Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model.

Inhibitors of BRAFV600E kinase are currently under investigations in preclinical and clinical studies involving BRAFV600E glioma. Studies demonstrated clinical response to such individualized therapy in the majority of patients whereas in some patients tumors continue to grow despite treatment. To study resistance mechanisms, which include feedback activation of mitogen-activated protein kinase (MAPK) signaling in melanoma, we developed a luciferase-modified cell line (2341luc) from a BrafV600E mutant and Cdkn2a- deficient murine high-grade glioma, and analyzed its molecular responses to BRAFV600E- and MAPK kinase (MEK)-targeted inhibition. Immunocompetent, syngeneic FVB/N mice with intracranial grafts of 2341luc were tested for effects of BRAFV600E and MEK inhibitor treatments, with bioluminescence imaging up to 14-days after start of treatment and survival analysis as primary indicators of inhibitor activity. Intracranial injected tumor cells consistently generated high-grade glioma-like tumors in syngeneic mice. Intraperitoneal daily delivery of BRAFV600E inhibitor dabrafenib only transiently suppressed MAPK signaling, and rather increased Akt signaling and failed to extend survival for mice with intracranial 2341luc tumor. MEK inhibitor trametinib delivered by oral gavage daily suppressed MAPK pathway more effectively and had a more durable anti-growth effect than dabrafenib as well as a significant survival benefit. Compared with either agent alone, combined BRAFV600E and MEK inhibitor treatment was more effective in reducing tumor growth and extending animal subject survival, as corresponding to sustained MAPK pathway inhibition. Results derived from the 2341luc engraftment model application have clinical implications for the management of BRAFV600E glioma

The Next Generation Virgo Cluster Survey. IX. Estimating the Efficiency of Galaxy Formation on the Lowest-Mass Scales

The Next Generation Virgo Cluster Survey has recently determined the luminosity function of galaxies in the core of the Virgo cluster down to unprecedented magnitude and surface brightness limits. Comparing simulations of cluster formation to the derived central stellar mass function, we attempt to estimate the stellar-to-halo-mass ratio (SHMR) for dwarf galaxies, as it would have been before they fell into the cluster. This approach ignores several details and complications, e.g., the contribution of ongoing star formation to the present-day stellar mass of cluster members, and the effects of adiabatic contraction and/or violent feedback on the subhalo and cluster potentials. The final results are startlingly simple, however; we find that the trends in the SHMR determined previously for bright galaxies appear to extend down in a scale-invariant way to the faintest objects detected in the survey. These results extend measurements of the formation efficiency of field galaxies by two decades in halo mass, or five decades in stellar mass, down to some of the least massive dwarf galaxies known, with stellar masses of $\sim 10^5 M_\odot$.Comment: 18 pages, 12 figures; published in ApJ July 1st 201

Evaluation of the Workplace Environment in the UK, and the Impact on Users’ Levels of Stimulation

The purpose of this study is to evaluate a number of recently completed workplaces in the UK. The first aim is to assess the impact of various aspects of the workplace environment on users’ levels of stimulation. The body of previous research undertaken into the workplace environment, identified the aspects to be investigated. Samples of employees from the sixteen businesses were surveyed to determine their perceptions of the workplaces. The results were entered into a regression analysis, and the most significant predictors of perceived stimulation identified. The data also revealed a dramatic reduction in staff arousal levels from mornings to afternoons. Thus, there is a second aim to determine whether changes to significant aspects of the workplace environment during the day can counteract the reduction in users’ stimulation. Two further workplaces were studied to enable changes to be made over a 12-week period. A sample of employees completed questionnaires, and semi-structured interviews revealed the reasons behind the results. It was found that provision of artwork, personal control of temperature and ventilation and regular breaks were the most significant contributions to increasing stimulation after lunch; while user choice of layout, and design and décor of workspaces and break areas, were the most significant aspects at design stage

The Cercal Organ May Provide Singing Tettigoniids a Backup Sensory System for the Detection of Eavesdropping Bats

Conspicuous signals, such as the calling songs of tettigoniids, are intended to attract mates but may also unintentionally attract predators. Among them bats that listen to prey-generated sounds constitute a predation pressure for many acoustically communicating insects as well as frogs. As an adaptation to protect against bat predation many insect species evolved auditory sensitivity to bat-emitted echolocation signals. Recently, the European mouse-eared bat species Myotis myotis and M. blythii oxygnathus were found to eavesdrop on calling songs of the tettigoniid Tettigonia cantans. These gleaning bats emit rather faint echolocation signals when approaching prey and singing insects may have difficulty detecting acoustic predator-related signals. The aim of this study was to determine (1) if loud self-generated sound produced by European tettigoniids impairs the detection of pulsed ultrasound and (2) if wind-sensors on the cercal organ function as a sensory backup system for bat detection in tettigoniids. We addressed these questions by combining a behavioral approach to study the response of two European tettigoniid species to pulsed ultrasound, together with an electrophysiological approach to record the activity of wind-sensitive interneurons during real attacks of the European mouse-eared bat species Myotis myotis. Results showed that singing T. cantans males did not respond to sequences of ultrasound pulses, whereas singing T. viridissima did respond with predominantly brief song pauses when ultrasound pulses fell into silent intervals or were coincident with the production of soft hemi-syllables. This result, however, strongly depended on ambient temperature with a lower probability for song interruption observable at 21°C compared to 28°C. Using extracellular recordings, dorsal giant interneurons of tettigoniids were shown to fire regular bursts in response to attacking bats. Between the first response of wind-sensitive interneurons and contact, a mean time lag of 860 ms was found. This time interval corresponds to a bat-to-prey distance of ca. 72 cm. This result demonstrates the efficiency of the cercal system of tettigoniids in detecting attacking bats and suggests this sensory system to be particularly valuable for singing insects that are targeted by eavesdropping bats