was protective for EMH, PHT, leg ulcers, hypothyroidism, and osteoporosis. Attention should be paid to the impact of age on complications in TI, and the beneficial role of splenectomy deserves revisiting. This study provides evidence that calls for prospective evaluation of the roles of transfusion, iron chelation, and hydroxyurea therapy in TI patients.
Large-scale identification of odorant-binding proteins and chemosensory proteins from expressed sequence tags in insects
Authors: Xu Ya-Long , He Peng , Zhang Lan , Fang Shao-Qing , Dong Shuang-Lin , Zhang Yong-Jun , Li Fei 
Published: December 2009

Abstract

Background
Insect odorant binding proteins (OBPs) and chemosensory proteins (CSPs) play an important role in chemical communication of insects. Gene discovery of these proteins is a time-consuming task. In recent years, expressed sequence tags (ESTs) of many insect species have accumulated, thus providing a useful resource for gene discovery.

Results
We have developed a computational pipeline to identify OBP and CSP genes from insect ESTs. In total, 752,841 insect ESTs were examined from 54 species covering eight Orders of Insecta. From these ESTs, 142 OBPs and 177 CSPs were identified, of which 117 OBPs and 129 CSPs are new. The complete open reading frames (ORFs) of 88 OBPs and 123 CSPs were obtained by electronic elongation. We randomly chose 26 OBPs from eight species of insects, and 21 CSPs from four species for RT-PCR validation. Twenty two OBPs and 16 CSPs were confirmed by RT-PCR, proving the efficiency and reliability of the algorithm. Together with all family members obtained from the NCBI (OBPs) or the UniProtKB (CSPs), 850 OBPs and 237 CSPs were analyzed for their structural characteristics and evolutionary relationship.

Conclusions
A large number of new OBPs and CSPs were found, providing the basis for deeper understanding of these proteins. In addition, the conserved motif and evolutionary analysis provide some new insights into the evolution of insect OBPs and CSPs. Motif pattern fine-tune the functions of OBPs and CSPs, leading to the minor difference in binding sex pheromone or plant volatiles in different insect Orders.
Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine-induced status epilepticus
Authors: Foresti Maira L , Arisi Gabriel M , Katki Khurshed , Montañez Andres , Sanchez Russell M , Shapiro Lee A 
Published: December 2009

Abstract

Background
Neuroinflammation occurs after seizures and is implicated in epileptogenesis. CCR2 is a chemokine receptor for CCL2 and their interaction mediates monocyte infiltration in the neuroinflammatory cascade triggered in different brain pathologies. In this work CCR2 and CCL2 expression were examined following status epilepticus (SE) induced by pilocarpine injection.

Methods
SE was induced by pilocarpine injection. Control rats were injected with saline instead of pilocarpine. Five days after SE, CCR2 staining in neurons and glial cells was examined using imunohistochemical analyses. The number of CCR2 positive cells was determined using stereology probes in the hippocampus. CCL2 expression in the hippocampus was examined by molecular assay.

Results
Increased CCR2 was observed in the hippocampus after SE. Seizures also resulted in alterations to the cell types expressing CCR2. Increased numbers of neurons that expressed CCR2 was observed following SE. Microglial cells were more closely apposed to the CCR2-labeled cells in SE rats. In addition, rats that experienced SE exhibited CCR2-labeling in populations of hypertrophied astrocytes, especially in CA1 and dentate gyrus. These CCR2+ astroctytes were not observed in control rats. Examination of CCL2 expression showed that it was elevated in the hippocampus following SE.

Conclusion
The data show that CCR2 and CCL2 are up-regulated in the hippocampus after pilocarpine-induced SE. Seizures also result in changes to CCR2 receptor expression in neurons and astrocytes. These changes might be involved in detrimental neuroplasticity and neuroinflammatory changes that occur following seizures.
Flux Design: In silico design of cell factories based on correlation of pathway fluxes to desired properties
Authors: Melzer Guido , Esfandabadi Manely Eslahpazir , Franco-Lara Ezequiel , Wittmann Christoph 
Published: December 2009

Abstract

Background
The identification of genetic target genes is a key step for rational engineering of production strains towards bio-based chemicals, fuels or therapeutics. This is often a difficult task, because superior production performance typically requires a combination of multiple targets, whereby the complex metabolic networks complicate straightforward identification. Recent attempts towards target prediction mainly focus on the prediction of gene deletion targets and therefore can cover only a part of genetic modifications proven valuable in metabolic engineering. Efficient in silico methods for simultaneous genome-scale identification of targets to be amplified or deleted are still lacking.

Results
Here we propose the identification of targets via flux correlation to a chosen objective flux as approach towards improved biotechnological production strains with optimally designed fluxes. The approach, we name Flux Design, computes elementary modes and, by search through the modes, identifies targets to be amplified (positive correlation) or down-regulated (negative correlation). Supported by statistical evaluation, a target potential is attributed to the identified reactions in a quantitative manner. Based on systems-wide models of the industrial microorganisms Corynebacterium glutamicum and Aspergillus niger, up to more than 20,000 modes were obtained for each case, differing strongly in production performance and intracellular fluxes. For lysine production in C. glutamicum the identified targets nicely matched with reported successful metabolic engineering strategies. In addition, simulations revealed insights, e.g. into the flexibility of energy metabolism. For enzyme production in A.niger flux correlation analysis suggested a number of targets, including non-obvious ones. Hereby, the relevance of most targets depended on the metabolic state of the cell and also on the carbon source.

Conclusions
Objective flux correlation analysis provided a detailed insight into the metabolic networks of industrially relevant prokaryotic and eukaryotic microorganisms. It was shown that capacity, pathway usage, and relevant genetic targets for optimal production partly depend on the network structure and the metabolic state of the cell which should be considered in future metabolic engineering strategies. The presented strategy can be generally used to identify priority sorted amplification and deletion targets for metabolic engineering purposes under various conditions and thus displays a useful strategy to be incorporated into efficient strain and bioprocess optimization.
Easily-accessible digital palaeontological databases-a new perspective for the storage of palaeontological information
Authors: Wolniewicz Paweł 
Published: December 2009

Easily-accessible digital palaeontological databases-a new perspective for the storage of palaeontological informationTechniques that allow to render diverse types of palaeontological data as publicly available internet resources are described. In order to develop an easily accessible digital palaeontological database, three steps should be followed: (1) digitization of the studied specimens, (2) acquisition of morphometric data, and (3) contribution of the data to open and searchable geoinformatic (palaeontological) databases. Digital data should be submitted to internet databases that allow a user to fetch various types of information from dispersed sources (semantic web services).
Global maps of the step-wise topography corrected and crustal components stripped geoids using the CRUST 2.0 model
Authors: Tenzer Robert ,   Hamayun, Vajda Peter 
Published: December 2009

Global maps of the step-wise topography corrected and crustal components stripped geoids using the CRUST 2.0 modelWe compile global maps of the step-wise topography corrected and crustal components stripped geoids based on the geopotential model EGM'08 complete to spherical harmonic degree 180 and the CRUST 2.0 global crustal model. The spectral resolution complete to degree 180 is used to compute the primary indirect bathymetric stripping and topographic effects on the geoid, while degree 90 for the primary indirect ice stripping effect. The primary indirect stripping effects of the soft and hard sediments, and the upper, middle and lower consolidated crust components are forward modeled in spatial form using the 2 × 2 arc-deg discrete data of the CRUST 2.0 model. The ocean, ice, sediment and consolidated crust density contrasts are defined relative to the adopted reference crustal density of 2670 kg/m3. Finally we compute and apply the primary indirect stripping effect of the density contrast (relative to the mantle) of the reference crust. The constant value of -520 kg/m3is adopted for this density contrast relative to the mantle. All data are evaluated on a 1 × 1 arc-deg geographical grid. The complete crust-stripped geoidal undulations, globally having a range of approximately 1.5 km, contain the gravitational signal coming from the global mantle lithosphere (upper mantle) morphology and density composition, and from the sub-lithospheric density heterogeneities. Large errors in the complete crust-stripped geoid are expected due to uncertainties of the CRUST 2.0 model, i.e., due to deviations of the CRUST 2.0 model density from the real earth's crustal density and due to the Moho-boundary uncertainties.
Homogenization of long-term GPS monitoring series at permanent stations in Central Europe and Balkan Peninsula
Authors: Hefty Ján , Igondová Miroslava , Droščák Branislav 
Published: December 2009

Homogenization of long-term GPS monitoring series at permanent stations in Central Europe and Balkan PeninsulaThe network of 54 permanent GPS stations situated in Central Europe, Alpine-Adriatic region and Balkan Peninsula is analyzed by unified processing strategy, using homogeneous models for reduction of physical effects, and is uniformly referred to as the International Terrestrial Reference Frame - ITRF2005. The resulting time series of observed site coordinates and site troposphere parameters from interval 1999.5 to 2008.5 are inspected for their continuity, homogeneity, long-term drift, and seasonal variations.
A global correlation of the step-wise consolidated crust-stripped gravity field quantities with the topography, bathymetry, and the CRUST 2.0 Moho boundary
Authors: Tenzer Robert ,   Hamayun, Vajda Peter 
Published: December 2009

A global correlation of the step-wise consolidated crust-stripped gravity field quantities with the topography, bathymetry, and the CRUST 2.0 Moho boundaryWe investigate globally the correlation of the step-wise consolidated cruststripped gravity field quantities with the topography, bathymetry, and the Moho boundary. Global correlations are quantified in terms of Pearson's correlation coefficient. The elevation and bathymetry data from the ETOPO5 are used to estimate the correlation of the gravity field quantities with the topography and bathymetry. The 2×2 arc-deg discrete data of the Moho depth from the global crustal model CRUST 2.0 are used to estimate the correlation of the gravity field quantities with the Moho boundary. The results reveal that the topographically corrected gravity field quantities have the highest absolute correlation with the topography. The negative correlation of the topographically corrected gravity disturbances with the topography over the continents reaches -0.97. The ocean, ice and sediment density contrasts stripped and topographically corrected gravity field quantities have the highest correlation with the bathymetry (ocean bottom relief). The correlation of the ocean, ice and sediment density contrasts stripped and topographically corrected gravity disturbances over the oceans reaches 0.93. The consolidated crust-stripped gravity field quantities have the highest absolute correlation with the Moho boundary. In particular, the global correlation of the consolidated crust-stripped gravity disturbances with the Moho boundary is found to be -0.92. Among all the investigated gravity field quantities, the consolidated crust-stripped gravity disturbances are thus the best suited for a refinement of the Moho density interface by means of the gravimetric modeling or inversion.