Looking Under the Hood and Tinkering with Voter Cynicism: Ross Perot and “Perspective by Incongruity”

This essay examines Ross Perot’s 1992 presidential bid as a comic catalyst for a reinvigorated view of civic responsibility. Despite the Texas maverick’s political naiveté and penchant for miscalculation, his very presence in the campaign reanimated Americans’ conception of grassroots democracy. By examining important and previously unexplored distinctions between planned and unplanned incongruity, we probe the means by which Perot invited consideration of alternative political perspectives and offered an appealing glimpse into a dormant, more deeply held democratic ideal

Efecto de un nuevo xanthanólido sesquiterpeno sobre la activación de mastocitos inducida por neurópeptidos pro-inflamatorios

Los mastocitos son células del tejido conectivo que participan en la génesis y modulación de las respuestas inflamatorias celulares. En trabajos previos hemos demostrado que xanthatina (xanthanólido sesquiterpeno aislado de Xanthium cavanillesii Schouw) inhibe la activación de mastocitos inducida por secretagogos experimentales. Sin embargo, se desconoce su efecto sobre la activación de mastocitos inducida por estímulos fisiopatológicos. Estos estímulos incluyen, entre otros, los neuropéptidos pro-inflamatorios sustancia P y neurotensina, responsables de una de las principales vías de inflamación neurogénica. El objetivo del presente trabajo fue estudiar el efecto de xanthatina sobre la activación de mastocitos inducida por sustancia P y neurotensina. Mastocitos peritoneales de rata se incubaron con: 1) PBS (basal); 2) sustancia P (100 Fm); 3) neurotensina (50 Fm); 4) xanthatina (8-320 Fm)+sustancia P; 5) xanthatina (8-320 Fm)+neurotensina. La viabilidad de los mastocitos se evaluó con azul tripán. En las soluciones de incubación se cuantificó serotonina liberada (marcador de activación). En las células se cuantificó serotonina remanente (no liberada) y se analizó la morfología celular por microscopía óptica y electrónica de transmisión. Tratamiento estadístico: ANOVA-1 y Tukey-Kramer. La incubación de mastocitos con xanthatina inhibió (P<0,01), en forma dosisdependiente, la liberación de serotonina inducida por sustancia P y neurotensina, sin modificar la viabilidad celular. Los mastocitos tratados con neuropéptidos mostraron características morfológicas de degranulación, mientras que la morfología de los mastocitos tratados con xanthatina+neuropéptido fue semejante a los basales. En conclusión, xanthatina inhibe la activación de mastocitos inducida por sustancia P y por neurotensina. Este sesquiterpeno podría representar una nueva alternativa en el tratamiento de las inflamaciones neurogénicas.The present study was designed to examine the effects of a novel natural xanthanolide with anti-ulcer and anti-inflammatory properties (xanthatin) on mast cell activation induced by pro-inflammatory peptides, such as substance P and neurotensin. Peritoneal mast cells from male adult were purified in Percoll, preincubated in the presence of xanthatin and then challenged with the mast cell activators substance P (100 Fm) or neurotensin (50 Fm). Concentration-response studies of mast cell serotonin release evoked by pro-inflammatory neuropeptides, evaluation of mast cell viability and morphology by light and electron microscopy, and drug stability analysis by thin layer chromatography (TLC) were performed. Serotonin release studies, carried out together with morphological studies, showed the effectiveness of xanthatin to stabilize mast cells. The present study provides the first strong evidence in favour of the hypothesis that xanthatin inhibits substance P- and neurotensin-induced serotonin release from peritoneal mast cells, acting thus as a mast cell stabilizer. Our findings may provide an insight into the design of novel pharmacological agents which may be used to regulate the mast cell response in neurogenic inflammation.Fil: Vargas, P.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histologia y Embriología Mendoza. "Dr. Mario H. Burgos"Fil: Martino, E.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Área de Anatomía NormalFil: Fogal, T.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histologia y Embriología Mendoza. "Dr. Mario H. Burgos"Fil: Tonn, C.. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química.Fil: Penissi, A.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histologia y Embriología Mendoza. "Dr. Mario H. Burgos

Computation of Single-Cell Metabolite Distributions Using Mixture Models

Metabolic heterogeneity is widely recognised as the next challenge in our understanding of non-genetic variation. A growing body of evidence suggests that metabolic heterogeneity may result from the inherent stochasticity of intracellular events. However, metabolism has been traditionally viewed as a purely deterministic process, on the basis that highly abundant metabolites tend to filter out stochastic phenomena. Here we bridge this gap with a general method for prediction of metabolite distributions across single cells. By exploiting the separation of time scales between enzyme expression and enzyme kinetics, our method produces estimates for metabolite distributions without the lengthy stochastic simulations that would be typically required for large metabolic models. The metabolite distributions take the form of Gaussian mixture models that are directly computable from single-cell expression data and standard deterministic models for metabolic pathways. The proposed mixture models provide a systematic method to predict the impact of biochemical parameters on metabolite distributions. Our method lays the groundwork for identifying the molecular processes that shape metabolic heterogeneity and its functional implications in disease.Comment: 5 Figures, 3 Table

Qualität des Weidefutters in der ökologischen Milchviehhaltung

Grazing of dairy cows is mandatory in organic farming. However, as in conventional farming there is a tendency to increase milk yield per cows by employing other feeding strategies than grazing. On-farm research was initiated on organic dairy farms in Lower Saxony to investigate the current practice of grassland utilization and dairy husbandry and to explore the potential of grazing for milk production. The results show that with an increased focus on grazing of dairy cows there is considerable room for more milk being produced from grazed grass. An in-depth analysis of the spatio-temporal pattern of the quality of the herbage on offer revealed steadily high net energy and protein concentrations almost irrespective of the sward botanical composition and the season of sampling. Research is needed to improve grazing management strategies in organic farming to make better use of the high potential of grazed grasslands and thereby increase the sustainability of milk production

Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies

Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology

Heat flow and calculus on metric measure spaces with Ricci curvature bounded below - the compact case

We provide a quick overview of various calculus tools and of the main results concerning the heat flow on compact metric measure spaces, with applications to spaces with lower Ricci curvature bounds. Topics include the Hopf-Lax semigroup and the Hamilton-Jacobi equation in metric spaces, a new approach to differentiation and to the theory of Sobolev spaces over metric measure spaces, the equivalence of the L^2-gradient flow of a suitably defined "Dirichlet energy" and the Wasserstein gradient flow of the relative entropy functional, a metric version of Brenier's Theorem, and a new (stronger) definition of Ricci curvature bound from below for metric measure spaces. This new notion is stable w.r.t. measured Gromov-Hausdorff convergence and it is strictly connected with the linearity of the heat flow.Comment: To the memory of Enrico Magenes, whose exemplar life, research and teaching shaped generations of mathematician

A comparative assessment of biomass ash preparation methods using X-ray fluorescence and wet chemical analysis

X-ray fluorescence (XRF) spectroscopy is a rapid method used to determine the composition of biomass ash, but the accuracy of the method is sensitive to various factors including ash preparation methods. In this study different types of biomass ash were examined by using wet chemical analysis (WCA) and compared with the respective XRF results. The biomass ash was initially prepared in accordance with the European Standard method at 550 °C. At this low combustion temperature the amount of residual unburned carbon is significant. To eliminate this, the ashes were heated at higher temperatures: a batch of twenty biomass ashes were heated at 850 °C and a batch of five heated to 815 °C. At these higher temperatures there may be loss of inorganic components by vaporisation. Variation in these effects may lead to unreliable results. The relationship between XRF and WCA results are given by regression equations. The ashes processed at 815 °C show better agreement between the two analysis methods

Association of pre-radiotherapy tumour burden and overall survival in newly diagnosed glioblastoma adjusted for MGMT promoter methylation status

PURPOSE: We retrospectively evaluated the association between postoperative pre-radiotherapy tumour burden and overall survival (OS) adjusted for the prognostic value of O$^{6}$-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with newly diagnosed glioblastoma treated with radio-/chemotherapy with temozolomide. MATERIALS AND METHODS: Patients were included from the CENTRIC (EORTC 26071-22072) and CORE trials if postoperative magnetic resonance imaging scans were available within a timeframe of up to 4weeks before radiotherapy, including both pre- and post-contrast T1w images and at least one T2w sequence (T2w or T2w-FLAIR). Postoperative (residual) pre-radiotherapy contrast-enhanced tumour (CET) volumes and non-enhanced T2w abnormalities (NT2A) tissue volumes were obtained by three-dimensional segmentation. Cox proportional hazard models and Kaplan Meier estimates were used to assess the association of pre-radiotherapy CET/NT2A volume with OS adjusted for known prognostic factors (age, performance status, MGMT status). RESULTS: 408 tumour (of which 270 MGMT methylated) segmentations were included. Median OS in patients with MGMT methylated tumours was 117 weeks versus 61weeks in MGMT unmethylated tumours (p < 0.001). When stratified for MGMT methylation status, higher CET volume (HR 1.020; 95% confidence interval CI [1.013-1.027]; p < 0.001) and older age (HR 1.664; 95% CI [1.214-2.281]; p = 0.002) were significantly associated with shorter OS while NT2A volume and performance status were not. CONCLUSION: Pre-radiotherapy CET volume was strongly associated with OS in patients receiving radio-/chemotherapy for newly diagnosed glioblastoma stratified by MGMT promoter methylation status

O6-Methylguanine-DNA Methyltransferase (MGMT) mRNA Expression Predicts Outcome in Malignant Glioma Independent of MGMT Promoter Methylation

Background: We analyzed prospectively whether MGMT (O(6)-methylguanine-DNA methyltransferase) mRNA expression gains prognostic/predictive impact independent of MGMT promoter methylation in malignant glioma patients undergoing radiotherapy with concomitant and adjuvant temozolomide or temozolomide alone. As DNA-methyltransferases (DNMTs) are the enzymes responsible for setting up and maintaining DNA methylation patterns in eukaryotic cells, we analyzed further, whether MGMT promoter methylation is associated with upregulation of DNMT expression. 12 Hide Figures Abstract Introduction Methods Results Discussion Acknowledgments Author Contributions References Reader Comments (0) Figures Abstract Background We analyzed prospectively whether MGMT (O6-methylguanine-DNA methyltransferase) mRNA expression gains prognostic/predictive impact independent of MGMT promoter methylation in malignant glioma patients undergoing radiotherapy with concomitant and adjuvant temozolomide or temozolomide alone. As DNA-methyltransferases (DNMTs) are the enzymes responsible for setting up and maintaining DNA methylation patterns in eukaryotic cells, we analyzed further, whether MGMT promoter methylation is associated with upregulation of DNMT expression. Methodology/Principal Findings: Adult patients with a histologically proven malignant astrocytoma (glioblastoma: N = 53, anaplastic astrocytoma: N = 10) were included. MGMT promoter methylation was determined by methylation-specific PCR (MSP) and sequencing analysis. Expression of MGMT and DNMTs mRNA were analysed by real-time qPCR. Prognostic factors were obtained from proportional hazards models. Correlation between MGMT mRNA expression and MGMT methylation status was validated using data from the Cancer Genome Atlas (TCGA) database (N = 229 glioblastomas). Low MGMT mRNA expression was strongly predictive for prolonged time to progression, treatment response, and length of survival in univariate and multivariate models (p<0.0001); the degree of MGMT mRNA expression was highly correlated with the MGMT promoter methylation status (p<0.0001); however, discordant findings were seen in 12 glioblastoma patients: Patients with methylated tumors with high MGMT mRNA expression (N = 6) did significantly worse than those with low transcriptional activity (p<0.01). Conversely, unmethylated tumors with low MGMT mRNA expression (N = 6) did better than their counterparts. A nearly identical frequency of concordant and discordant findings was obtained by analyzing the TCGA database (p<0.0001). Expression of DNMT1 and DNMT3b was strongly upregulated in tumor tissue, but not correlated with MGMT promoter methylation and MGMT mRNA expression. Conclusions/Significance: MGMT mRNA expression plays a direct role for mediating tumor sensitivity to alkylating agents. Discordant findings indicate methylation-independent pathways of MGMT expression regulation. DNMT1 and DNMT3b are likely to be involved in CGI methylation. However, their exact role yet has to be defined

Association of pre-radiotherapy tumour burden and overall survival in newly diagnosed glioblastoma adjusted for <i>MGMT </i>promoter methylation status

PURPOSE: We retrospectively evaluated the association between postoperative pre-radiotherapy tumour burden and overall survival (OS) adjusted for the prognostic value of O$^{6}$-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with newly diagnosed glioblastoma treated with radio-/chemotherapy with temozolomide. MATERIALS AND METHODS: Patients were included from the CENTRIC (EORTC 26071-22072) and CORE trials if postoperative magnetic resonance imaging scans were available within a timeframe of up to 4weeks before radiotherapy, including both pre- and post-contrast T1w images and at least one T2w sequence (T2w or T2w-FLAIR). Postoperative (residual) pre-radiotherapy contrast-enhanced tumour (CET) volumes and non-enhanced T2w abnormalities (NT2A) tissue volumes were obtained by three-dimensional segmentation. Cox proportional hazard models and Kaplan Meier estimates were used to assess the association of pre-radiotherapy CET/NT2A volume with OS adjusted for known prognostic factors (age, performance status, MGMT status). RESULTS: 408 tumour (of which 270 MGMT methylated) segmentations were included. Median OS in patients with MGMT methylated tumours was 117 weeks versus 61weeks in MGMT unmethylated tumours (p < 0.001). When stratified for MGMT methylation status, higher CET volume (HR 1.020; 95% confidence interval CI [1.013-1.027]; p < 0.001) and older age (HR 1.664; 95% CI [1.214-2.281]; p = 0.002) were significantly associated with shorter OS while NT2A volume and performance status were not. CONCLUSION: Pre-radiotherapy CET volume was strongly associated with OS in patients receiving radio-/chemotherapy for newly diagnosed glioblastoma stratified by MGMT promoter methylation status