Non-invasive assessment of murine PD-L1 levels in syngeneic tumor models by nuclear imaging with nanobody tracers

Blockade of the inhibitory PD-1/PD-L1 immune checkpoint axis is a promising cancer treatment. Nonetheless, a significant number of patients and malignancies do not respond to this therapy. To develop a screen for response to PD-1/PD-L1 inhibition, it is critical to develop a non-invasive tool to accurately assess dynamic immune checkpoint expression. Here we evaluated non-invasive SPECT/CT imaging of PD-L1 expression, in murine tumor models with varying PD-L1 expression, using high affinity PD-L1-specific nanobodies (Nbs). We generated and characterized 37 Nbs recognizing mouse PD-L1. Among those, four Nbs C3, C7, E2 and E4 were selected and evaluated for preclinical imaging of PD-L1 in syngeneic mice. We performed SPECT/CT imaging in wild type versus PD-L1 knock-out mice, using Technetium-99m (99mTc) labeled Nbs. Nb C3 and E2 showed specific antigen binding and beneficial biodistribution. Through the use of CRISPR/Cas9 PD-L1 knock-out TC-1 lung epithelial cell lines, we demonstrate that SPECT/CT imaging using Nb C3 and E2 identifies PD-L1 expressing tumors, but not PD-L1 non-expressing tumors, thereby confirming the diagnostic potential of the selected Nbs. In conclusion, these data show that Nbs C3 and E2 can be used to non-invasively image PD-L1 levels in the tumor, with the strength of the signal correlating with PD-L1 levels. These findings warrant further research into the use of Nbs as a tool to image inhibitory signals in the tumor environment

Self-Affirmation Improves Problem-Solving under Stress

High levels of acute and chronic stress are known to impair problem-solving and creativity on a broad range of tasks. Despite this evidence, we know little about protective factors for mitigating the deleterious effects of stress on problem-solving. Building on previous research showing that self-affirmation can buffer stress, we tested whether an experimental manipulation of self-affirmation improves problem-solving performance in chronically stressed participants. Eighty undergraduates indicated their perceived chronic stress over the previous month and were randomly assigned to either a self-affirmation or control condition. They then completed 30 difficult remote associate problem-solving items under time pressure in front of an evaluator. Results showed that self-affirmation improved problem-solving performance in underperforming chronically stressed individuals. This research suggests a novel means for boosting problem-solving under stress and may have important implications for understanding how self-affirmation boosts academic achievement in school settings. © 2013 Creswell et al

How and When Socially Entrepreneurial Nonprofit Organizations Benefit From Adopting Social Alliance Management Routines to Manage Social Alliances?

Social alliance is defined as the collaboration between for-profit and nonprofit organizations. Building on the insights derived from the resource-based theory, we develop a conceptual framework to explain how socially entrepreneurial nonprofit organizations (SENPOs) can improve their social alliance performance by adopting strategic alliance management routines. We test our framework using the data collected from 203 UK-based SENPOs in the context of cause-related marketing campaign-derived social alliances. Our results confirm a positive relationship between social alliance management routines and social alliance performance. We also find that relational mechanisms, such as mutual trust, relational embeddedness, and relational commitment, mediate the relationship between social alliance management routines and social alliance performance. Moreover, our findings suggest that different types of social alliance motivation can influence the impact of social alliance management routines on different types of the relational mechanisms. In general, we demonstrate that SENPOs can benefit from adopting social alliance management routines and, in addition, highlight how and when the social alliance management routines–social alliance performance relationship might be shaped. Our study offers important academic and managerial implications, and points out future research directions

Freshwater flux to Sermilik Fjord, SE Greenland

Terrestrial inputs of freshwater flux to Sermilik Fjord, SE Greenland, were estimated, indicating ice discharge to be the dominant source of freshwater. A freshwater flux of 40.4 ± 4.9×10<sup>9</sup> m<sup>3</sup> y<sup>−1</sup> was found (1999–2008), with an 85% contribution originated from ice discharge (65% alone from Helheim Glacier), 11% from terrestrial surface runoff (from melt water and rain), 3% from precipitation at the fjord surface area, and 1% from subglacial geothermal and frictional melting due to basal ice motion. The results demonstrate the dominance of ice discharge as a primary mechanism for delivering freshwater to Sermilik Fjord. Time series of ice discharge for Helheim Glacier, Midgård Glacier, and Fenris Glacier were calculated from satellite-derived average surface velocity, glacier width, and estimated ice thickness, and fluctuations in terrestrial surface freshwater runoff were simulated based on observed meteorological data. These simulations were compared and bias corrected against independent glacier catchment runoff observations. Modeled runoff to Sermilik Fjord was variable, ranging from 2.9 ± 0.4×10<sup>9</sup> m<sup>3</sup> y<sup>−1</sup> in 1999 to 5.9 ± 0.9×10<sup>9</sup> m<sup>3</sup> y<sup>−1</sup> in 2005. The sub-catchment runoff of the Helheim Glacier region accounted for 25% of the total runoff to Sermilik Fjord. The runoff distribution from the different sub-catchments suggested a strong influence from the spatial variation in glacier coverage, indicating high runoff volumes, where glacier cover was present at low elevations

Spontaneous closure of the hymen during term pregnancy

The hymen is a thin fold of mucous membrane; partially closing the external vaginal opening.1It is composed mainly of elastic, collagenous connective tissue and covered on its both surfaces by stratified squamous epithelium. At pregnancy, the epithelium of hymen becomes very thick and rich in glycogen, which may lead to spontaneous closure. We aim to report a rare case of spontaneous closure of hymen in a 23-year old primigravida in labour with no prior history of menstrual problems or problems during intercourse. Two conditions can cause the secondary closure of the hymen: following previous scarring and in pregnancy. In pregnancy, it could be spontaneous closure due to increase glycogen content of the hymen or due to extensive scarring as seen in previous hymenal surgeries. Spontaneous closure of hymen during pregnancy though very rare can occur. Along with extensive scarring, prolonged abstinence and oestrogenic effect on hymen, gonococcal infection can also cause sponatenous closure of hymen during pregnancy.

A case study on practical live event sound exposure monitoring

The recently launched WHO Global Standard for Safe Listening Venues and Events aims to make listening safer and more enjoyable for audiences around the world. Some key questions remain on how to practically monitor sound exposure as well as on how patrons’ hearing may be affected after significant exposure. This paper presents a case study where various sound exposure monitoring systems and methods were trialed in an indoor music venue. The aim of the work was to develop and validate a practical, accurate and repeatable technique to track sound exposure across music venues that can be presented in real-time. Results indicate that this can be achieved with no more than four, and as few as two, sound level monitoring locations alongside fixed calibration measurements and a small number of spot measurements at the mix position during a performance

Design of a global soil moisture initialization procedure for the simple biosphere model

Global soil moisture and land-surface evapotranspiration fields are computed using an analysis scheme based on the Simple Biosphere (SiB) soil-vegetation-atmosphere interaction model. The scheme is driven with observed precipitation, and potential evapotranspiration, where the potential evapotranspiration is computed following the surface air temperature-potential evapotranspiration regression of Thomthwaite (1948). The observed surface air temperature is corrected to reflect potential (zero soil moisture stress) conditions by letting the ratio of actual transpiration to potential transpiration be a function of normalized difference vegetation index (NDVI). Soil moisture, evapotranspiration, and runoff data are generated on a daily basis for a 10-year period, January 1979 through December 1988, using observed precipitation gridded at a 4 deg by 5 deg resolution

Distributed Modeling of Ablation (1996–2011) and Climate Sensitivity on the Glaciers of Taylor Valley, Antarctica

The McMurdo Dry Valleys of Antarctica host the coldest and driest ecosystem on Earth, which is acutely sensitive to the availability of water coming from glacial runoff. We modeled the spatial variability in ablation and assessed climate sensitivity of the glacier ablation zones using 16 years of meteorological and surface mass-balance observations collected in Taylor Valley. Sublimation was the primary form of mass loss over much of the ablation zones, except for near the termini where melt, primarily below the surface, dominated. Microclimates in ~10 m scale topographic basins generated melt rates up to ten times higher than over smooth glacier surfaces. In contrast, the vertical terminal cliffs on the glaciers can have higher or lower melt rates than the horizontal surfaces due to differences in incoming solar radiation. The model systematically underpredicted ablation for the final 5 years studied, possibly due to an increase of windblown sediment. Surface mass-balance sensitivity to temperature was ~−0.02 m w.e. K−1, which is among the smallest magnitudes observed globally. We also identified a high sensitivity to ice albedo, with a decrease of 0.02 having similar effects as a 1 K increase in temperature, and a complex sensitivity to wind speed