bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of River Flows in HadGEM1 and HadCM3 with the TRIP River Flow Model
Authors: Falloon Pete , Betts Richard , Wiltshire Andrew , Dankers Rutger , Mathison Camilla , McNeall Doug , Bates Paul , Trigg Mark 
Published: May 2011

AbstractThe Total Runoff Integrating Pathways (TRIP) global river-routing scheme in the third climate configuration of the Met Office Unified Model (HadCM3) and the newer Hadley Centre Global Environmental Model version 1 (HadGEM1) general circulation models (GCMs) have been validated against long-term average measured river discharge data from 40 stations on 24 major river basins from the Global Runoff Data Centre (GRDC). TRIP was driven by runoff produced directly by the two GCMs in order to assess both the skill of river flows produced within GCMs in general and to test this as a method for validating large-scale hydrology in GCMs. TRIP predictions of long-term-averaged annual discharge were improved at 28 out of 40 gauging stations on 24 of the world’s major rivers in HadGEM1 compared to HadCM3, particularly for low- and high-latitude basins, with predictions ranging from “good” (within 20% of observed values) to “poor” (biases exceeding 50%). For most regions, the modeled annual average river flows tended to be exaggerated in both models, largely reflecting inflated estimates of precipitation, although lack of human interventions in this modeling setup may have been an additional source of error. Within individual river basins, there were no clear trends in the accuracy of HadGEM1 versus HadCM3 predictions at up- or downstream gauging stations. Relative root-mean-square error (RRMSE) scores for the annual cycle of river flow ranged from poor (>50%) to “fair” (20%–50%) with an overall range of 20.7%–1023.5%, comparable to that found in similar global-scale studies. In both models, simulations of the annual cycle of river flow were generally better for high-latitude basins than in low or midlatitudes. There was a relatively small improvement in the annual cycle of river flow in HadGEM1 compared to HadCM3, mostly in the low-latitude rivers. The findings suggest that there is still substantial work to be done to enable GCMs to simulate monthly discharge consistently well over the majority of basins, including improvements to both (i) GCM simulation of basin-scale precipitation and evaporation and (ii) hydrological processes (e.g., representation of dry land hydrology, floodplain inundation, lakes, snowmelt, and human intervention).
Conditional Probability Estimation for Significant Tornadoes Based on Rapid Update Cycle (RUC) Profiles
Authors: Togstad William E. , Davies Jonathan M. , Corfidi Sarah J. , Bright David R. , Dean Andrew R. 
Published: May 2011

Abstract
Recent literature has identified several supercell/tornado forecast parameters in common use that are operationally beneficial in assessing environments supportive of supercell tornadoes. These parameters are utilized in the computation of tornado forecast guidance such as the significant tornado parameter (STP), a dimensionless parameter developed at the Storm Prediction Center (SPC) that applies a subjectively chosen scale. The goal of this research is to determine if useful logistic regression equations can be developed to estimate the conditional probability of supercell tornadoes that are categorized as level 2 or stronger on the enhanced Fujita scale (EF) when a similar set of environmental background parameters is applied as variables. A large database of Rapid Update Cycle (RUC) analysis soundings in proximity to a representative sample of tornadic and nontornadic supercells over the central and eastern United States, a number of which were associated with EF2 or stronger tornadoes, was used to compute supercell tornado forecast parameters similar to those in the original version of STP. Three logistic regression equations were developed from this database, two of which are described and analyzed in detail. Statistical verification for both equations was accomplished using independent data from 2008 in proximity to supercell storms identified by staff at SPC. A recent version of the STP was utilized as a comparison diagnostic to accomplish part of the statistical verification. The results of this research suggest that output from both logistic regression equations can provide valuable guidance in a probabilistic sense, when adjustments are made for the ongoing convective mode. Case studies presented also suggest that this guidance can provide information complementary to STP in severe weather situations with potential for supercell tornadoes.
ERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer
Authors: Thoms Julie A. I. , Birger Yehudit , Foster Sam , Knezevic Kathy , Kirschenbaum Yael , Chandrakanthan Vashe , Jonquieres Georg , Spensberger Dominik , Wong Jason W. , Oram S. Helen , Kinston Sarah J. , Groner Yoram , Lock Richard , MacKenzie Karen L. , Göttgens Berthold , Izraeli Shai , Pimanda John E. 
Published: May 2011

AbstractThe Ets-related gene (ERG) is an Ets-transcription factor required for normal blood stem cell development. ERG expression is down-regulated during early T-lymphopoiesis but maintained in T-acute lymphoblastic leukemia (T-ALL), where it is recognized as an independent risk factor for adverse outcome. However, it is unclear whether ERG is directly involved in the pathogenesis of T-ALL and how its expression is regulated. Here we demonstrate that transgenic expression of ERG causes T-ALL in mice and that its knockdown reduces the proliferation of human MOLT4 T-ALL cells. We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. This enhancer is not active in normal T cells but in transgenic mice targets expression to fetal liver c-kit+ cells, adult bone marrow stem/progenitors and early CD4−CD8− double-negative thymic progenitors. Taken together, these data illustrate that ERG promotes T-ALL and that failure to extinguish activity of stem cell enhancers associated with regulatory transcription factors such as ERG can contribute to the development of leukemia.
Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score
Authors: Hasford Joerg , Baccarani Michele , Hoffmann Verena , Guilhot Joelle , Saussele Susanne , Rosti Gianantonio , Guilhot François , Porkka Kimmo , Ossenkoppele Gert , Lindoerfer Doris , Simonsson Bengt , Pfirrmann Markus , Hehlmann Rudiger 
Published: May 2011

AbstractThe outcome of chronic myeloid leukemia (CML) has been profoundly changed by the introduction of tyrosine kinase inhibitors into therapy, but the prognosis of patients with CML is still evaluated using prognostic scores developed in the chemotherapy and interferon era. The present work describes a new prognostic score that is superior to the Sokal and Euro scores both in its prognostic ability and in its simplicity. The predictive power of the score was developed and tested on a group of patients selected from a registry of 2060 patients enrolled in studies of first-line treatment with imatinib-based regimes. The EUTOS score using the percentage of basophils and spleen size best discriminated between high-risk and low-risk groups of patients, with a positive predictive value of not reaching a CCgR of 34%. Five-year progression-free survival was significantly better in the low- than in the high-risk group (90% vs 82%, P = .006). These results were confirmed in the validation sample. The score can be used to identify CML patients with significantly lower probabilities of responding to therapy and survival, thus alerting physicians to those patients who require closer observation and early intervention.
Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures
Authors: Alberts Rudi , Lu Lu , Williams Robert W , Schughart Klaus 
Published: May 2011

Abstract

Background
The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics.

Methods
Steady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL) analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org.

Results
Expression values were highly variable across strains and in many cases exhibited a high heri-tability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P450 transcript had a strong trans-acting eQTL (LOD 11.8) on Chr 12 at 36 ± 1 Mb. This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR.

Conclusions
Large-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions.
Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: Derivation of a clinical algorithm
Authors: Albrich Werner C , Dusemund Frank , Rüegger Kristina , Christ-Crain Mirjam , Zimmerli Werner , Bregenzer Thomas , Irani Sarosh , Buergi Ulrich , Reutlinger Barbara , Mueller Beat , Schuetz Philipp 
Published: May 2011

Abstract

Background
Proadrenomedullin (ProADM) confers additional prognostic information to established clinical risk scores in lower respiratory tract infections (LRTI). We aimed to derive a practical algorithm combining the CURB65 score with ProADM-levels in patients with community-acquired pneumonia (CAP) and non-CAP-LRTI.

Methods
We used data of 1359 patients with LRTI enrolled in a multicenter study. We chose two ProADM cut-off values by assessing the association between ProADM levels and the risk of adverse events and mortality. A composite score (CURB65-A) was created combining CURB65 classes with ProADM cut-offs to further risk-stratify patients.

Results
CURB65 and ProADM predicted both adverse events and mortality similarly well in CAP and non-CAP-LRTI. The combined CURB65-A risk score provided better prediction of death and adverse events than the CURB65 score in the entire cohort and in CAP and non-CAP-LRTI patients. Within each CURB65 class, higher ProADM-levels were associated with an increased risk of adverse events and mortality. Overall, risk of adverse events (3.9%) and mortality (0.65%) was low for patients with CURB65 score 0-1 and ProADM ≤0.75 nmol/l (CURB65-A risk class I); intermediate (8.6% and 2.6%, respectively) for patients with CURB65 score of 2 and ProADM ≤1.5 nmol/l or CURB classes 0-1 and ProADM levels between 0.75-1.5 nmol/L (CURB65-A risk class II), and high (21.6% and 9.8%, respectively) for all other patients (CURB65-A risk class III). If outpatient treatment was recommended for CURB65-A risk class I and short hospitalization for CURB65-A risk class II, 17.9% and 40.8% of 1217 hospitalized patients could have received ambulatory treatment or a short hospitalization, respectively.

Conclusions
The new CURB65-A risk score combining CURB65 risk classes with ProADM cut-off values accurately predicts adverse events and mortality in patients with CAP and non-CAP-LRTI. Additional prospective cohort or intervention studies need to validate this score and demonstrate its safety and efficacy for the management of patients with LRTI.

Trial Registration
Procalcitonin-guided antibiotic therapy and hospitalisation in patients with lower respiratory tract infections: the prohosp study; isrctn.org Identifier: ISRCTN: ISRCTN95122877
Luminal and basal-like breast cancer cells show increased migration induced by hypoxia, mediated by an autocrine mechanism
Authors: Voss Melanie J , Möller Mischa F , Powe Desmond G , Niggemann Bernd , Zänker Kurt S , Entschladen Frank 
Published: May 2011

Abstract

Background
Some breast cancer patients receiving anti-angiogenic treatment show increased metastases, possibly as a result of induced hypoxia. The effect of hypoxia on tumor cell migration was assessed in selected luminal, post-EMT and basal-like breast carcinoma cell lines.

Methods
Migration was assessed in luminal (MCF-7), post-EMT (MDA-MB-231, MDA-MB-435S), and basal-like (MDA-MB-468) human breast carcinoma cell lines under normal and oxygen-deprived conditions, using a collagen-based assay. Cell proliferation was determined, secreted cytokine and chemokine levels were measured using flow-cytometry and a bead-based immunoassay, and the hypoxic genes HIF-1α and CA IX were assessed using PCR. The functional effect of tumor-cell conditioned medium on the migration of neutrophil granulocytes (NG) was tested.

Results
Hypoxia caused increased migratory activity but not proliferation in all tumor cell lines, involving the release and autocrine action of soluble mediators. Conditioned medium (CM) from hypoxic cells induced migration in normoxic cells. Hypoxia changed the profile of released inflammatory mediators according to cell type. Interleukin-8 was produced only by post-EMT and basal-like cell lines, regardless of hypoxia. MCP-1 was produced by MDA-MB-435 and -468 cells, whereas IL-6 was present only in MDA-MB-231. IL-2, TNF-α, and NGF production was stimulated by hypoxia in MCF-7 cells. CM from normoxic and hypoxic MDA-MB-231 and MDA-MB-435S cells and hypoxic MCF-7 cells, but not MDA-MB-468, induced NG migration.

Conclusions
Hypoxia increases migration by the autocrine action of released signal substances in selected luminal and basal-like breast carcinoma cell lines which might explain why anti-angiogenic treatment can worsen clinical outcome in some patients.
Antigenic repertoire of Plasmodium vivax transmission-blocking vaccine candidates from the Indian subcontinent
Authors: Prajapati Surendra K , Joshi Hema , Dua Virendra K 
Published: May 2011

Abstract

Background
Genetic polymorphism is an inevitable component of a multistage infectious organism, such as the malaria parasite. By means of genetic polymorphism, parasite opts particular polymorph and reveals survival advantage. Pvs25 and pvs28 are sexual stage antigen genes, expressed at the ookinete stage inside the mosquito gut, and considered as potential transmission-blocking vaccine candidates. This study presents sequence variations in two important transmission blocking antigen genes pvs25 and pvs28 in the field isolates of P. vivax from the Indian subcontinent.

Methods
One hundred microscopically diagnosed P. vivax isolates were collected from five geographical regions of India. Pvs25 and pvs28 genes were PCR amplified and sequenced to assess sequence variation among field isolates.

Results
A total of 26 amino acid substitutions were observed in Pvs25 (10) and Pvs28 (16) among field isolates of P. vivax. Tandem repeat polymorphism observed in pvs28 shows 3-6 tandem repeats in the field isolates. Seven and eight novel amino acid substitutions were observed in Pvs25 and Pvs28, respectively in Indian isolates. Comparison of amino acid substitutions suggests that majority of substitutions observed in global isolates were also present in Indian subcontinent. A single haplotype was observed to be major haplotype among isolates of Delhi, Nadiad, Chennai and Panna except in isolates of Kamrup. Further, population comparison analyses suggest that P. vivax isolates inhabiting in north-eastern region (Kamrup) were distantly related with the isolates from remaining parts of the country. Majority of the amino acid substitutions observed in Indian isolates were more identical to the substitutions reported from isolates of Thailand and Bangladesh.

Conclusion
Study uncovered many new amino acid substitutions as well as a predominance of single haplotype in Indian subcontinent except in north-eastern region of the country. The amino acid substitutions data generated in this study from different geographical regions of the Indian subcontinent could be helpful in designing a more effective anti-malarial transmission-blocking vaccine.
MDM2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer
Authors: Tovar Christian , Higgins Brian , Kolinsky Kenneth , Xia Mingxuan , Packman Kathryn , Heimbrook David C , Vassilev Lyubomir T 
Published: May 2011

Abstract

Background
Hormone therapy is the standard of care for newly diagnosed or recurrent prostate cancers. It uses anti-androgen agents, castration, or both to eliminate cancer promoting effect of testicular androgen. The p53 tumor suppressor controls a major pathway that can block cell proliferation or induce apoptosis in response to diverse forms of oncogenic stress. Activation of the p53 pathway in cancer cells expressing wild-type p53 has been proposed as a novel therapeutic strategy and recently developed MDM2 antagonists, the nutlins, have validated this in preclinical models of cancer. The crosstalk between p53 and androgen receptor (AR) signaling suggest that p53 activation could augment antitumor outcome of androgen ablation in prostate cancer. Here, we test this hypothesis in vitro and in vivo using the MDM2 antagonist, nutlin-3 and the p53 wild-type prostate cancer cell line, LNCaP.

Results
Using charcoal-stripped serum as a cellular model of androgen deprivation, we show an increased apoptotic effect of p53 activation by nutlin-3a in the androgen-dependent LNCaP cells and to a lesser extent in androgen-independent but responsive 22Rv1 cell line. This effect is due, at least in part, to an enhanced downregulation of AR expression by activated p53. In vivo, androgen deprivation followed by two weeks of nutlin administration in LNCaP-bearing nude mice led to a greater tumor regression and dramatically increased survival.

Conclusions
Since majority of prostate tumors express wild-type p53, its activation by MDM2 antagonists in combination with androgen depletion may offer an efficacious new approach to prostate cancer therapy.
Should Global Burden of Disease Estimates Include Depression as a Risk Factor for Coronary Heart Disease?
Authors: Charlson Fiona J , Stapelberg Nicholas JC , Baxter Amanda J , Whiteford Harvey A 
Published: May 2011

Abstract
The 2010 Global Burden of Disease Study estimates the premature mortality and disability of all major diseases and injuries. In addition it aims to quantify the risk that diseases and other factors play in the aetiology of disease and injuries. Mental disorders and coronary heart disease are both significant public health issues due to their high prevalence and considerable contribution to global disease burden. For the first time the Global Burden of Disease Study will aim to assess mental disorders as risk factors for coronary heart disease. We show here that current evidence satisfies established criteria for considering depression as an independent risk factor in development of coronary heart disease. A dose response relationship appears to exist and plausible biological pathways have been proposed. However, a number of challenges exist when conducting a rigorous assessment of the literature including heterogeneity issues, definition and measurement of depression and coronary heart disease, publication bias and residual confounding. Therefore, despite some limitations in the available data, it is now appropriate to consider major depression as a risk factor for coronary heart disease in the new Global Burden of Disease Study.
Antiviral activity of α-helical stapled peptides designed from the HIV-1 capsid dimerization domain
Authors: Zhang Hongtao , Curreli Francesca , Zhang Xihui , Bhattacharya Shibani , Waheed Abdul A , Cooper Alan , Cowburn David , Freed Eric O , Debnath Asim K 
Published: May 2011

Abstract

Background
The C-terminal domain (CTD) of HIV-1 capsid (CA), like full-length CA, forms dimers in solution and CTD dimerization is a major driving force in Gag assembly and maturation. Mutations of the residues at the CTD dimer interface impair virus assembly and render the virus non-infectious. Therefore, the CTD represents a potential target for designing anti-HIV-1 drugs.

Results
Due to the pivotal role of the dimer interface, we reasoned that peptides from the α-helical region of the dimer interface might be effective as decoys to prevent CTD dimer formation. However, these small peptides do not have any structure in solution and they do not penetrate cells. Therefore, we used the hydrocarbon stapling technique to stabilize the α-helical structure and confirmed by confocal microscopy that this modification also made these peptides cell-penetrating. We also confirmed by using isothermal titration calorimetry (ITC), sedimentation equilibrium and NMR that these peptides indeed disrupt dimer formation. In in vitro assembly assays, the peptides inhibited mature-like virus particle formation and specifically inhibited HIV-1 production in cell-based assays. These peptides also showed potent antiviral activity against a large panel of laboratory-adapted and primary isolates, including viral strains resistant to inhibitors of reverse transcriptase and protease.

Conclusions
These preliminary data serve as the foundation for designing small, stable, α-helical peptides and small-molecule inhibitors targeted against the CTD dimer interface. The observation that relatively weak CA binders, such as NYAD-201 and NYAD-202, showed specificity and are able to disrupt the CTD dimer is encouraging for further exploration of a much broader class of antiviral compounds targeting CA. We cannot exclude the possibility that the CA-based peptides described here could elicit additional effects on virus replication not directly linked to their ability to bind CA-CTD.