bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overnight transduction with foamyviral vectors restores the long-term repopulating activity of Fancc−/− stem cells
Authors: Si Yue , Pulliam Anna C. , Linka Yvonne , Ciccone Samantha , Leurs Cordula , Yuan Jin , Eckermann Olaf , Fruehauf Stefan , Mooney Sean , Hanenberg Helmut , Clapp D. Wade 
Published: August 2008

AbstractFanconi anemia (FA) is a complex genetic disorder characterized by congenital abnormalities, bone marrow failure, and myeloid malignancies. Identification of 13 FA genes has been instrumental to explore gene transfer technologies aimed at correction of autologous FA-deficient stem cells. To date, 3 human FA stem cell gene therapy trials with standard 4-day transduction protocols using gammaretroviral vectors failed to provide clinical benefit. In addition, 2- to 4 day ex vivo manipulation of bone marrow from mice containing a disruption of the homologue of human FANCC (Fancc) results in a time-dependent increase in apoptosis and a risk for malignant transformation of hematopoietic cells. Here, we show that a 14-hour transduction period allows a foamyviral vector construct expressing the human FANCC cDNA to efficiently transduce murine FA stem cells with 1 to 2 proviral integrations per genome. Functionally, the repopulating activity of Fancc−/− stem cells from reconstituted mice expressing the recombinant FANCC transgene was comparable with wild-type controls. Collectively, these data provide evidence that short-term transduction of c-kit+ cells with a foamyviral vector is sufficient for functional correction of a stem cell phenotype in a murine FA model. These data could have implications for future gene therapy trials for FA patients.
Point mutation in the gene encoding p300 suppresses thrombocytopenia in Mpl−/− mice
Authors: Kauppi Maria , Murphy James M. , de Graaf Carolyn A. , Hyland Craig D. , Greig Kylie T. , Metcalf Donald , Hilton Adrienne A. , Nicola Nicos A. , Kile Benjamin T. , Hilton Douglas J. , Alexander Warren S. 
Published: August 2008

AbstractIn an N-nitroso-N-ethylurea (ENU) mutagenesis screen using Mpl−/− mice, we isolated a semidominant suppressor of thrombocytopenia, termed Plt6. The gene mutated in Plt6 mice encodes the transcriptional coregulator p300, and the mutation, a tyrosine to asparagine substitution at amino acid 630 (Y630N), disrupts the interaction between p300 and c-Myb. Mpl−/−p300Plt6/+ mice displayed elevated platelet counts relative to Mpl−/−p300+/+ controls, whereas mice homozygous for the Plt6 mutation produced supraphysiological levels of circulating platelets. On a wild-type genetic background, mice homozygous for the p300Plt6 mutation, or recipients of Mpl+/+p300Plt6/Plt6 bone marrow, also exhibited thrombocytosis as well as deficiencies in B-lymphoid cells. Increased platelet numbers in Plt6 mutant mice were accompanied by significant increases in megakaryocyte progenitor cells within the bone marrow and spleen with concomitantly elevated numbers of megakaryocytes. The expansion of megakaryocytopoiesis and suppression of Mpl−/− thrombocytopenia in Plt6 mutants is highly reminiscent of that observed in mice with mutations affecting the p300 partner protein c-Myb, suggesting an indispensable repressive role for the c-Myb/p300 transcriptional regulatory complex in megakaryocyte develop-ment, the inhibition of which allows substantial thrombopoietin (TPO)–independent platelet production.
Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3α
Authors: Lamprecht Björn , Kreher Stephan , Anagnostopoulos Ioannis , Jöhrens Korinna , Monteleone Giovanni , Jundt Franziska , Stein Harald , Janz Martin , Dörken Bernd , Mathas Stephan 
Published: August 2008

Abstract
The malignant Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (HL) are derived from mature B cells, but have lost a considerable part of the B cell–specific gene expression pattern. Consequences of such a lineage infidelity for lymphoma pathogenesis are currently not defined. Here, we report that HRS cells aberrantly express the common cytokine-receptor γ-chain (γc) cytokine IL-21, which is usually restricted to a subset of CD4+ T cells, and the corresponding IL-21 receptor. We demonstrate that IL-21 activates STAT3 in HRS cells, up-regulates STAT3 target genes, and protects HRS cells from CD95 death receptor–induced apoptosis. Furthermore, IL-21 is involved in up-regulation of the CC chemokine macrophage-inflammatory protein-3α (MIP-3α) in HRS cells. MIP-3α in turn attracts CCR6+CD4+CD25+FoxP3+CD127lo regulatory T cells toward HRS cells, which might favor their immune escape. Together, these data support the concept that aberrant expression of B lineage–inappropriate genes plays an important role for the biology of HL tumor cells.
Cell signaling directing the formation and function of hemogenic endothelium during murine embryogenesis
Authors: Goldie Lauren C. , Lucitti Jennifer L. , Dickinson Mary E. , Hirschi Karen K. 
Published: August 2008

AbstractDuring developmental hematopoiesis, multilineage hematopoietic progenitors are thought to derive from a subset of vascular endothelium. Herein, we define the phenotype of such hemogenic endothelial cells and demonstrate, on a clonal level, that they exhibit multilineage hematopoietic potential. Furthermore, we have begun to define the molecular signals that regulate their development. We found that the formation of yolk sac hemogenic endothelium and its hematopoietic potential were significantly impaired in the absence of retinoic acid (RA) signaling, and could be restored in RA-deficient (Raldh2−/−) embryos by provision of exogenous RA in utero. Thus, we identify a novel, critical role for RA signaling in the development of hemogenic endothelium that contributes to definitive hematopoiesis.
Leukemic challenge unmasks a requirement for PI3Kδ in NK cell–mediated tumor surveillance
Authors: Zebedin Eva , Simma Olivia , Schuster Christian , Putz Eva Maria , Fajmann Sabine , Warsch Wolfgang , Eckelhart Eva , Stoiber Dagmar , Weisz Eva , Schmid Johannes A. , Pickl Winfried F. , Baumgartner Christian , Valent Peter , Piekorz Roland P. , Freissmuth Michael , Sexl Veronika 
Published: August 2008

AbstractSpecific inhibitors of PI3K isoforms are currently evaluated for their therapeutic potential in leukemia. We found that BCR/ABL+ human leukemic cells express PI3Kδ and therefore explored its impact on leukemia development. Using PI3Kδ-deficient mice, we define a dual role of PI3Kδ in leukemia. We observed a growth-promoting effect in tumor cells and an essential function in natural killer (NK) cell–mediated tumor surveillance: Abelson-transformed PI3Kδ-deficient cells induced leukemia in RAG2-deficient mice with an increased latency, indicating that PI3Kδ accelerated leukemia progression in vivo. However, the absence of PI3Kδ also affected NK cell–mediated tumor surveillance. PI3Kδ-deficient NK cells failed to lyse a large variety of target cells because of defective degranulation, as also documented by capacitance recordings. Accordingly, transplanted leukemic cells killed PI3Kδ-deficient animals more rapidly. As a net effect, no difference in disease latency in vivo was detected if both leukemic cells and NK cells lack PI3Kδ. Other tumor models confirmed that PI3Kδ-deficient mice succumbed more rapidly when challenged with T- or B-lymphoid leukemic or B16 melanoma cells. Thus, the action of PI3Kδ in the NK compartment is as relevant to survival of the mice as the delayed tumor progression. This dual function must be taken into account when using PI3Kδ inhibitors as antileukemic agents in clinical trials.
Megakaryocyte endomitosis is a failure of late cytokinesis related to defects in the contractile ring and Rho/Rock signaling
Authors: Lordier Larissa , Jalil Abdelali , Aurade Fréderic , Larbret Fréderic , Larghero Jerôme , Debili Najet , Vainchenker William , Chang Yunhua 
Published: August 2008

AbstractMegakaryocyte (MK) is the naturally polyploid cell that gives rise to platelets. Polyploidization occurs by endomitosis, which was a process considered to be an incomplete mitosis aborted in anaphase. Here, we used time-lapse confocal video microscopy to visualize the endomitotic process of primary human megakaryocytes. Our results show that the switch from mitosis to endomitosis corresponds to a late failure of cytokinesis accompanied by a backward movement of the 2 daughter cells. No abnormality was observed in the central spindle of endomitotic MKs. A furrow formation was present, but the contractile ring was abnormal because accumulation of nonmuscle myosin IIA was lacking. In addition, a defect in cell elongation was observed in dipolar endomitotic MKs during telophase. RhoA and F-actin were partially concentrated at the site of furrowing. Inhibition of the Rho/Rock pathway caused the disappearance of F-actin at midzone and increased MK ploidy level. This inhibition was associated with a more pronounced defect in furrow formation as well as in spindle elongation. Our results suggest that the late failure of cytokinesis responsible for the endomitotic process is related to a partial defect in the Rho/Rock pathway activation.
Ligation of erythrocyte CR1 induces its clustering in complex with scaffolding protein FAP-1
Authors: Ghiran Ionita , Glodek Aleksandra M. , Weaver Gregory , Klickstein Lloyd B. , Nicholson-Weller Anne 
Published: August 2008

AbstractThe primary identified function of complement receptor 1 (CR1/CD35) on primate erythrocytes is to bind complement-tagged inflammatory particles including microbes and immune complexes. When erythrocytes circulate through liver and spleen, sinusoidal phagocytes remove CR1-adherent particles and erythrocytes return to the circulation. This process of immune adherence clearance is important for host defense and prevention of autoimmunity. CR1 was previously described as clustered in the human erythrocyte membrane, which was thought to be necessary for binding complement-opsonized particles. In contrast, we demonstrate that on erythrocytes CR1 is not clustered, but dispersed, and able to bind complement-tagged particles. When fresh erythrocytes are solubilized by nonionic detergent, CR1 partitions to the cytoskeleton fraction. Using a PDZ-peptide array, CR1's cytoplasmic tail, which contains 2 PDZ-motifs, binds PDZ domains 2, 3, and 5 of Fas-associated phosphatase 1 (FAP-1), a scaffolding protein. We show that FAP-1, not previously recognized as an erythroid protein, is expressed on circulating erythrocytes. CR1 and FAP-1 coimmunoprecipitate, which confirms their molecular association. Disperse CR1 on erythrocytes may be advantageous for capturing immune-complexes, while ligation-induced CR1 clustering may prevent ingestion of the erythrocyte during the immune-complex transfer to the macrophages by keeping the opsonic stimulus localized thus preventing phagocyosis.
Prevalence and risk factors of airflow obstruction in an elderly Chinese population
Authors: Ko F. W. S. , Woo J. , Tam W. , Lai C. K. W. , Ngai J. , Kwok T. , Hui D. S. C. 
Published: August 2008

It is common practice to use a forced expiratory volume in one second (FEV1)/ forced vital capacity (FVC) ratio of <70% as evidence of airflow obstruction. As the FEV1/FVC ratio falls with age, the lower limit of normal range (LLN), defined as the bottom 5% in a health reference population, of FEV1/FVC ratio has been suggested as a better index to reduce over-diagnosis of chronic obstructive pulmonary disease (COPD), particularly in the elderly. However, there are no large scale studies that focus on the diagnosis of COPD in the elderly based on these definitions. The present prospective epidemiological study involved 1,149 elderly subjects aged ≥60 yrs in the community. Detailed questionnaires, pre- and post-bronchodilator spirometry were performed.In total, 1,008 subjects (mean age 74.2±6.4 yrs; 271 males) completed satisfactory spirometry testing. Airflow obstruction was present in 25.9% as defined by the post-bronchodilator FEV1/FVC ratio of <70% and in 12.4% defined by the LLN of FEV1/FVC ratio. Moderate COPD, at least, was found in 14.0% of patients according to the post-bronchodilator FEV1/FVC ratio of <70% and in 8.5% of patients according to LLN of FEV1/FVC ratio.In the present elderly Chinese population (mostly females, with low education level and previous exposure to biomass during formative years), the prevalence of chronic obstructive pulmonary disease varied markedly depending on definitions adopted. Further longitudinal studies are needed to determine the precise definition of chronic obstructive pulmonary disease.
Genome-wide analyses reveal lineage specific contributions of positive selection and recombination to the evolution of Listeria monocytogenes
Authors: Orsi Renato H , Sun Qi , Wiedmann Martin 
Published: August 2008

AbstractBackgroundThe genusListeriaincludes two closely related pathogenic and non-pathogenic species,L. monocytogenesandL. innocua.L. monocytogenesis an opportunistic human foodborne and animal pathogen that includes two common lineages. While lineage I is more commonly found among human listeriosis cases, lineage II appears to be overrepresented among isolates from foods and environmental sources. This study used the genome sequences for oneL. innocuastrain and fourL. monocytogenesstrains representing lineages I and II, to characterize the contributions of positive selection and recombination to the evolution of theL. innocua/L. monocytogenescore genome.ResultsAmong the 2267 genes in theL. monocytogenes/L. innocuacore genome, 1097 genes showed evidence for recombination and 36 genes showed evidence for positive selection. Positive selection was strongly associated with recombination. Specifically, 29 of the 36 genes under positive selection also showed evidence for recombination. Recombination was more common among isolates in lineage II than lineage I; this trend was confirmed by sequencing five genes in a larger isolate set. Positive selection was more abundant in the ancestral branch of lineage II (20 genes) as compared to the ancestral branch of lineage I (9 genes). Additional genes under positive selection were identified in the branch separating the two species; for this branch, genes in the role category "Cell wall and membrane biogenesis" were significantly more likely to have evidence for positive selection. Positive selection of three genes was confirmed in a larger isolate set, which also revealed occurrence of multiple premature stop codons in one positively selected gene involved in flagellar motility (flaR).ConclusionWhile recombination and positive selection both contribute to evolution ofL. monocytogenes, the relative contributions of these evolutionary forces seem to differ byL. monocytogeneslineages and appear to be more important in the evolution of lineage II, which seems to be found in a broader range of environments, as compared to the apparently more host adapted lineage I. Diversification of cell wall and membrane biogenesis and motility-related genes may play a particularly important role in the evolution ofL. monocytogenes.
The incidence and prevalence of diabetes in patients with serious mental illness in North West Wales: Two cohorts, 1875–1924 & 1994–2006 compared
Authors: Le Noury Joanna , Khan Afshan , Harris Margaret , Wong Winnie , Williams Dawn , Roberts Tony , Tranter Richard , Healy David 
Published: August 2008

Abstract

Background
Against a background of interest in rates of diabetes in schizophrenia and related psychoses and claims that data from historical periods demonstrate a link that antedates modern antipsychotics, we sought to establish the rate of diabetes in first onset psychosis and subsequent prevalence in historical and contemporary cohorts.

Methods
Analysis of two epidemiologically complete databases of individuals admitted for mental illness. 3170 individuals admitted to the North Wales Asylum between 1875–1924 and tracked over 18,486 patient years and 394 North West Wales first admissions for schizophrenia and related psychoses between 1994 and 2006 and tracked after treatment.

Results
The prevalence of Type 2 diabetes among patients with psychoses at time of first admission in both historical and contemporary samples was 0%. The incidence of diabetes remained 0% in the historical sample throughout 15 years of follow-up but rose in the contemporary sample after 3, 5 and 6 years of treatment with an incidence rate double the expected population rate so that the 15 year prevalence is likely to be over 8%.

Conclusion
No association was found between diabetes and serious mental illness, but there may be an association between diabetes and treatment.
Sugar-added beverages consumption among kindergarten children of Crete: effects on nutritional status and risk of obesity
Authors: Linardakis Manolis , Sarri Katerina , Pateraki Maria-Styliani , Sbokos Manolis , Kafatos Anthony 
Published: August 2008

AbstractObjectiveTo assess the intake of sugar-added beverages such as soft drinks and commercially available fruit juices in kindergarten children, and to examine its association with obesity indices, physical activity levels and dietary habits.MethodsA total of 856 children aged 4–7 years living in Crete, Greece in 2004–5 were included in this cross-sectional study. Nutrient and food intake was assessed with the use of 3-day weighed food records. Body measurements were used in order to assess BMI and waist circumference, and moderate-to-vigorous physical activity was calculated with the use of a questionnaire.ResultsApproximately 59.8% of all children consumed sugar-added beverages on a daily basis. High intake of sugar-added beverages (> 250 g/day) was associated with low intakes of calcium (p < 0.001), vitamin A and E (p < 0.010), fruits and vegetables (p = 0.007), and milk and yogurt (p = 0.048). Compared to non or low consumers, high consumers of sugar-added beverages (> 250 g/day) had higher BMI levels and two times greater risk of being overweight and/or obese (OR:2.35, p = 0.023).ConclusionHigh intake of sugar-added beverages in kindergarten children is associated with poor eating habits and inadequate nutrient intake, as well as increased risk for developing childhood obesity.
Patient's dissatisfaction with the public and private laboratory services in conducting HIV related testing in Tanzania
Authors: Mfinanga SG , Kahwa A , Kimaro G , Kilale A , Kivuyo S , Senkoro M , Ngowi B , Mtandu R , Mutayoba B , Ngadaya E , Mashoto K 
Published: August 2008

AbstractBackgroundPatient's satisfaction with both private and public laboratory services is important for the improvement of the health care delivery in any country.MethodsA cross-sectional survey was conducted in 24 randomly selected health facilities with laboratories that are conducting HIV related testing, in Mainland Tanzania. The study assessed patient's satisfaction with the laboratory services where by a total of 295 patients were interviewed.ResultsOf data analyzed for a varying totals from 224 to 294 patients, the percentage of dissatisfaction with both public and private laboratory services, ranged from 4.3% to 34.8%, with most of variables being more than 15%. Patients who sought private laboratory services were less dissatisfied with the cleanness (3/72, 4.2%) and the privacy (10/72, 13.9%) than those sought public laboratory service for the same services of cleanness (41/222, 18.5%) and privacy (61/222, 27.5%), and proportional differences were statistically significant (X2= 8.7, p = 0.003 and X2= 5.5, p = 0.01, respectively). Patients with higher education were more likely to be dissatisfied with privacy (OR = 1.8, 95% CI: 1.1–3.1) and waiting time (OR = 2.5, 95% CI: 1.5 – 4.2) in both private and public facilities. Patients with secondary education were more likely to be dissatisfied with the waiting time (OR = 5.2; 95%CI: 2.2–12.2) and result notification (OR = 5.1 95%CI (2.2–12.2) than those with lower education.ConclusionAbout 15.0% to 34.8% of patients were not satisfied with waiting time, privacy, results notification cleanness and timely instructions. Patients visited private facilities were less dissatisfied with cleanness and privacy of laboratory services than those visited public facilities. Patients with higher education were more likely to be dissatisfied with privacy and waiting time in both private and public facilities.
High cell density media for Escherichia coli are generally designed for aerobic cultivations – consequences for large-scale bioprocesses and shake flask cultures
Authors: Soini Jaakko , Ukkonen Kaisa , Neubauer Peter 
Published: August 2008

Abstract

Background
For the cultivation of Escherichia coli in bioreactors trace element solutions are generally designed for optimal growth under aerobic conditions. They do normally not contain selenium and nickel. Molybdenum is only contained in few of them. These elements are part of the formate hydrogen lyase (FHL) complex which is induced under anaerobic conditions. As it is generally known that oxygen limitation appears in shake flask cultures and locally in large-scale bioreactors, function of the FHL complex may influence the process behaviour. Formate has been described to accumulate in large-scale cultures and may have toxic effects on E. coli.
Although the anaerobic metabolism of E. coli is well studied, reference data which estimate the impact of the FHL complex on bioprocesses of E. coli with oxygen limitation have so far not been published, but are important for a better process understanding.

Results
Two sets of fed-batch cultures with conditions triggering oxygen limitation and formate accumulation were performed. Permanent oxygen limitation which is typical for shake flask cultures was caused in a bioreactor by reduction of the agitation rate. Transient oxygen limitation, which has been described to eventually occur in the feed-zone of large-scale bioreactors, was mimicked in a two-compartment scale-down bioreactor consisting of a stirred tank reactor and a plug flow reactor (PFR) with continuous glucose feeding into the PFR.
In both models formate accumulated up to about 20 mM in the culture medium without addition of selenium, molybdenum and nickel. By addition of these trace elements the formate accumulation decreased below the level observed in well-mixed laboratory-scale cultures. Interestingly, addition of the extra trace elements caused accumulation of large amounts of lactate and reduced biomass yield in the simulator with permanent oxygen limitation, but not in the scale-down two-compartment bioreactor.

Conclusion
The accumulation of formate in oxygen limited cultivations of E. coli can be fully prevented by addition of the trace elements selenium, nickel and molybdenum, necessary for the function of FHL complex. For large-scale cultivations, if glucose gradients are likely, the results from the two-compartment scale-down bioreactor indicate that the addition of the extra trace elements is beneficial. No negative effects on the biomass yield or on any other bioprocess parameters could be observed in cultures with the extra trace elements if the cells were repeatedly exposed to transient oxygen limitation.