Solar cosmic ray events

Nature of charged particle fluxes in vicinity of earth to estimate hazard to Apollo astronauts due to solar cosmic ray event

The space science data service: A study of its efficiencies and costs

Factors affecting the overall advantages and disadvantages of a centralized facility for both the data base and processing capability for NASA's Office of Space Science programs are examined in an effort to determine the best approach to data management in the light of the increasing number of data bits collected annually. Selected issues considered relate to software and storage savings, security precautions, and the phase-in plan. Information on the current mode of processing and on the potential impact of changes resulting from a conversion to a space science data base service was obtained from five user groups and is presented as an aid in determining the dollar benefits and advantages of a centralized system

Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients

Background: Nintedanib is a clinically approved multikinase receptor inhibitor to treat non-small cell lung cancer with adenocarcinoma (ADC) histology in combination with docetaxel, based on the clinical benefits reported on ADC but not on squamous cell carcinoma (SCC), which are the two most common histologic lung cancer subtypes.Methods: We examined the potential role of tumour-associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in histologic sections, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with the potent fibroblast activator TGF-beta 1, which is upregulated in lung cancer.Results: Nintedanib dose-dependently inhibited the TGF-beta 1-induced expression of a panel of pro-fibrotic activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibition was very modest in SCC-TAFs. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC, thereby supporting that TGF-beta signalling and aberrant TAF-carcinoma cross-talk is regulated by different mechanisms in ADC and SCC.Conclusions: These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumour-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumours

Improved understanding of dynamic water and mass budgets of high‐alpine karst systems obtained from studying a well‐defined catchment area

Large areas of Europe, especially in the Alps, are covered by carbonate rocks and in many alpine regions, karst springs are important sources for drinking water supply. Because of their high variability and heterogeneity, the understanding of the hydrogeological functioning of karst aquifers is of particular importance for their protection and utilisation. Climate change and heavy rainfall events are major challenges in managing alpine karst aquifers which possess an enormous potential for future drinking water supply. In this study, we present research from a high‐alpine karst system in the UNESCO Biosphere Reserve Großes Walsertal in Austria, which has a clearly defined catchment and is drained by only one spring system. Results show that (a) the investigated system is a highly dynamic karst aquifer with distinct reactions to rainfall events in discharge and electrical conductivity; (b) the estimated transient atmospheric CO2 sink is about 270 t/a; (c) the calculated carbonate rock denudation rate is between 23 and 47 mm/1000a and (d) the rainfall‐discharge behaviour and the internal flow dynamics can be successfully simulated using the modelling package KarstMod. The modelling results indicate the relevance of matrix storage in determining the discharge behaviour of the spring, particularly during low‐flow periods. This research and the consequent results can contribute and initiate a better understanding and management of alpine karst aquifers considering climate change with more heavy rainfall events and also longer dry periods.The investigated karst system contributes to the transient atmospheric CO2 sink with about 270 t/a. Carbonate denudation rates vary between 23 and 47 mm/1000a. Rainfall‐discharge modelling results indicate the importance of matrix storage particularly during low‐flow periods. imageBundesministerium für Bildung und Forschung http://dx.doi.org/10.13039/501100002347FP7 People: Marie‐Curie Actions http://dx.doi.org/10.13039/10001126

Defining aggressive or early progressing nononcogene-addicted non-small-cell lung cancer: a separate disease entity?

A substantial proportion of patients with nononcogene-addicted non-small-cell lung cancer (NSCLC) has 'aggressive disease', as reflected in short time to progression or lack of disease control with initial platinum-based chemotherapy. Recently, clinical correlates of aggressive disease behavior during first-line therapy have been shown to predict greater benefit from addition of nintedanib to second-line docetaxel in adenocarcinoma NSCLC. Positive predictive effects of aggressive disease have since been reported with other anti-angiogenic agents (ramucirumab and bevacizumab), while such features may negatively impact on outcomes with nivolumab in nonsquamous NSCLC with low PD-L1 expression. Based on a review of the clinical data, we recommend aggressive nonsquamous NSCLC should be defined by progression within <6-9 months of first-line treatment initiation

Error threshold in optimal coding, numerical criteria and classes of universalities for complexity

The free energy of the Random Energy Model at the transition point between ferromagnetic and spin glass phases is calculated. At this point, equivalent to the decoding error threshold in optimal codes, free energy has finite size corrections proportional to the square root of the number of degrees. The response of the magnetization to the ferromagnetic couplings is maximal at the values of magnetization equal to half. We give several criteria of complexity and define different universality classes. According to our classification, at the lowest class of complexity are random graph, Markov Models and Hidden Markov Models. At the next level is Sherrington-Kirkpatrick spin glass, connected with neuron-network models. On a higher level are critical theories, spin glass phase of Random Energy Model, percolation, self organized criticality (SOC). The top level class involves HOT design, error threshold in optimal coding, language, and, maybe, financial market. Alive systems are also related with the last class. A concept of anti-resonance is suggested for the complex systems.Comment: 17 page

The construction of mental health as a technological problem in India

This paper points to an underexplored relationship of reinforcement between processes of quantification and digitization in the construction of mental health as amenable to technological intervention, in India. Increasingly, technology is used to collect mental health data, to diagnose mental health problems, and as a route of mental health intervention and clinical management. At the same time, mental health has become recognized as a new public health priority in India, and within national and global public health agendas. We explore two sites of the technological problematisation of mental health in India: a large-scale survey calculating prevalence, and a smartphone app to manage stress. We show how digital technology is deployed both to frame a ‘need’ for, and to implement, mental health interventions. We then trace the epistemologies and colonial histories of ‘psy’ technologies, which question assumptions of digital empowerment and of top-down ‘western’ imposition. Our findings show that in India such technologies work both to discipline and liberate users. The paper aims to encourage global debate inclusive of those positioned inside and outside of the ‘black box’ of mental health technology and data production, and to contribute to shaping a future research agenda that analyzes quantification and digitization as key drivers in global advocacy to make mental health count

Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis

The KIT D816V mutation is found in >80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. Therefore, KIT D816V represents a prime therapeutic target for SM. Here, we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM and mast cell leukemia to develop a patient-specific SM disease model for mechanistic and drug-discovery studies. KIT D816V iPSCs differentiated into neoplastic hematopoietic progenitor cells and MCs with patient-specific phenotypic features, thereby reflecting the heterogeneity of the disease. CRISPR/Cas9n-engineered KIT D816V human embryonic stem cells (ESCs), when differentiated into hematopoietic cells, recapitulated the phenotype observed for KIT D816V iPSC hematopoiesis. KIT D816V causes constitutive activation of the KIT tyrosine kinase receptor, and we exploited our iPSCs and ESCs to investigate new tyrosine kinase inhibitors targeting KIT D816V. Our study identified nintedanib, a US Food and Drug Administration-approved angiokinase inhibitor that targets vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, as a novel KIT D816V inhibitor. Nintedanib selectively reduced the viability of iPSC-derived KIT D816V hematopoietic progenitor cells and MCs in the nanomolar range. Nintedanib was also active on primary samples of KIT D816V SM patients. Molecular docking studies show that nintedanib binds to the adenosine triphosphate binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V-targeted therapy of advanced SM.Peer reviewe