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  • 1
    Language: English
    In: Combustion and Flame, January 2014, Vol.161(1), pp.240-255
    Description: High-speed fuel, flow, and flame imaging are combined with spark discharge measurements to investigate the causes of rare misfires and partial burns in a spray-guided spark-ignited direct-injection (SG-SIDI) engine over a range of nitrogen dilution levels (0–26% by volume). Planar laser induced fluorescence (PLIF) of biacetyl is combined with planar particle image velocimetry (PIV) to provide quantitative measurements of equivalence ratio and flow velocity within the tumble plane of an optical engine. Mie scattering images used for PIV are also used to identify the enflamed region to resolve the flame development. Engine parameters were selected to mimic low-load idle operating conditions with stratified fuel injection, which provided stable engine performance with the occurrence of rare misfire and partial burn cycles. Nitrogen dilution was introduced into the intake air, thereby displacing the oxygen, which destabilized combustion and increased the occurrence of poor burning cycles. Spark measurements revealed that all cycles exhibited sufficient spark energy and duration for successful ignition. High-speed PLIF, PIV, and Mie scattering images were utilized to analyze the spatial and temporal evolution of the fuel distribution and flow velocity on flame kernel development to better understand the nature of poor burning cycles at each dilution level. The images revealed that all cycles exhibited a flammable mixture near the spark plug at spark timing and a flame kernel was present for all cycles, but the flame failed to develop for misfire and partial burn cycles. Improper flame development was caused by slow flame propagation which prevented the flame from consuming the bulk of the fuel mixture within the piston bowl, which was a crucial step to achieve further combustion. The mechanisms identified in this work that caused slower flame development are: (1) lean mixtures, (2) external dilution, and (3) convection velocities that impede transport of the flame into the fuel mixture.
    Keywords: Misfires ; Ignition and Flame Stability ; Spark-Ignition Engines ; High-Speed Imaging ; Particle Image Velocimetry ; Planar Laser Induced Fluorescence ; Engineering ; Chemistry
    ISSN: 0010-2180
    E-ISSN: 1556-2921
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  • 2
    In: Nature, 2018
    Description: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
    Keywords: DNA Methylation ; Central Nervous System Neoplasms -- Diagnosis;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
    Language: English
    In: PLoS ONE, 2010, Vol.5(7), p.e11858
    Description: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive tumors which originate from Schwann cells and develop in about 10% of neurofibromatosis type 1 (NF1) patients. The five year survival rate is poor and more effective therapies are needed. Sunitinib is a drug targeting receptor tyrosine kinases (RTK) like PDGFRα, c-Kit and VEGFR-2. These genes are structurally related and cluster on chromosomal segment 4q12. ; Here we characterize this region by multiplex ligation-dependent probe amplification (MLPA) in MPNST. Our probe set encompasses the 3 adjacent RTK genes (, , ) and 6 flanking genes. We found amplification of several genes within this region in a subset of MPNST and MPNST cell lines. Transcript and protein expression of matched well with its increased copy number suggesting a central role of within the amplicon. Studying the effect of sunitinib on 5 MPNST cell lines revealed that cell line S462 harboring the 4q12 amplicon was extremely sensitive to the drug with an IC below 1.0µM. Moreover, sunitinib induced apoptosis and prevented PDGF-AA induced signaling via PDGFRα as determined by western blotting. Co-expression of VEGF and its receptor VEGFR-2 () was present in MPNST cell lines suggesting an autocrine loop. We show that VEGF triggered signal transduction via the MAPK pathway, which could be blocked by sunitinib. ; Since multiple receptors targeted by sunitinib are expressed or over-expressed by MPNST cells sunitinib appears as an attractive drug for treatment of MPNST patients. Presence of the 4q12 amplicon and subsequent over-expression of might serve as predictive markers for efficacy of sunitinib.
    Keywords: Research Article ; Oncology ; Oncology -- Neuro-oncology ; Oncology -- Oncology Agents
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Experiments in Fluids, Oct, 2011, Vol.51(4), p.1139(13)
    Description: Byline: Hao Chen (1), David L. Reuss (2), Volker Sick (1,2,3) Abstract: Previous work demonstrated that the occasional misfired and partially burned cycles (MF) in a stratified-charge, spark-ignited direct injection engine always achieved an early flame kernel, but failed to reach and inflame the fuel in the bottom of the piston bowl. This conclusion was derived from intra-cycle crank angle resolved velocity and fuel concentration images that were recorded simultaneously using high-speed particle image velocimetry and planar laser-induced fluorescence. In this study, both ensemble average analysis, conditionally sampled on either MF or Well Burned (WB) cycles and proper orthogonal decomposition (POD) are applied separately to the velocity and fuel distributions. POD of the velocity and fuel distributions near the spark plug were performed, and the mode energy and structure of the modes are compared. This analysis is used to assess the similarity and differences between the MF and the WB cycles and to identify physical insight gained by POD. The POD modes were determined from the combined set of 200 WB and 37 MF cycles to create two sets of 237 orthogonal modes, one set for the velocity, V, and one for the equivalence ratio, [epsilon]. Then, conditionally sampled averages of the POD coefficients could be used to quantify the extent to which each mode contributed to the MFs. Also, the probability density functions of the coefficients quantified the cyclic variability of each mode's contribution. The application of proper orthogonal decomposition to velocity and equivalence ratio images was useful in identifying and analyzing the differences in flow and mixture conditions at the time of spark between well-burning and misfiring cycles. However, POD results alone were not sufficient to identify which of the cycles were misfiring cycles, and additional information was required for conditional sampling. Author Affiliation: (1) Shanghai Jiao Tong University, Shanghai, China (2) The University of Michigan, Ann Arbor, MI, USA (3) Center of Smart Interfaces, TU Darmstadt, Darmstadt, Germany Article History: Registration Date: 26/05/2011 Received Date: 22/12/2010 Accepted Date: 26/05/2011 Online Date: 12/06/2011
    Keywords: Fluorescence -- Analysis ; Internal Combustion Engines -- Analysis
    ISSN: 0723-4864
    E-ISSN: 14321114
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  • 5
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(2), p.e57152
    Description: Malignant peripheral nerve sheath tumor (MPNST) is a rare aggressive form of sarcoma often associated with the tumor syndrome neurofibromatosis type 1 (NF1). We investigated the effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) on NF1 associated MPNST and determinants of TRAIL sensitivity. MPNST cell lines with complete neurofibromin deficiency were sensitive to apoptotic cell death induced by TRAIL whereas MPNST cells with retained neurofibromin expression or normal human Schwann cells were resistant. Increased sensitivity to TRAIL was associated with overexpression of death receptors, especially DR5. Re-expression of the GAP related domain of neurofibromin (NF1-GRD) suppressed DR5 expression and decreased sensitivity to TRAIL. We show that death receptor expression and TRAIL sensitivity critically depend on c-MYC and that c-MYC amounts are increased by MEK/ERK and PI3K/AKT signalling pathways which are suppressed by neurofibromin. Furthermore PI3K/AKT signalling strongly suppresses the MYC-antagonist MAD1 which significantly contributes to TRAIL sensitivity. Re-expression of the NF1-GRD decreased c-MYC and increased MAD1 amounts suggesting that neurofibromin influences TRAIL sensitivity at least in part by modulating the MYC/MAX/MAD network. The phytochemical curcumin further increased the sensitivity of neurofibromin deficient MPNST cells to TRAIL. This was presumably mediated by ROS, as it correlated with increased ROS production, was blocked by N-acetylcysteine and mimicked by exogenous ROS.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: 2012, Vol.7(11), p.e47595
    Description: Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that develop in about 10% of patients with the genetic disease neurofibromatosis type 1 (NF1). Molecular alterations contributing to MPNST formation have only partially been resolved. Here we examined the role of Pten, a key regulator of the Pi3k/Akt/mTOR pathway, in human MPNST and benign neurofibromas. Immunohistochemistry showed that Pten expression was significantly lower in MPNST (n = 16) than in neurofibromas (n = 16) and normal nervous tissue. To elucidate potential mechanisms for Pten down-regulation or Akt/mTOR activation in MPNST we performed further experiments. Mutation analysis revealed absence of somatic mutations in PTEN (n = 31) and PIK3CA (n = 38). However, we found frequent PTEN promotor methylation in primary MPNST (11/26) and MPNST cell lines (7/8) but not in benign nerve sheath tumours. PTEN methylation was significantly associated with early metastasis. Moreover, we detected an inverse correlation of Pten-regulating miR-21 and Pten protein levels in MPNST cell lines. The examination of NF1 −/− and NF1 +/+Schwann cells and fibroblasts showed that Pten expression is not regulated by NF1 . To determine the significance of Pten status for treatment with the mTOR inhibitor rapamycin we treated 5 MPNST cell lines with rapamycin. All cell lines were sensitive to rapamycin without a significant correlation to Pten levels. When rapamycin was combined with simvastatin a synergistic anti-proliferative effect was achieved. Taken together we show frequent loss/reduction of Pten expression in MPNST and provide evidence for the involvement of multiple Pten regulating mechanisms.
    Keywords: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Oncology
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(7), p.e69209
    Description: Nibrin (NBN or NBS1) and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair. Mutations in NBN or ATM result in Nijmegen Breakage Syndrome and Ataxia telangiectasia. These syndromes share common features such as radiosensitivity, neurological developmental defects and cancer predisposition. However, the functional synergy of Nbn and Atm in different tissues and developmental stages is not yet understood. Here, we show in vivo consequences of conditional inactivation of both genes in neural stem/progenitor cells using Nestin-Cre mice. Genetic inactivation of Atm in the central nervous system of Nbn-deficient mice led to reduced life span and increased DSBs, resulting in increased apoptosis during neural development. Surprisingly, the increase of DSBs and apoptosis was found only in few tissues including cerebellum, ganglionic eminences and lens. In sharp contrast, we showed that apoptosis associated with Nbn deletion was prevented by simultaneous inactivation of Atm in developing retina. Therefore, we propose that Nbn and Atm collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: SAE International Journal of Fuels and Lubricants, 2012, Vol.5(3), pp.1096-1113
    Description: ABSTRACT The lean-burn stratified-charge DISI engine has a strong potential for increased thermal efficiency compared to the traditional throttled SI engine. This experimental study of a spray-guided stratified-charge combustion system compares the engine response to injection-timing retard for gasoline and E85. Focus is on engine-out NO and soot, and combustion stability. The results show that for either fuel, injection-timing retard lowers the engine-out NO emissions. This is partly attributed to a combination of lower peak-combustion temperatures and shorter residence time at high temperatures, largely caused by a more retarded combustion phasing. However, for the current conditions using a single-injection strategy, the potential of NO reduction with gasoline is limited by both elevated soot emissions and the occurrence of misfire cycles. In strong contrast, when E85 fuel is used, the combustion system responds very well to injection-timing retard. By using near-TDC injection of E85 ultra-low emissions of NO can be achieved. Despite the low NO emissions, both combustion efficiency and stability remain relatively high, but a mitigation of partial-burn cycles is desirable. One striking aspect of engine operation with near-TDC injection of E85 is the requirement and ability to ignite the head of one of the penetrating fuel jets. This early ignition results in a relatively short time delay between the end of the injection event and CA50. The closely-coupled injection and ignition lead to a combustion event that visually appears to have a finer structure, possibly indicative of a higher turbulence level during combustion. Furthermore, for gasoline it was not possible to operate with near-TDC injection to achieve very low NO emissions since gasoline required spark ignition at the end of the injection event. Modeling of fuel vaporization and mixing suggests that the gas-phase equivalence ratio is too high for gasoline to allow stable ignition of the head of one of the fuel jets. For E85, the model shows that the high heat of vaporization prevents the formation of ultra-rich gas-phase mixtures, which together with the high oxygen content of the fuel might explain the ability to ignite the E85 fuel jet during the injection event. Flame modeling in CHEMKIN shows that the strong vaporization cooling of ethanol suppresses the flame speed in rich areas; together with the high oxygen content of the fuel, suppressed flame activity in rich zones could be an important contributor to the low soot emissions that are realized despite highly stratified and mixing-controlled combustion for near-TDC fuel injection. Direct comparison of stratified combustion with nearly identical heat-release rates for gasoline and E85 reveals 43% lower exhaust NO emissions for E85. This reduction of NO is attributed to two factors: 1) A reduction of the combustion-product temperatures due to strong vaporization cooling of ethanol in E85. 2) Increased post-combustion mixing rates caused by a more closely coupled injection and combustion event, and 52% more fuel injected due to the lower heating value of E85.
    Keywords: Nitrogen Oxides ; Spark Ignition Engines ; Fuel Injection;
    ISSN: 19463952
    E-ISSN: 19463960
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  • 9
    In: Brain, 2012, Vol. 135(5), pp.1622-1638
    Description: Classical paraneoplastic encephalitis syndromes with ‘onconeural’ antibodies directed to intracellular antigens, and the recently described paraneoplastic or non-paraneoplastic encephalitides and antibodies against both neural surface antigens (voltage-gated potassium channel-complexes, N -methyl- d -aspartate receptors) and intracellular antigens (glutamic acid decarboxylase-65), constitute an increasingly recognized group of immune-mediated brain diseases. Evidence for specific immune mechanisms, however, is scarce. Here, we report qualitative and quantitative immunopathology in brain tissue (biopsy or autopsy material) of 17 cases with encephalitis and antibodies to either intracellular (Hu, Ma2, glutamic acid decarboxylase) or surface antigenic targets (voltage-gated potassium channel-complex or N -methyl- d -aspartate receptors). We hypothesized that the encephalitides with antibodies against intracellular antigens (intracellular antigen-onconeural and intracellular antigen-glutamic acid decarboxylase groups) would show neurodegeneration mediated by T cell cytotoxicity and the encephalitides with antibodies against surface antigens would be antibody-mediated and would show less T cell involvement. We found a higher CD8/CD3 ratio and more frequent appositions of granzyme-B + cytotoxic T cells to neurons, with associated neuronal loss, in the intracellular antigen-onconeural group (anti-Hu and anti-Ma2 cases) compared to the patients with surface antigens (anti- N -methyl- d -aspartate receptors and anti-voltage-gated potassium channel complex cases). One of the glutamic acid decarboxylase antibody encephalitis cases (intracellular antigen-glutamic acid decarboxylase group) showed multiple appositions of GrB-positive T cells to neurons. Generally, however, the glutamic acid decarboxylase antibody cases showed less intense inflammation and also had relatively low CD8/CD3 ratios compared with the intracellular antigen-onconeural cases. Conversely, we found complement C9neo deposition on neurons associated with acute neuronal cell death in the surface antigen group only, specifically in the voltage-gated potassium channel-complex antibody patients. N -methyl- d -aspartate receptors-antibody cases showed no evidence of antibody and complement-mediated tissue injury and were distinguished from all other encephalitides by the absence of clear neuronal pathology and a low density of inflammatory cells. Although tissue samples varied in location and in the stage of disease, our findings strongly support a central role for T cell-mediated neuronal cytotoxicity in encephalitides with antibodies against intracellular antigens. In voltage-gated potassium channel-complex encephalitis, a subset of the surface antigen antibody encephalitides, an antibody- and complement-mediated immune response appears to be responsible for neuronal loss and cerebral atrophy; the apparent absence of these mechanisms in N -methyl- d -aspartate receptors antibody encephalitis is intriguing and requires further study.
    Keywords: Encephalitis ; Antibodies ; Pathogenic ; Cytotoxic T Lymphocytes ; Complement
    ISSN: 0006-8950
    E-ISSN: 1460-2156
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  • 10
    Language: English
    In: SAE International Journal of Engines, 2014, Vol.7(2), pp.642-655
    Description: ABSTRACT This study compares the role of the in-cylinder flow field for spray-guided stratified-charge combustion and for traditional well-mixed stoichiometric operation, both using E70 fuel. The in-cylinder flow field is altered by changing the engine speed between 1000 and 2000 rpm. The stratified operation with the ethanol blend enabled “head ignition” of the fuel sprays, thus minimizing the available fuel/air-mixing time prior to combustion, creating a highly stratified combustion event. For well-mixed stoichiometric operation, the heat-release rate (HRR) scales proportionally with engine speed due to increased in-cylinder turbulence, as is well-known from literature. In contrast, increasing the engine speed influences the stratified combustion process very differently. Ensemble-averaged over 500 cycles, the time-based HRR in kW remains comparatively unchanged as the engine speed increases. However, cyclic variability of the stratified combustion increases substantially with engine speed. These observations lead to the development of two hypotheses; a) For highly stratified spray-guided combustion, the heat-release rate of the main combustion phase is primarily controlled by mixing rates and turbulence level associated with fuel-jet penetration. b) During the main combustion phase, the role of the in-cylinder flow field generated by the intake and compression strokes is primarily its stochastic disturbance of the mixing and flow associated with the fuel jets, thereby causing cycle-to-cycle variations of the spray-guided stratified combustion. These hypotheses are supported by cycle-resolved heat-release analysis, and also by PIV measurements in a companion paper [1], which show that the magnitude of the flow variations increases with engine speed. This increased variability may explain the occurrence of partial-burn cycles at high engine speed. In particular, the in-cylinder flow frequently becomes sufficiently strong to disturb both fuel/air-mixing and flame spread, both being critically important for the heat-release rate of the highly stratified charge.
    Keywords: Fuel Injection ; Combustion / Combustion Processes;
    ISSN: 19463936
    E-ISSN: 19463944
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