Chemoresistance of glioblastoma cancer stem cells - much more complex than expected

Glioblastomas (GBM) are a paradigm for the investigation of cancer stem cells (CSC) in solid malignancies. The susceptibility of GBM CSC to standard chemotherapeutic drugs is controversial as the existing literature presents conflicting experimental data. Here, we summarize the experimental evidence on the resistance of GBM CSC to alkylating chemotherapeutic agents, with a special focus on temozolomide (TMZ). The data suggests that CSC are neither resistant nor susceptible to chemotherapy per se. Detoxifying proteins such as O6-methylguanine-DNA-methyltransferase (MGMT) confer a strong intrinsic resistance to CSC in all studies. Extrinsic factors may also contribute to the resistance of CSC to TMZ. These may include TMZ concentrations in the brain parenchyma, TMZ dosing schemes, hypoxic microenvironments, niche factors, and the re-acquisition of stem cell properties by non-stem cells. Thus, the interaction of CSC and chemotherapy is more complex than may be expected and it is necessary to consider these factors in order to overcome chemoresistance in the patient

OpenGM: A C++ Library for Discrete Graphical Models

OpenGM is a C++ template library for defining discrete graphical models and performing inference on these models, using a wide range of state-of-the-art algorithms. No restrictions are imposed on the factor graph to allow for higher-order factors and arbitrary neighborhood structures. Large models with repetitive structure are handled efficiently because (i) functions that occur repeatedly need to be stored only once, and (ii) distinct functions can be implemented differently, using different encodings alongside each other in the same model. Several parametric functions (e.g. metrics), sparse and dense value tables are provided and so is an interface for custom C++ code. Algorithms are separated by design from the representation of graphical models and are easily exchangeable. OpenGM, its algorithms, HDF5 file format and command line tools are modular and extendible

The Atg1-kinase complex tethers Atg9-vesicles to initiate autophagy

Autophagosomes are double-membrane vesicles that sequester cytoplasmic material for lysosomal degradation. Their biogenesis is initiated by recruitment of Atg9-vesicles to the phagophore assembly site. This process depends on the regulated activation of the Atg1-kinase complex. However, the underlying molecular mechanism remains unclear. Here we reconstitute this early step in autophagy from purified components in vitro. We find that on assembly from its cytoplasmic subcomplexes, the Atg1-kinase complex becomes activated, enabling it to recruit and tether Atg9-vesicles. The scaffolding protein Atg17 targets the Atg1-kinase complex to autophagic membranes by specifically recognizing the membrane protein Atg9. This interaction is inhibited by the two regulatory subunits Atg31 and Atg29. Engagement of the Atg1-Atg13 subcomplex restores the Atg9-binding and membrane-tethering activity of Atg17. Our data help to unravel the mechanism that controls Atg17-mediated tethering of Atg9-vesicles, providing the molecular basis to understand initiation of autophagosome-biogenesis

Improving the Socio-emotional Well-being of the Older Generation through the Implementation of Territorial Marketing

This article is based on the analysis of the possibility of using Berkman's conceptual model of mechanism of social networks influence on human health to improve the well-being of the older generation in Russia. The emphasis is put on the development of social contacts of older people through the implementation of territorial marketing. Objective and subjective indicators of well-being of older people are directly related to the characteristics and peculiarities of the territory where they live and carry out their activities (city, region, country). In this context, marketing of territory can be regarded as an activity aimed at creating and maintaining comfortable living conditions of different age groups, taking into considerations their characteristics. Special attention is paid to the social and emotional mechanisms of social support, social influence, social inclusion, social participation, interpersonal contacts and access to resources and benefits the territory of older generation. Specificity of older adults segmentation of the region (the city) is defined. The importance of active cooperation of various age groups identified in the process of territorial segmentation of the market is particularly stressed, in terms of improving the lives of older adults

Particle astrophysics

The following scientific areas are reviewed: (1) cosmology and particle physics (particle physics and the early universe, dark matter, and other relics); (2) stellar physics and particles (solar neutrinos, supernovae, and unconventional particle physics); (3) high energy gamma ray and neutrino astronomy; (4) cosmic rays (space and ground observations). Highest scientific priorities for the next decade include implementation of the current program, new initiatives, and longer-term programs. Essential technological developments, such as cryogenic detectors of particles, new solar neutrino techniques, and new extensive air shower detectors, are discussed. Also a certain number of institutional issues (the funding of particle astrophysics, recommended funding mechanisms, recommended facilities, international collaborations, and education and technology) which will become critical in the coming decade are presented

Exposure to the rxr agonist sr11237 in early life causes disturbed skeletal morphogenesis in a rat model

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation in EO. Rats given SR11237 from post-natal day 5 to post-natal day 15 were harvested for micro-computed tomography (microCT) scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole-mount evaluation. RXR agonist-treated rats had shorter long bones than the controls and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape, in correspondence with p57 immunostaining. Additionally, SOX9-positive cells were found surrounding the calcified tissue. The epiphysis of SR11237-treated bones showed increased TRAP staining and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of the treated animals. This study suggests that stimulation of RXR causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models

Rifting of the oceanic Azores Plateau with episodic volcanic activity

Extension of the Azores Plateau along the Terceira Rift exposes a lava sequence on the steep northern flank of the Hirondelle Basin. Unlike typical tholeiitic basalts of oceanic plateaus, the 1.2 km vertical submarine stratigraphic profile reveals two successive compositionally distinct basanitic to alkali basaltic eruptive units. The lower unit is volumetrically more extensive with similar to 1060 m of the crustal profile forming between similar to 2.02 and similar to 1.66 Ma, followed by a second unit erupting the uppermost similar to 30 m of lavas in similar to 100 kyrs. The age of similar to 1.56 Ma of the youngest in-situ sample at the top of the profile implies that the 35 km-wide Hirondelle Basin opened after this time along normal faults. This rifting phase was followed by alkaline volcanism at D. JoAo de Castro seamount in the basin center indicating episodic volcanic activity along the Terceira Rift. The mantle source compositions of the two lava units change towards less radiogenic Nd, Hf, and Pb isotope ratios. A change to less SiO2-undersaturated magmas may indicate increasing degrees of partial melting beneath D. JoAo de Castro seamount, possibly caused by lithospheric thinning within the past 1.5 million years. Our results suggest that rifting of oceanic lithosphere alternates between magmatically and tectonically dominated phases.Peer reviewe