bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arabidopsis ELONGATED MITOCHONDRIA1 Is Required for Localization of DYNAMIN-RELATED PROTEIN3A to Mitochondrial Fission Sites
Authors: Arimura Shin-ichi , Fujimoto Masaru , Doniwa Yoko , Kadoya Naoki , Nakazono Mikio , Sakamoto Wataru , Tsutsumi Nobuhiro 
Published: June 2008

Abstract
Mitochondrial fission is achieved partially by the activity of self-assembling dynamin-related proteins (DRPs) in diverse organisms. Mitochondrial fission in Arabidopsis thaliana is mediated by DRP3A and DRP3B, but the other genes and molecular mechanisms involved have yet to be elucidated. To identify these genes, we screened and analyzed Arabidopsis mutants with longer and fewer mitochondria than those of the wild type. ELM1 was found to be responsible for the phenotype of elongated mitochondria. This phenotype was also observed in drp3a plants. EST and genomic sequences similar to ELM1 were found in seed plants but not in other eukaryotes. ELM1:green fluorescent protein (GFP) was found to surround mitochondria, and ELM1 interacts with both DPR3A and DRP3B. In the elm1 mutant, DRP3A:GFP was observed in the cytosol, whereas in wild-type Arabidopsis, DRP3A:GFP localized to the ends and constricted sites of mitochondria. These results collectively suggest that mitochondrial fission in Arabidopsis is mediated by the plant-specific factor ELM1, which is required for the relocalization of DRP3A (and possibly also DRP3B) from the cytosol to mitochondrial fission sites.
Allostery and cooperativity revisited
Authors: Cui Qiang , Karplus Martin 
Published: June 2008

AbstractAlthough phenomenlogical models that account for cooperativity in allosteric systems date back to the early and mid‐60's (e.g., the KNF and MWC models), there is resurgent interest in the topic due to the recent experimental and computational studies that attempted to reveal, at an atomistic level, how allostery actually works. In this review, using systems for which atomistic simulations have been carried out in our groups as examples, we describe the current understanding of allostery, how the mechanisms go beyond the classical MWC/Pauling‐KNF descriptions, and point out that the “new view” of allostery, emphasizing “population shifts,” is, in fact, an “old view.” The presentation offers not only an up‐to‐date description of allostery from a theoretical/computational perspective, but also helps to resolve several outstanding issues concerning allostery.
Enzymatic and structural analysis of the I47A mutation contributing to the reduced susceptibility to HIV protease inhibitor lopinavir
Authors: Šašková Klára Grantz , Kožíšek Milan , Lepšík Martin , Brynda Jiří , Řezáčová Pavlína , Václavíková Jana , Kagan Ron M. , Machala Ladislav , Konvalinka Jan 
Published: June 2008

AbstractLopinavir (LPV) is a second‐generation HIV protease inhibitor (PI) designed to overcome resistance development in patients undergoing long‐term antiviral therapy. The mutation of isoleucine at position 47 of the HIV protease (PR) to alanine is associated with a high level of resistance to LPV. In this study, we show that recombinant PR containing a single I47A substitution has the inhibition constant (Ki) value for lopinavir by two orders of magnitude higher than for the wild‐type PR. The addition of the I47A substitution to the background of a multiply mutated PR species from an AIDS patient showed a three‐order‐of‐magnitude increase in Ki in vitro relative to the patient PR without the I47A mutation. The crystal structure of I47A PR in complex with LPV showed the loss of van der Waals interactions in the S2/S2′ subsites. This is caused by the loss of three side‐chain methyl groups due to the I47A substitution and by structural changes in the A47 main chain that lead to structural changes in the flap antiparallel β‐strand. Furthermore, we analyzed possible interaction of the I47A mutation with secondary mutations V32I and I54V. We show that both mutations in combination with I47A synergistically increase the relative resistance to LPV in vitro. The crystal structure of the I47A/I54V PR double mutant in complex with LPV shows that the I54V mutation leads to a compaction of the flap, and molecular modeling suggests that the introduction of the I54V mutation indirectly affects the strain of the bound inhibitor in the PR binding cleft.
Vessel features of threeCaraganaspecies in their natural habitats in the inner Mongolia Plateau of China
Authors: Li Jing , Gao Yubao , Wu Jianbo , Guo Hongyu 
Published: June 2008

We studied the vessel features of ten populations of threeCaraganaspecies (C. microphyllaLam,C. davazamciiSancz,C. korshinskiiKom.), which form a geographical cline in the inner Mongolia Plateau of China.All sampled shrubs had common vessel features of xeric plants, such as coexistence of wide and narrow vessels in one xylem, high vessel density, short element length, distinct helical thickenings, which were all associated with strong drought resistance. The quantitative vessel features changed gradually along the geographical gradient of the threeCaraganaspecies. Mean vessel diameter, D100, generally decreased from the east to the west. However, D95(the mean diameter of vessels responsible for 95% of the total stem conductance) changed in an opposite direction to D100, which might be attributed to different proportions of wide and narrow vessels of the ten populations. The more xeric the habitat was, the smaller the proportion of wide vessels (which contributed mainly to water conductance). There was also a tradeoff between efficiency and safety in water transport. The intervessel pit size, density of vessel elements, intervessel pits and helical thickenings increased from the east to the west with the increase of environmental aridity. The trend of vessel element length and wall thickness was similar to that of D100, i.e. they decreased from the east to the west. All these gradually changing features confirmed the geographical transition among the threeCaraganaspecies, and indicated an order of drought resistance asC. korshinskii>C. davazamcii>C. microphylla.
NPR1 and EDS11 contribute to host resistance against Fusarium culmorum in Arabidopsis buds and flowers
Authors: CUZICK ALAYNE , LEE SARAH , GEZAN SALVADOR , HAMMOND‐KOSACK KIM E. 
Published: June 2008

SUMMARYThe cereal ear blight fungal pathogen Fusarium culmorum can infect Arabidopsis floral tissue, causing disease symptoms and mycotoxin production. Here we assessed the effect of seven mutants and one transgenic overexpression line, residing in either the salicylic acid (SA), jasmonic acid (JA) or ethylene (ET) defence signalling pathways, on the outcome of the Fusarium–Arabidopsis floral interaction. The bacterial susceptiblity mutant eds11 was also assessed. Flowering plants were spray inoculated with F. culmorum conidia to determine the host responses to initial infection and subsequent colonization. Enhanced susceptibility and higher concentrations of deoxynivalenol mycotoxin were observed in buds and flowers of the npr1 and eds11 mutants than in the wild‐type Col‐0 plants. An effect of the other two defence signalling pathways on disease was either absent (ET/JA combined), absent/minimal (ET) or inconclusive (JA). Overall, this study highlights a role for NPR1 and EDS11 in basal defence against F. culmorum in some floral organs. This is the first time that any of these well‐characterized defence signalling mutations have been evaluated for a role in floral defence in any plant species.
Delineation of distinct tumour profiles in mantle cell lymphoma by detailed cytogenetic, interphase genetic and morphological analysis
Authors: Katzenberger Tiemo , Kienle Dirk , Stilgenbauer Stephan , Höller Sylvia , Schilling Carolin , Mäder Uwe , Puppe Bernhard , Petzoldt Celine , Sander Sandrine , Bullinger Lars , Stöcklein Heike , Kalla Jörg , Hartmann Elena , Adam Patrick , Ott M. Michaela , Müller‐Hermelink Hans‐Konrad , Rosenwald Andreas , Ott German 
Published: June 2008

SummaryMantle cell lymphoma (MCL) is an aggressive lymphoid tumour characterized by the translocation t(11;14)(q13;q32) and a poor clinical outcome (median survival: 3–4 years). Recent studies revealed that increased proliferation of the tumour cells and certain chromosomal aberrations, such as deletions of 17p13 and 9p21 represent major adverse biological markers in this disease, although the molecular targets of chromosomal imbalances in MCL have not been identified for the large majority of loci affected. To correlate histomorphological and proliferation features of MCL with genetic findings, we investigated 223 MCL by fluorescence in situ hybridization (FISH) (n = 157) and/or classical cytogenetic banding analysis (n = 129). FISH analysis turned out to be distinctly more sensitive in the delineation of aberrations. Complex karyotypic alterations were associated with higher proliferation indices and inferior prognosis. A comprehensive analysis of biological features including genetic alterations in MCL by hierarchical clustering resulted in the delineation of four tumour subgroups differing with respect to their genetic constitution and suggesting different transformation or progression pathways. Moreover, in one of the groups identified, a more indolent clinical behaviour was associated with few secondary aberrations and fewer known high‐risk chromosomal aberrations, which points to the importance of the quality of karyotypic evolution in MCL tumours.
Clinical features and outcome of pulmonary embolism in children
Authors: Biss Tina T. , Brandão Leonardo R. , Kahr Walter H. , Chan Anthony K. , Williams Suzan 
Published: June 2008

SummaryPulmonary embolism (PE) is rare in childhood but evidence suggests it is under‐recognised. Children diagnosed with PE at a large tertiary centre over an 8‐year period were retrospectively reviewed. Fifty‐six children with radiologically proven PE were identified, 31 males and 25 females, median age 12 years. Eighty‐four per cent had symptoms of PE. Risk factors for thromboembolism were present in 54 patients (96·4%); most commonly immobility (58·9%), central venous line (35·7%) and recent surgery (28·6%). Investigation revealed a thrombophilic abnormality in 14/40 patients (35%). Concurrent deep vein thrombosis was confirmed in 31 patients (55·4%), predominantly lower limb. D dimer was elevated at presentation in 26/30 patients (86·7%). Eight patients underwent systemic thrombolysis. An inferior vena cava filter was placed in five patients. Therapy was complicated by major haemorrhage in 12 patients (21·4%). The majority (82·1%) had complete or partial resolution of PE following a median of 3 months anticoagulation. Seven patients had a recurrent thromboembolic event and 12 patients died (mortality 21·4%); five due to thromboembolism (8·9%) and two due to haemorrhage. Risk factors for PE in children are distinct from adults and morbidity and mortality is significant. Multicentre prospective studies are required to determine optimal treatment and long‐term outcome of childhood PE.
Understanding and harnessing the graft‐versus‐leukaemia effect
Authors: Barrett A. John 
Published: June 2008

SummaryThe graft‐versus‐leukaemia (GVL) effect is a central component of the stem cell allograft’s ability to cure haematological malignancies. The GVL effect is mediated by donor‐derived natural killer cells and T lymphocytes, which have distinct mechanisms of recognizing and targeting the recipient’s malignant cells. After transplantation the cytokine milieu is favourable to the early establishment of a GVL effect, but the need to prevent graft‐versus‐host disease limits the full potential of this process. Clinical studies have identified some critical components of the transplant preparation, donor selection, stem cell source (peripheral blood versus bone marrow) and post‐transplant management that can be manipulated to optimize the GVL effect. However, further developments focusing on the selective depletion of unwanted alloreactivity with preservation of GVL effects, and the use of vaccines or the adoptive transfer of leukaemia‐specific lymphocytes, will be required to enhance the GVL effect to reliably eradicate more resistant leukaemias.
High expression of the cGMP‐specific phosphodiesterase, PDE9A, in sickle cell disease (SCD) and the effects of its inhibition in erythroid cells and SCD neutrophils
Authors: Almeida Camila Bononi , Traina Fabiola , Lanaro Carolina , Canalli Andreia A. , Saad Sara T. O. , Costa Fernando F. , Conran Nicola 
Published: June 2008

SummaryModulation of intracellular cyclic guanosine monophosphate (cGMP) may characterize a therapeutic target for sickle cell disease (SCD); cGMP‐dependent signalling may be important for erythroid foetal haemoglobin induction and exert anti‐inflammatory functions in leucocytes. As the inhibition of phosphodiesterases (PDEs), which regulate intracellular cGMP, can result in tissue‐specific elevation of cGMP, we studied the gene expressions of cGMP‐specific PDEs (−1A, −5A and −9A) in the reticulocytes and neutrophils of healthy controls, steady‐state SCD patients and SCD patients on hydroxycarbamide therapy (SCDHC). PDE9A gene expression was found in numerous cell types; however, high expression was found in neutrophils, reticulocytes, CD34+‐derived erythroid cells and K562 erythroleukaemic cells, indicating a high haematopoietic cell expression. PDE9A gene expression was, however, significantly higher in the reticulocytes and neutrophils of SCD individuals, compared to control cells; Western blotting confirmed the production of PDE9A protein in SCD neutrophils and K562 cells. Inhibition of PDE9A enzyme with the specific inhibitor, BAY73‐6691, significantly increased production of the γ‐globin gene (HBG) in K562 cells and reversed the increased adhesive properties of SCD neutrophils. Since elevation of haematopoietic intracellular cGMP may be beneficial in SCD, the relatively limited tissue distribution of PDE9A suggests that it could represent a novel drug target worthy of further study.
Thrombin generation testing in routine clinical practice: are we there yet?
Authors: Van Veen J. J. , Gatt A. , Makris M. 
Published: June 2008

SummaryThrombin is the central enzyme in the coagulation cascade. Estimation of an individual’s potential to generate thrombin may correlate more closely with a hyper‐ or hypo‐coagulable phenotype, compared to traditional coagulation tests. The possible correlation and recent technical advances in thrombin generation measurement has caused a significant interest in the method and the development of commercial assays. Several variations of the assay exist depending on the defect to be investigated. Fluorogenic thrombin generation assays have acceptable intra‐laboratory variation but a higher inter‐laboratory variation. Variation in preanalytical variables makes comparisons between studies difficult. Thrombin generation is highly variable between individuals and there are suggestions that this may allow individualized treatment based on global haemostatic response in patients with bleeding disorders or on anticoagulant therapy. In patients with thrombotic disorders it may be possible to identify those at higher risk of recurrent thrombosis. For both scenarios, however, data from large prospective studies are lacking or inconclusive and a good relationship between thrombin generation and phenotype remains to be established. Further standardization of the assay is needed before large multicentre studies can be conducted and until then thrombin generation in routine clinical practice is not yet a reality.
Multiplex ligation‐dependent probe amplification for detection of genomic alterations in chronic lymphocytic leukaemia
Authors: Coll‐Mulet Llorenç , Santidrián Antonio F. , Cosialls Ana M. , Iglesias‐Serret Daniel , De Frias Mercè , Grau Javier , Menoyo Anna , González‐Barca Eva , Pons Gabriel , Domingo Alicia , Gil Joan 
Published: June 2008

SummaryChronic lymphocytic leukaemia (CLL) is the commonest form of leukaemia in adults in Western countries. We performed multiplex ligation‐dependent probe amplification (MLPA) analysis in 50 CLL patients to identify multiple genomic CLL‐specific targets, including genes located at 13q14, 17p13 (TP53), 11q23 (ATM) and chromosome 12, and compared the results with those obtained with fluorescence in situ hybridization (FISH). There was a good correlation between MLPA and FISH results, as most alterations (89%) were detected by both techniques. Only three cases with a low percentage (<25%) of cells carrying the alterations were not detected by MLPA. On the other hand, as MLPA uses multiple probes it identified intragenic or small alterations undetected by FISH in three cases. MLPA also detected alterations in 8q24 (MYC) and 6q25–26. In summary, unlike interphase FISH, MLPA enabled the simultaneous analysis of many samples with automated data processing at a low cost. Therefore, the combination of robust multiplexing and high throughput makes MLPA a useful technique for the analysis of genomic alterations in CLL.
Disease staging with positron emission tomography or gallium scanning and use of rituximab predict outcome for patients with diffuse large B‐cell lymphoma treated with autologous stem cell transplantation
Authors: Alousi Amin M. , Saliba Rima M. , Okoroji Grace‐Julia , Macapinlac Homer A. , Hosing Chitra , Korbling Martin , Samuels Barry I. , Popat Uday , Kebriaei Partow , Anderlini Paolo , Qazilbash Muzaffar H. , De Lima Marcos , Giralt Sergio A. , Champlin Richard E. , Khouri Issa F. 
Published: June 2008

SummaryTumor status, as determined by positron emission tomography or gallium scanning (PET/G), may be an important predictor of outcome for patients with diffuse large B‐cell lymphoma (DLBCL) undergoing autologous stem cell transplantation (ASCT). ASCT conditioning regimens that include rituximab may reduce the rate of relapse. We evaluated the influence of rituximab on overall and progression‐free survival in patients with DLBCL based on PET/G status before ASCT. A retrospective review of all patients with chemosensitive DLBCL who underwent ASCT in the context of research protocols at our institution between 1995 and 2005 was performed. Our study included 174 patients. Disease status before ASCT, according to PET/G, was negative in 136 patients (78%), positive in 29 patients (17%), and unknown in nine patients (5%). PET/G status and rituximab use were the only factors predictive of progression‐free survival in multivariate analyses: the hazard ratios for relapse were 2·9 for PET/G‐positive versus ‐negative patients (P < 0·001) and 0·4 for rituximab versus no rituximab use (P = 0·001). We conclude that evidence of disease on PET/G scanning prior to transplantation is associated with an increased risk for relapse after ASCT. Transplantation regimens containing rituximab can reduce this risk, regardless of PET/G status.
Peanut‐specific B and T cell responses are correlated in peanut‐allergic but not in non‐allergic individuals
Authors: Turcanu V. , Winterbotham M. , Kelleher P. , Lack G. 
Published: June 2008

SummaryObjective
We aim to find what is the relationship between B cell antibody responses and specific T cell help in the specific cases of allergy and tolerance to peanuts.Background
B cell antibody responses to foreign proteins usually depend upon antigen‐specific T cell help. However, specific antibody levels can sometimes be maintained lifelong after infections or vaccination.Methods
We measured peanut‐specific proliferation and antibody levels in peanut‐allergic and non‐allergic children using tritiated thymidine incorporation and UniCAP, respectively. We also investigated the corresponding tetanus toxoid specific responses in both groups.Results
We found that tetanus‐specific IgG did not correlate with lymphocyte proliferation (Spearman rank correlation coefficient r′=0.08, P=0.74) nor with tetanus‐specific cytokine production (IFN‐γ: r′=0.198, P=0.285; TNF‐α: r′=0.274, P=0.146; IL‐4: r′=−0.007, P=0.96; P=0.221; IL‐13: r′=0.363, P=0.056). Conversely, in peanut‐allergic donors, peanut‐specific IgE (average 21 kU/L, median 2.27 kU/L, range 0.34‐100 kU/L) but not peanut‐specific IgG was positively correlated with proliferation (r′=0.751, P=0.003). In these donors, specific IgE was positively correlated with peanut‐specific Th2 cytokines production: r′=0.635, P=0.02 for IL‐4 and r′=0.641, P=0.025 for IL‐13 and negatively correlated with Th1 cytokines (r′=−0.71, P=0.007 for IFN‐γ and r′=−0.746, P=0.005 for TNF‐α, respectively). However, peanut‐specific IgE was not correlated with T cell proliferation or cytokine production in non‐allergic individuals. In conclusion, in allergic individuals, B and T cell responses to peanut antigens are correlated whereas normal immune responses B and T cell responses are uncoupled.Conclusion
Our results support the view that B cell responses to allergens but not those to non‐allergenic proteins are correlated with specific T cell responses and therefore specific immunotherapy targeting of such T cells would inhibit allergen‐specific B cells.
Heterogeneity of commercial timothy grass pollen extracts
Authors: Focke M. , Marth K. , Flicker S. , Valenta R. 
Published: June 2008

SummaryBackground
The diagnosis and specific immunotherapy of allergy is currently performed with allergen extracts prepared from natural allergen sources.Objective
To analyse commercial timothy grass pollen allergen extracts used for in vivo diagnosis regarding their qualitative and quantitative allergen composition and in vivo biological activity.Methods
Antibodies specific for eight timothy grass pollen allergens (Phl p 1, Phl p 2, Phl p 4, Phl p 5, Phl p 6, Phl p 7, Phl p 12, Phl p 13) were used to detect these allergens in timothy grass pollen extracts from four manufacturers by immunoblotting. ELISA assays were developed and used to quantify the three major allergens (Phl p 1, Phl p 2, Phl p 5) in the extracts. The magnitude of skin responses to the four extracts was studied by skin prick testing in 10 grass pollen‐allergic patients.Results
The allergen extracts showed broad variations in protein compositions and amounts (24.1–197.7 μg/mL extract). Several allergens could not be detected in certain extracts or appeared degraded. A considerable variability regarding the contents of major allergens was found (Phl p 1: 32–384 ng/mL; Phl p 2: 1128–6530 ng/mL, Phl p 5: 40–793 ng/mL). Heterogeneous skin test results were obtained with the extracts in grass pollen‐allergic patients.Conclusions
Timothy grass pollen extracts from different manufacturers exhibit a considerable heterogeneity regarding the presence of individual allergens and hence yield varying in vivo test results. Problems related to the use of natural grass pollen allergen extracts may be circumvented by using defined recombinant grass pollen allergens.