bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling the Flash Rate of Thunderstorms. Part II: Implementation
Authors: Dahl Johannes M. L. , Höller Hartmut , Schumann Ulrich 
Published: June 2011

Abstract
In Part I of this two-part paper a new method of predicting the total lightning flash rate in thunderstorms was introduced. In this paper, the implementation of this method into the convection-permitting Consortium for Small Scale Modeling (COSMO) model is presented.
The new approach is based on a simple theoretical model that consists of a dipole charge structure, which is maintained by a generator current and discharged by lightning and, to a small extent, by a leakage current. This approach yields a set of four predictor variables, which are not amenable to direct observations and consequently need to be parameterized (Part I).
Using an algorithm that identifies thunderstorm cells and their properties, this approach is applied to determine the flash frequency of every thunderstorm cell in the model domain. With this information, the number of flashes that are accumulated by each cell and during the interval between the activation of the lightning scheme can be calculated.
These flashes are then randomly distributed in time and beneath each cell. The output contains the longitude, the latitude, and the time of occurrence of each simulated discharge.
Simulations of real-world scenarios are presented, which are compared to measurements with the lightning detection network, LINET. These comparisons are done on the cloud scale as well as in a mesoscale region composing southern Germany (two cases each). The flash rates of individual cumulonimbus clouds at the extreme ends of the intensity spectrum are realistically simulated. The simulated overall lightning activity over southern Germany is dominated by spatiotemporal displacements of the modeled convective clouds, although the scheme generally reproduces realistic patterns such as coherent lightning swaths.
Verification of Operational Analyses Using an Extremely High-Density Surface Station Network
Authors: Kann Alexander , Haiden Thomas , von der Emde Klaus , Gruber Christine , Kabas Thomas , Leuprecht Armin , Kirchengast Gottfried 
Published: June 2011

Abstract
Operational analyses of 2-m temperature, 2-m humidity, and 10-m wind speed are verified independently against observations obtained from the WegenerNet, an extremely high-density, grid-type surface station network in southeastern Austria with an average distance between stations of 1.4 km. The Integrated Nowcasting through Comprehensive Analysis (INCA) system provides high-resolution analyses in space (1 km) and time (1 h) over the eastern Alpine region and has been specially designed for use in complex terrain. The quality of the system is investigated within a small domain with gentle topography ranging in elevation from 250 to 500 m. A comprehensive validation of INCA relative to WegenerNet for a 3-yr period from December 2007 to November 2010 indicates high analysis skill during all seasons. A sensitivity study reveals the importance of a sufficiently dense station network used by the system and, even more important, the relevance of adequate representativeness of the observation data.
Association between Cerebrospinal Fluid Leak and Meningitis after Skull Base Surgery
Authors: Horowitz Gilad , Fliss Dan M. , Margalit Nevo , Wasserzug Oshri , Gil Ziv 
Published: June 2011

BackgroundMeningitis and cerebrospinal fluid (CSF) leak are serious complications of skull base surgery, but whether postoperative CSF leak increases the risk of meningitis is unknown.ObjectiveTo evaluate any association between meningitis and CSF leak after open or endoscopic skull base resection.Study Design and SettingA retrospective case series with chart review in a tertiary care university‐affiliated medical center.MethodsA total of 156 patients underwent intradural tumor resection in our institution between 1994 and 2009, 135 (86%) via the subcranial approach and 21 (14%) through the expanded endonasal approach. All occurrences of meningitis, brain abscess, and CSF leak had been recorded and were available for analysis.ResultsNine patients (5.7%) had postoperative meningitis, and 3 patients had postoperative CSF leak (1.9%). The risk of meningitis in patients without CSF leak was 4.5% (7/153) compared to 66% (2/3) in those with CSF leak. A statistical analysis revealed a significant association between CSF leak and meningitis, with a relative risk of 14.6 (95% confidence interval, 4.95‐42; P =. 008).ConclusionPostoperative CSF leak significantly increases the risk of meningitis. Most cases of meningitis after skull base operation are probably associated with lumbar drainage infection or from an obscure leak.
Septal Perforation Repairing with Combination of Mucosal Flaps and Auricular Interpositional Grafts in Revision Patients
Authors: Taskin Umit , Yigit Ozgur , Sisman Sezim A. 
Published: June 2011

ObjectivesTo examine the closure of nasal septal perforations with bilateral nasal floor flaps combined with auricular cartilage grafts and a normally functioning nose in revision patients.Study DesignCase series with chart review.SettingA tertiary referral hospital in Turkey.Subjects and MethodsSeventeen patients (11 men, 6 women) with nasal septal reperforation were treated surgically using combined bilateral nasal floor mucosal flaps with bilateral auricular cartilage interpositional grafts.ResultsThe mean follow‐up was 15.2 (range, 9‐28) months. The average anteroposterior diameter of perforation was 28 ± 3 (range, 20‐38) mm, and the average vertical diameter was 23 ± 8 (range, 20‐27) mm at the widest site. The nasal septal perforations were closed completely in 16 cases; in 1 case, the perforation was not repaired completely.ConclusionsA successful multilayer closure technique with good exposure was applied in patients with reperforation.
Analysis of glycoprotein E-selectin ligands on human and mouse marrow cells enriched for hematopoietic stem/progenitor cells
Authors: Merzaban Jasmeen S. , Burdick Monica M. , Gadhoum S. Zeineb , Dagia Nilesh M. , Chu Julia T. , Fuhlbrigge Robert C. , Sackstein Robert 
Published: June 2011

AbstractAlthough well recognized that expression of E-selectin on marrow microvessels mediates osteotropism of hematopoietic stem/progenitor cells (HSPCs), our knowledge regarding the cognate E-selectin ligand(s) on HSPCs is incomplete. Flow cytometry using E-selectin-Ig chimera (E-Ig) shows that human marrow cells enriched for HSPCs (CD34+ cells) display greater E-selectin binding than those obtained from mouse (lin−/Sca-1+/c-kit+ [LSK] cells). To define the relevant glycoprotein E-selectin ligands, lysates from human CD34+ and KG1a cells and from mouse LSK cells were immunoprecipitated using E-Ig and resolved by Western blot using E-Ig. In both human and mouse cells, E-selectin ligand reactivity was observed at ∼ 120- to 130-kDa region, which contained two E-selectin ligands, the P-selectin glycoprotein ligand-1 glycoform “CLA,” and CD43. Human, but not mouse, cells displayed a prominent ∼ 100-kDa band, exclusively comprising the CD44 glycoform “HCELL.” E-Ig reactivity was most prominent on CLA in mouse cells and on HCELL in human cells. To further assess HCELL's contribution to E-selectin adherence, complementary studies were performed to silence (via CD44 siRNA) or enforce its expression (via exoglycosylation). Under physiologic shear conditions, CD44/HCELL-silenced human cells showed striking decreases (> 50%) in E-selectin binding. Conversely, enforced HCELL expression of LSK cells profoundly increased E-selectin adherence, yielding > 3-fold more marrow homing in vivo. These data define the key glycoprotein E-selectin ligands of human and mouse HSPCs, unveiling critical species-intrinsic differences in both the identity and activity of these structures.
A switch toward angiostatic gene expression impairs the angiogenic properties of endothelial progenitor cells in low birth weight preterm infants
Authors: Ligi Isabelle , Simoncini Stéphanie , Tellier Edwige , Vassallo Paula Frizera , Sabatier Florence , Guillet Benjamin , Lamy Edouard , Sarlon Gabrielle , Quemener Cathy , Bikfalvi Andreas , Marcelli Maxime , Pascal Alain , Dizier Blandine , Simeoni Umberto , Dignat-George Françoise , Anfosso Francine 
Published: June 2011

Abstract
Low birth weight (LBW) is associated with increased risk of cardiovascular diseases at adulthood. Nevertheless, the impact of LBW on the endothelium is not clearly established. We investigate whether LBW alters the angiogenic properties of cord blood endothelial colony forming cells (LBW-ECFCs) in 25 preterm neonates compared with 25 term neonates (CT-ECFCs). We observed that LBW decreased the number of colonies formed by ECFCs and delayed the time of appearance of their clonal progeny. LBW dramatically reduced LBW-ECFC capacity to form sprouts and tubes, to migrate and to proliferate in vitro. The angiogenic defect of LBW-ECFCs was confirmed in vivo by their inability to form robust capillary networks in Matrigel plugs injected in nu/nu mice. Gene profile analysis of LBW-ECFCs demonstrated an increased expression of antiangiogenic genes. Among them, thrombospondin 1 (THBS1) was highly expressed at RNA and protein levels in LBW-ECFCs. Silencing THBS1 restored the angiogenic properties of LBW-ECFCs by increasing AKT phosphorylation. The imbalance toward an angiostatic state provide a mechanistic link between LBW and the impaired angiogenic properties of ECFCs and allows the identification of THBS1 as a novel player in LBW-ECFC defect, opening new perspectives for novel deprogramming agents.
Association of natural anti-platelet factor 4/heparin antibodies with periodontal disease
Authors: Greinacher Andreas , Holtfreter Birte , Krauel Krystin , Gätke Daniela , Weber Claudia , Ittermann Till , Hammerschmidt Sven , Kocher Thomas 
Published: June 2011

Abstract
Platelet factor 4 (PF4) and heparin (H) form PF4/H complexes, the target of the immune reaction in heparin-induced thrombocytopenia (HIT). HIT seems to be a secondary immune response as anti-PF4/H-IgG antibodies occur as early as day 4 of heparin treatment. This study investigated whether prevalent infections such as periodontitis may induce the PF4/H immune response as: (1) natural anti-PF4/H Abs are present in the normal population; (2) PF4 bound to bacteria exposes the same antigen(s) as PF4/H complexes; and (3) sepsis induces PF4/H Abs in mice. We found PF4 bound to periodontal pathogens (Aggregatibacter actinomycetemcomitans; Porphyromonas gingivalis) enabling subsequent binding of human anti-PF4/H Abs. The association of natural PF4/H Abs and periodontitis was assessed in a case-control study, enrolling individuals with natural anti-PF4/H Abs (n = 40 matched pairs), and in the cross-sectional population-based Study of Health in Pomerania (SHIP; n = 3500). Both studies showed a robust association between periodontitis and presence of anti-PF4/H Abs independent of inflammation markers (case-control study: lowest vs highest tertile, odds ratio, 7.12 [95% confidence interval, 1.73-46.13; P = .005]; SHIP study, ptrend ≤ 0.001). Thus, preimmunization to PF4/bacteria complexes by prevalent infections, for example, periodontitis, likely explains the presence of natural anti-PF4/heparin Abs and the early occurrence of anti-PF4/H-IgG in HIT.
Cost-effectiveness of three strategies for second-line erlotinib initiation in nonsmall-cell lung cancer: the ERMETIC study part 3
Authors: Borget I. , Cadranel J. , Pignon J-P. , Quoix E. , Coudert B. , Westeel V. , Dansin E. , Madelaine J. , Madroszyk A. , Friard S. , Daniel C. , Morin F. , Chouaid C. ,   the ERMETIC Collaborative Group
Published: June 2011

Several clinical and biological parameters are known to influence the efficacy of second-line erlotinib therapy for nonsmall cell lung cancer (NSCLC), but their medico-economic impact has not been evaluated. The objective of this study was to compare the incremental cost-effectiveness ratios of strategies for second-line erlotinib initiation in NSCLC: clinically guided initiation (nonsmoking females with adenocarcinoma received erlotinib; all other patients received docetaxel) and biologically guided selection (patients with epidermal growth factor receptor (EGFR) mutation received erlotinib; patients with wild-typeEGFRor unknown status received docetaxel), compared with initiation with no patient selection (strategy reference).A Markov model was constructed. Outcomes (overall and progression-free survival), transition probabilities and direct medical costs (from the French third-party payer's perspective) were prospectively collected for individual patients treated with either erlotinib or docetaxel, from treatment initiation to disease progression. Published data were used to estimate utilities and post-progression costs. Sensitivity analyses were performed.The biologically and clinically guided strategies were both more efficient (incremental quality-adjusted life-yrs equal to 0.080 and 0.081, respectively) and less expensive (cost decrease equal to €5,020 and €5,815, respectively) than the no-selection strategy, and the biologically guided strategy was slightly less expensive than the clinically guided strategy. Sensitivity analyses confirmed the robustness of the results.The cost-effectiveness of second-line NSCLC treatment is improved when patients are selected on either clinical or biological grounds.
The two tryptophans of β2-microglobulin have distinct roles in function and folding and might represent two independent responses to evolutionary pressure
Authors: Raimondi Sara , Barbarini Nicola , Mangione Palma , Esposito Gennaro , Ricagno Stefano , Bolognesi Martino , Zorzoli Irene , Marchese Loredana , Soria Cristina , Bellazzi Riccardo , Monti Maria , Stoppini Monica , Stefanelli Mario , Magni Paolo , Bellotti Vittorio 
Published: June 2011

Abstract

Background
We have recently discovered that the two tryptophans of human β2-microglobulin have distinctive roles within the structure and function of the protein. Deeply buried in the core, Trp95 is essential for folding stability, whereas Trp60, which is solvent-exposed, plays a crucial role in promoting the binding of β2-microglobulin to the heavy chain of the class I major histocompatibility complex (MHCI). We have previously shown that the thermodynamic disadvantage of having Trp60 exposed on the surface is counter-balanced by the perfect fit between it and a cavity within the MHCI heavy chain that contributes significantly to the functional stabilization of the MHCI. Therefore, based on the peculiar differences of the two tryptophans, we have analysed the evolution of β2-microglobulin with respect to these residues.

Results
Having defined the β2-microglobulin protein family, we performed multiple sequence alignments and analysed the residue conservation in homologous proteins to generate a phylogenetic tree. Our results indicate that Trp60 is highly conserved, whereas some species have a Leu in position 95; the replacement of Trp95 with Leu destabilizes β2-microglobulin by 1 kcal/mol and accelerates the kinetics of unfolding. Both thermodynamic and kinetic data fit with the crystallographic structure of the Trp95Leu variant, which shows how the hydrophobic cavity of the wild-type protein is completely occupied by Trp95, but is only half filled by Leu95.

Conclusions
We have established that the functional Trp60 has been present within the sequence of β2-microglobulin since the evolutionary appearance of proteins responsible for acquired immunity, whereas the structural Trp95 was selected and stabilized, most likely, for its capacity to fully occupy an internal cavity of the protein thereby creating a better stabilization of its folded state.
Liposome-based DNA carriers may induce cellular stress response and change gene expression pattern in transfected cells
Authors: Fiszer-Kierzkowska Anna , Vydra Natalia , Wysocka-Wycisk Aleksandra , Kronekova Zuzana , Jarząb Michał , Lisowska Katarzyna Marta , Krawczyk Zdzisław 
Published: June 2011

AbstractBackgroundDuring functional studies on the rat stress-inducibleHspa1b(hsp70.1) gene we noticed that some liposome-based DNA carriers, which are used for transfection, induce its promoter activity. This observation concerned commercial liposome formulations (LA), Lipofectin and Lipofectamine 2000. This work was aimed to understand better the mechanism of this phenomenon and its potential biological and practical consequences.ResultsWe found that a reporter gene driven byHspa1bpromoter is activated both in the case of transient transfections and in the stably transfected cells treated with LA. Using several deletion clones containing different fragments ofHspa1bpromoter, we found that the regulatory elements responsible for most efficient LA-driven inducibility were located between nucleotides -269 and +85, relative to the transcription start site. Further studies showed that the induction mechanism was independent of the classical HSE-HSF interaction that is responsible for gene activation during heat stress. Using DNA microarrays we also detected significant activation of the endogenousHspa1bgene in cells treated with Lipofectamine 2000. Several other stress genes were also induced, along with numerous genes involved in cellular metabolism, cell cycle control and pro-apoptotic pathways.ConclusionsOur observations suggest that i) some cationic liposomes may not be suitable for functional studies onhsppromoters, ii) lipofection may cause unintended changes in global gene expression in the transfected cells.
GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells
Authors: Abrhale Tesfom , Brodie Angela , Sabnis Gauri , Macedo Luciana , Tian Changsheng , Yue Binbin , Serrero Ginette 
Published: June 2011

AbstractBackgroundAromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER+) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+breast cancer cellsMethodsWe used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined.ResultsGP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole.ConclusionOur findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+breast cancer.
Comparative study of clinical grade human tolerogenic dendritic cells
Authors: Naranjo-Gómez M , Raïch-Regué D , Oñate C , Grau-López L , Ramo-Tello C , Pujol-Borrell R , Martínez-Cáceres E , Borràs Francesc E 
Published: June 2011

AbstractBackgroundThe use of tolerogenic DCs is a promising therapeutic strategy for transplantation and autoimmune disorders. Immunomodulatory DCs are primarily generated from monocytes (MDDCs) forin vitroexperiments following protocols that fail to fulfil the strict regulatory rules of clinically applicable products. Here, we compared the efficacy of three different tolerance-inducing agents, dexamethasone, rapamycin and vitamin D3, on DC biology using GMP (Good Manufacturing Practice) or clinical grade reagents with the aim of defining their use for human cell therapy.MethodsTolerogenic MDDCs were generated by adding tolerogenic agents prior to the induction of maturation using TNF-α, IL-β and PGE2. We evaluated the effects of each agent on viability, efficiency of differentiation, phenotype, cytokine secretion and stability, the stimulatory capacity of tol-DCs and the T-cell profiles induced.ResultsDifferences relevant to therapeutic applicability were observed with the cellular products that were obtained. VitD3-induced tol-DCs exhibited a slightly reduced viability and yield compared to Dexa-and Rapa-tol-DCs. Phenotypically, while Dexa-and VitD3-tol-DCs were similar to immature DCs, Rapa-tol-DCs were not distinguishable from mature DCs. In addition, only Dexa-and moderately VitD3-tol-DCs exhibited IL-10 production. Interestingly, in all cases, the cytokine secretion profiles of tol-DCs were not modified by a subsequent TLR stimulation with LPS, indicating that all products had stable phenotypes. Functionally, clearly reduced alloantigen T cell proliferation was induced by tol-DCs obtained using any of these agent. Also, total interferon-gamma (IFN-γ) secretion by T cells stimulated with allogeneic tol-DCs was reduced in all three cases, but only T cells co-cultured with Rapa-tol-DCs showed impaired intracellular IFN-γ production. In addition, Rapa-DCs promoted CD4+ CD127 low/negative CD25high and Foxp3+ T cells.ConclusionsOur results demonstrate contrasting influences of different clinical-grade pharmacological agents on human tol-DC generation. This should be taken into account for decisions on the use of a specific agent for the appropriate cellular therapy in the context of a particular disease.
Assessing causal relationships in genomics: From Bradford-Hill criteria to complex gene-environment interactions and directed acyclic graphs
Authors: Geneletti Sara , Gallo Valentina , Porta Miquel , Khoury Muin J , Vineis Paolo 
Published: June 2011

AbstractObservational studies of human health and disease (basic, clinical and epidemiological) are vulnerable to methodological problems -such as selection bias and confounding- that make causal inferences problematic. Gene-disease associations are no exception, as they are commonly investigated using observational designs. A rich body of knowledge exists in medicine and epidemiology on the assessment of causal relationships involving personal and environmental causes of disease; it includes seminal causal criteria developed by Austin Bradford Hill and more recently applied directed acyclic graphs (DAGs). However, such knowledge has seldom been applied to assess causal relationships in clinical genetics and genomics, even in studies aimed at making inferences relevant for human health. Conversely, incorporating genetic causal knowledge into clinical and epidemiological causal reasoning is still a largely unexplored area.As the contribution of genetics to the understanding of disease aetiology becomes more important, causal assessment of genetic and genomic evidence becomes fundamental. The method we develop in this paper provides a simple and rigorous first step towards this goal. The present paper is an example of integrative research, i.e., research that integrates knowledge, data, methods, techniques, and reasoning from multiple disciplines, approaches and levels of analysis to generate knowledge that no discipline alone may achieve.