The holistic phase model of early adult crisis

The objective of the current study was to explore the structural, temporal and experiential manifestations of crisis episodes in early adulthood, using a holistic-systemic theoretical framework. Based on an analysis of 50 interviews with individuals about a crisis episode between the ages of 25 and 35, a holistic model was developed. The model comprises four phases: (1) Locked-in, (2) Separation/Time-out, (3) Exploration and (4) Rebuilding, which in turn have characteristic features at four levels—person-in-environment, identity, motivation and affect-cognition. A crisis starts out with a commitment at work or home that has been made but is no longer desired, and this is followed by an emotionally volatile period of change as that commitment is terminated. The positive trajectory of crisis involves movement through an exploratory period towards active rebuilding of a new commitment, but ‘fast-forward’ and ‘relapse’ loops can interrupt Phases 3 and 4 and make a positive resolution of the episode less likely. The model shows conceptual links with life stage theories of emerging adulthood and early adulthood, and it extends current understandings of the transitional developmental challenges that young adults encounter

Identifying spatial and temporal dynamics of proglacial groundwater-surface-water exchange using combined temperature-tracing methods

The effect of proglacial groundwater systems on surface hydrology and ecology in cold regions often is neglected when assessing the ecohydrological implications of climate change. We present a novel approach in which we combined 2 temperature-tracing techniques to assess the spatial patterns and short-term temporal dynamics of groundwater–surface-water exchange in the proglacial zone of Skaftafellsjökull, a retreating glacier in southeastern Iceland. Our study focuses on localized groundwater discharge to a surface-water environment, where high temporal- and spatial-resolution mapping of sediment surface and subsurface temperatures (10–15 cm depth) were obtained by Fiber-Optic Distributed Temperature Sensing (FO-DTS). The FO-DTS survey identified temporally consistent locations of temperature anomalies at the sediment–water interface, indicating distinct zones of cooler groundwater upwelling. The high-resolution FO-DTS surveys were combined with calculations of 1-dimensional groundwater seepage fluxes based on 3 vertical sediment temperature profiles, covering depths of 10, 25, and 40 cm below the lake bed. The calculated groundwater seepage rates ranged between 1.02 to 6.10 m/d. We used the combined techniques successfully to identify substantial temporal and spatial heterogeneities in groundwater–surface exchange fluxes that have relevance for the ecohydrological functioning of the investigated system and its potential resilience to environmental change

Identification of signaling pathways in early mammary gland development by mouse genetics

The mammary gland develops as an appendage of the ectoderm. The prenatal stage of mammary development is hormone independent and is regulated by sequential and reciprocal signaling between the epithelium and the mesenchyme. A number of recent studies using human and mouse genetics, in particular targeted gene deletion and transgenic expression, have identified some of the signals that control specific steps in development. This process involves cell specification and proliferation, reciprocal tissue interactions and cell migration. Since some of these events are recapitulated during tumorigenesis, an understanding of these signaling pathways may contribute to the development of targeted therapies and novel drugs

Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis

Anti-CTLA-4 antibodies have pioneered the field of tumour immunotherapy. However, despite impressive clinical response data, the mechanism by which anti-CTLA-4 antibodies work is still controversial. Two major checkpoint antibodies (ipilimumab and tremelimumab) have been trialled clinically. Both have high affinity binding to CTLA-4 and occupy the ligand binding site, however recently it has been suggested that in some settings such antibodies may not block ligand-CTLA-4 interactions. Here we evaluated blocking capabilities of these antibodies in a variety of settings using both soluble and cell bound target proteins. We found that when ligands (CD80 or CD86) were expressed on cells, soluble CTLA-4-Ig bound in line with affinity expectations and that this interaction was effectively disrupted by both ipilimumab and tremelimumab antibodies. Similarly, cellular CTLA-4 binding to soluble ligands was comparably prevented. We further tested the ability of these antibodies to block transendocytosis, whereby CTLA-4 captures ligands from target cells during a cognate cell-cell interaction. Once again ipilimumab and tremelimumab were similar in preventing removal of ligand by transendocytosis. Furthermore, even once transendocytosis was ongoing and cell contact was fully established, the addition of these antibodies could prevent further ligand transfer. Together these data indicate that the above checkpoint inhibitors performed in-line with predictions based on affinity and binding site data and are capable of blocking CTLA-4-ligand interactions in a wide range of settings tested

Scalable microaccordion mesh for deformable and stretchable metallic films

Elastically deformable materials can be created from rigids sheets through patterning appropriate meshes which can locally bend and flex. We demonstrate how micro-accordion patterns can be fabricated across large areas using three-beam interference lithography. Our resulting mesh induces a large and robust elasticity within any rigid material film. Gold coating the micro-accordion produces stretchable conducting films. Conductivity changes are negligible when the sample is stretched reversibly up to 30% and no major defects are introduced, in comparison to continuous sheets which quickly tear. Scaling analysis shows that our method is suited to further miniaturisation and large- scale fabrication of stretchable functional films. It thus opens routes to stretchable interconnects in electronic, photonic and sensing applications, as well as a wide variety of other deformable structures.We are grateful for funding from the Cambridge NanoDTC, ERC LINASS 320503 and UK EPSRC grants EP/G060649/1, EP/G037221/1, EP/L027151/1 and EP/L015978/1, as well as Nokia Research. RWB thanks Queens’ College Cambridge for financial support.This is the author accepted manuscript. The final version is available from APS via http://dx.doi.org/10.1103/PhysRevApplied.4.04400

Solving ill-posed bilevel programs

This paper deals with ill-posed bilevel programs, i.e., problems admitting multiple lower-level solutions for some upper-level parameters. Many publications have been devoted to the standard optimistic case of this problem, where the difficulty is essentially moved from the objective function to the feasible set. This new problem is simpler but there is no guaranty to obtain local optimal solutions for the original optimistic problem by this process. Considering the intrinsic non-convexity of bilevel programs, computing local optimal solutions is the best one can hope to get in most cases. To achieve this goal, we start by establishing an equivalence between the original optimistic problem an a certain set-valued optimization problem. Next, we develop optimality conditions for the latter problem and show that they generalize all the results currently known in the literature on optimistic bilevel optimization. Our approach is then extended to multiobjective bilevel optimization, and completely new results are derived for problems with vector-valued upper- and lower-level objective functions. Numerical implementations of the results of this paper are provided on some examples, in order to demonstrate how the original optimistic problem can be solved in practice, by means of a special set-valued optimization problem