Delivering safer immunotherapies for cancer

Cancer immunotherapy is now a powerful clinical reality, with a steady progression of new drug approvals and a massive pipeline of additional treatments in clinical and preclinical development. However, modulation of the immune system can be a double-edged sword: Drugs that activate immune effectors are prone to serious non-specific systemic inflammation and autoimmune side effects. Drug delivery technologies have an important role to play in harnessing the power of immune therapeutics while avoiding on-target/off-tumor toxicities. Here we review mechanisms of toxicity for clinically-relevant immunotherapeutics, and discuss approaches based in drug delivery technology to enhance the safety and potency of these treatments. These include strategies to merge drug delivery with adoptive cellular therapies, targeting immunotherapies to tumors or select immune cells, and localizing therapeutics intratumorally. Rational design employing lessons learned from the drug delivery and nanomedicine fields has the potential to facilitate immunotherapy reaching its full potential

Seasonal temperature acclimatization in a semi-fossorial mammal and the role of burrows as thermal refuges.

Small mammals in habitats with strong seasonal variation in the thermal environment often exhibit physiological and behavioral adaptations for coping with thermal extremes and reducing thermoregulatory costs. Burrows are especially important for providing thermal refuge when above-ground temperatures require high regulatory costs (e.g., water or energy) or exceed the physiological tolerances of an organism. Our objective was to explore the role of burrows as thermal refuges for a small endotherm, the pygmy rabbit (Brachylagus idahoensis), during the summer and winter by quantifying energetic costs associated with resting above and below ground. We used indirect calorimetry to determine the relationship between energy expenditure and ambient temperature over a range of temperatures that pygmy rabbits experience in their natural habitat. We also measured the temperature of above- and below-ground rest sites used by pygmy rabbits in eastern Idaho, USA, during summer and winter and estimated the seasonal thermoregulatory costs of resting in the two microsites. Although pygmy rabbits demonstrated seasonal physiological acclimatization, the burrow was an important thermal refuge, especially in winter. Thermoregulatory costs were lower inside the burrow than in above-ground rest sites for more than 50% of the winter season. In contrast, thermal heterogeneity provided by above-ground rest sites during summer reduced the role of burrows as a thermal refuge during all but the hottest periods of the afternoon. Our findings contribute to an understanding of the ecology of small mammals in seasonal environments and demonstrate the importance of burrows as thermal refuge for pygmy rabbits

Techniques to determine the quiet day curve for a long period of subionospheric VLF observations

Very low frequency (VLF) transmissions propagating between the conducting Earth's surface and lower edge of the ionosphere have been used for decades to study the effect of space weather events on the upper atmosphere. The VLF response to these events can only be quantified by comparison of the observed signal to the estimated quiet time or undisturbed signal levels, known as the quiet day curve (QDC). A common QDC calculation approach for periods of investigation of up to several weeks is to use observations made on quiet days close to the days of interest. This approach is invalid when conditions are not quiet around the days of interest. Longer-term QDCs have also been created from specifically identified quiet days within the period and knowledge of propagation characteristics. This approach is time consuming and can be subjective. We present three algorithmic techniques, which are based on either (1) a mean of previous days' observations, (2) principal component analysis, or (3) the fast Fourier transform (FFT), to calculate the QDC for a long-period VLF data set without identification of specific quiet days as a basis. We demonstrate the effectiveness of the techniques at identifying the true QDCs of synthetic data sets created to mimic patterns seen in actual VLF data including responses to space weather events. We find that the most successful technique is to use a smoothing method, developed within the study, on the data set and then use the developed FFT algorithm. This technique is then applied to multiyear data sets of actual VLF observations

A Comparison of Two Methods for Completing Sudoku Puzzles

This study compared two methods for completing Sudoku puzzles. More specifically, students in mathematics classes in Grades 4 and 5 completed Sudoku puzzles using either paper or a specially designed electronic spreadsheet which disallowed the entry of duplicate numbers. Performance was measured by the number of entries in the puzzle and the percentage of correct entries. Results showed that the Grade 5 participants did not differ on either performance measure. On the other hand, the participants in Grade 4 using paper placed significantly more numbers, but the participants using the spreadsheet placed the numbers much more accurately. These mixed results encourage teachers to continually reflect on the utility of instructional technologies in light of learner characteristics and subject matter

Performing heritage: the use of live 'actors' in heritage presentations

This paper investigates the phenomenon of 'living history' presentations of heritage, using live 'actors' to portray historical characters. Its aim is to discuss these presentations in the context of what may be understood as 'heritage', and of the nature of 'performance'. Four case studies of heritage sites, each important as a tourist attraction, have been selected for detailed study, together with a number of other examples of heritage performance. It is clear from the empirical work that different performance strategies are employed within the heritage industry and by individual 'actors'. Most of the performers take part as a leisure activity, and many do not consider themselves to be 'performing' at all. The greatest concern of participants lies in the degree of authenticity of the performance. Through 'living history', the 'actors' are drawn into an experience of heritage which has real meaning for them, and which may contribute both to a sense of identity and to an enhanced understanding of society, past and present. The popularity of such presentations with visitors also indicates that similar benefits are perceived by the 'audience'

ULF wave derived radiation belt radial diffusion coefficients

Waves in the ultra-low-frequency (ULF) band have frequencies which can be drift resonant with electrons in the outer radiation belt, suggesting the potential for strong interactions and enhanced radial diffusion. Previous radial diffusion coefficient models such as those presented by Brautigam and Albert (2000) have typically used semiempirical representations for both the ULF wave’s electric and magnetic field power spectral densities (PSD) in space in the magnetic equatorial plane. In contrast, here we use ground- and space-based observations of ULF wave power to characterize the electric and magnetic diffusion coefficients. Expressions for the electric field power spectral densities are derived from ground-based magnetometer measurements of the magnetic field PSD, and in situ AMPTE and GOES spacecraft measurements are used to derive expressions for the compressional magnetic field PSD as functions of Kp, solar wind speed, and L-shell. Magnetic PSD results measured on the ground are mapped along the field line to give the electric field PSD in the equatorial plane assuming a guided Alfvén wave solution and a thin sheet ionosphere. The ULF wave PSDs are then used to derive a set of new ULF-wave driven diffusion coefficients. These new diffusion coefficients are compared to estimates of the electric and magnetic field diffusion coefficients made by Brautigam and Albert (2000) and Brautigam et al. (2005). Significantly, our results, derived explicitly from ULF wave observations, indicate that electric field diffusion is much more important than magnetic field diffusion in the transport and energization of the radiation belt electrons