The Neural Correlates of Similarity- and Rule-based Generalization

The idea that there are multiple learning systems has become increasingly influential in recent years with many studies providing evidence that there is both a quick, similarity, or feature-based, system, and a more effortful, rule-based system. A smaller number of imaging studies have also examined whether neurally dissociable learning systems are detectable. We further investigate this by employing for the first time in an imaging study a combined positive and negative patterning procedure originally developed by Shanks and Darby (1998). Unlike previous related studies employing other procedures, rule generalization in the Shanks-Darby task is beyond any simple non-rule-based (e.g., associative) account. We found that rule- and similarity-based generalization evoked common activation in diverse regions including the prefrontal cortex and the bilateral parietal and occipital lobes indicating that both strategies likely share a range of common processes. No differences between strategies were identified in whole-brain comparisons but exploratory analyses indicated that rule-based generalization led to greater activation in the right middle frontal cortex than similarity-based generalization. Conversely, the similarity group activated the anterior medial frontal lobe and right inferior parietal lobes more than the rule group did. The implications of these results are discussed

Metastability in pressure-induced structural transformations of CdSe/ZnS core/shell nanocrystals

The kinetics and thermodynamics of structural transformations under pressure depend strongly on particle size due to the influence of surface free energy. By suitable design of surface structure, composition, and passivation it is possible, in principle, to prepare nanocrystals in structures inaccessible to bulk materials. However, few realizations of such extreme size-dependent behavior exist. Here we show with molecular dynamics computer simulation that in a model of CdSe/ZnS core/shell nanocrystals the core high pressure structure can be made metastable under ambient conditions by tuning the thickness of the shell. In nanocrystals with thick shells, we furthermore observe a wurtzite to NiAs transformation, which does not occur in the pure bulk materials. These phenomena are linked to a fundamental change in the atomistic transformation mechanism from heterogenous nucleation at the surface to homogenous nucleation in the crystal core. Our results suggest a new route towards expanding the range of available nanoscale materials

Bathymetric and terminus evolution as determined by remote-sensing techniques: Tasman Glacier, New Zealand

Global glacier recession is increasing the number of glaciers that terminate in proglacial lakes, yet knowledge about the processes that drive ice-berg calving are still poorly understood. This knowledge-gap is in part due to the challenge of obtaining good data sets in a highly dynamic and dangerous environment. We are using emerging remote technologies, in the form of a remote controlled jet boat to survey bathymetry, and Structure from Motion (SfM) to characterise terminus morphology, to better understand relationships between lake growth and terminus evolution. Comparison of results between the jet boat mounted dual-frequency Garmin fish-finder with an Odom Echotrac DF3200 MKII with 200/38 kHz dual-frequency transducer, showed that after a sound velocity adjustment, the remote survey obtained depth data within ± 1 m of the higher grade survey equipment. A maximum water depth of 240 m was recorded 250 m away from the terminus, and the sub-aerial cliff height ranged from 5-44 m. However in some regions, water depth was 180 m only 20 m away from the calving face. Here the sub-aerial cliff height was around 20-25 m, meaning portions of the terminus were, or very close to, buoyancy. A sub-aqueous ice-ramp, 30 m below the water, extended out into the lake from the terminus for approximately 80 m in the central-eastern region. Despite a lake expansion of nearly 1 km since the survey of Dykes et al. (2011), the spatial similarity of the sub-aqueous ramp may indicate that other processes, for example, subglacial hydrology, have influence on the evolving terminus morphology

Glacier retreat: Feedbacks and implications for glacier tourism

Since the culmination of the most recent advance period in 2008/09, the Fox and Franz Josef Glaciers situated on the West Coast of New Zealand, have lost around 500 m in length and experienced significant ice thinning in their lower regions. But even as the glaciers rapidly retreat, they remain some of New Zealand’s most popular tourist attractions, with over 300,000 international tourists visiting the glacier region each year. In this research we take a multidisciplinary approach combining cutting-edge technology (unmanned aerial surveys and structure from motion modelling) to measure and monitor the rapidly changing physical characteristics of the glaciers, along with face-to-face semi-structured interviews with local tourism stakeholders (n=13) and visitor interviews (n=500), to explore the impact of these changes on the visitor experience. It was found that in addition to shortening and thinning, the region of the Fox Glacier that is heavily utilised for tourism is becoming increasingly debris-covered. This is due to melt-out of englacial debris and increased rockfall from the surrounding recently exposed valley slopes. With thinning the previously convex glacier cross-profile has flattened and modelling has demonstrated that falling rocks can now travel up to 50 m further out onto the glacier surface than was the case in 2008/09 – potentially into regions utilised for guided glacier walks. Overwhelmingly, the majority of the visitors surveyed expected the glaciers to get smaller in the future, and a number identified the importance of seeing the glaciers before they disappeared due to climate-related change. Interestingly, some stakeholder interviews revealed local optimism in that the glacier will readvance in the future, and that the tourists will continue to visit. When visitors were asked if they would still visit the glaciers even if the only way to see them was by helicopter, over one-half of respondents indicated they would still visit. By integrating physical and social perspectives we gain greater understanding of the impacts that climate change will have on glacier tourism in New Zealand

Development of therapeutic anti-JAGGED1 antibodies for cancer therapy

The role of Notch signaling and its ligand JAGGED1 (JAG1) in tumor biology have been firmly established, making them appealing therapeutic targets for cancer treatment. Here we report the development and characterization of human/rat-specific JAG1-neutralizing monoclonal antibodies. Epitope mapping identified their binding to the Notch receptor interaction site within the JAG1 Delta/Serrate/Lag2 domain, where E228D substitution prevented effective binding to the murine Jag1 orthologue. These antibodies were able to specifically inhibit JAG1-Notch binding in vitro, downregulate Notch signaling in cancer cells and to block the heterotypic JAG1-mediated Notch signaling between endothelial and vascular smooth muscle cells. Functionally, in vitro treatment impaired 3D growth of breast cancer cell spheroids, in association with a reduction in cancer stem cell number. In vivo testing showed variable effects on human xenograft growth when only tumor-expressed JAG1 was targeted (mouse models) but a more robust effect when stromal expressed Jag1 was also targeted (rat MDA-MB-231 xenograft model). Importantly, treatment of established triple receptor negative breast cancer brain metastasis in rats showed a significant reduction in neoplastic growth. MRI imaging demonstrated that this was associated with a substantial improvement in blood-brain-barrier function and tumor perfusion. Lastly, JAG1-targeting antibody treatment did not cause any detectable toxicity, further supporting its clinical potential for cancer therapy

Development of therapeutic anti-JAGGED1 antibodies for cancer therapy

The role of Notch signaling and its ligand JAGGED1 (JAG1) in tumor biology have been firmly established, making them appealing therapeutic targets for cancer treatment. Here we report the development and characterization of human/rat-specific JAG1-neutralizing monoclonal antibodies. Epitope mapping identified their binding to the Notch receptor interaction site within the JAG1 Delta/Serrate/Lag2 domain, where E228D substitution prevented effective binding to the murine Jag1 orthologue. These antibodies were able to specifically inhibit JAG1-Notch binding in vitro, downregulate Notch signaling in cancer cells and to block the heterotypic JAG1-mediated Notch signaling between endothelial and vascular smooth muscle cells. Functionally, in vitro treatment impaired 3D growth of breast cancer cell spheroids, in association with a reduction in cancer stem cell number. In vivo testing showed variable effects on human xenograft growth when only tumor-expressed JAG1 was targeted (mouse models) but a more robust effect when stromal expressed Jag1 was also targeted (rat MDA-MB-231 xenograft model). Importantly, treatment of established triple receptor negative breast cancer brain metastasis in rats showed a significant reduction in neoplastic growth. MRI imaging demonstrated that this was associated with a substantial improvement in blood-brain-barrier function and tumor perfusion. Lastly, JAG1-targeting antibody treatment did not cause any detectable toxicity, further supporting its clinical potential for cancer therapy