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The ability to properly model intravascular steps in metastasis is essential in identifying key physical, cellular, and molecular determinants that can be targeted therapeutically to prevent metastatic disease. Research on the vascular microenvironment has been hindered by challenges in studying this compartment in metastasis under conditions that reproduce in vivo physiology while allowing facile experimental manipulation. We present a microfluidic vasculature system to model interactions between circulating breast cancer cells with microvascular endothelium at potential sites of metastasis. The microfluidic vasculature produces spatially-restricted stimulation from the basal side of the endothelium that models both organ-specific localization and polarization of chemokines and many other signaling molecules under variable flow conditions. We used this microfluidic system to produce site-specific stimulation of microvascular endothelium with CXCL12, a chemokine strongly implicated in metastasis. When added from the basal side, CXCL12 acts through receptor CXCR4 on endothelium to promote adhesion of circulating breast cancer cells, independent of CXCL12 receptors CXCR4 or CXCR7 on tumor cells. These studies suggest that targeting CXCL12-CXCR4 signaling in endothelium may limit metastases in breast and other cancers and highlight the unique capabilities of our microfluidic device to advance studies of the intravascular microenvironment in metastasis.

The seasonal decline in foliar nutritional quality in deciduous trees also effects the availability of essential micronutrients, such as ascorbate and alpha-tocopherol, to herbivorous insects. This study first examined whether there are consistent patterns of seasonal change in antioxidant concentrations in deciduous tree leaves. Alpha-tocopherol concentrations increased substantially through time in late summer in sugar maple (Acer saccharum), red oak (Quercus rubra), and trembling aspen (Populus tremuloides). However, seasonal change in the concentrations of other antioxidants differed between each species: P. tremuloides had higher levels of ascorbate and glutathione in the spring, Q. rubra had higher levels of glutathione but lower levels of ascorbate in the spring, and A. saccharum had lower levels of both ascorbate and glutathione in the spring. To test the hypothesis that tannin-tolerant caterpillars maintain higher concentrations of antioxidants in their midgut fluids than do tannin-sensitive species, we measured antioxidants in Orgyia leucostigma (a spring- and summer-feeding, tannin-tolerant species) and Malacosoma disstria (a spring-feeding, tannin-sensitive species) that were fed tree leaves in the spring and summer. The midgut fluids of O. leucostigma larvae generally had higher concentrations of antioxidants in the summer than did those of M. disstria, and were significantly higher overall. The results of this study are consistent with the hypothesis that higher concentrations of antioxidants form an important component of the defenses of herbivores that feed on mature, phenol-rich tree leaves. Some limitations of the interpretation of total antioxidant capacity are also discussed.

Diabetes mellitus affects the metabolism of carbohydrates, thus patients should monitor carbohydrate intake and eat a heart-healthy diet using nutrition labels. To assess carbohydrate counting skills, knowledge of heart-healthy diet, and nutrition label-reading skills the Heart-Healthy Carb Quiz (HHCQ) was developed and assessed for its validity and reliability in adults with diabetes. Data were analyzed for 55 subjects; average age was 41.7 ± 17.6 years and 29 participants were women. Thirty-six participants had type 1 diabetes and 19 had type 2; average duration of diabetes was 14.3 ± 12.3 years. Average HbA1c was 8.0% ± 2.0%. HHCQ total scores correlated significantly with CarbQuiz total scores (r=0.39, p = 0.003) and the HHCQ demonstrated good stability in the test-retest measure (r=0.74, p = 0.001) (both assessed using a Pearson product-moment correlation). Cronbach α was 0.70; inter-item total correlation was 0.45. This study supports the validity and reliability of the HHCQ.

\"I have been to the mountain\" were the words that he spoke.

Early childhood development programmes vary in coordination and quality, with inadequate and inequitable access, especially for children younger than 3 years. New estimates, based on proxy measures of stunting and poverty, indicate that 250 million children (43%) younger than 5 years in low-income and middle-income countries are at risk of not reaching their developmental potential. There is therefore an urgent need to increase multisectoral coverage of quality programming that incorporates health, nutrition, security and safety, responsive caregiving, and early learning. Equitable early childhood policies and programmes are crucial for meeting Sustainable Development Goals, and for children to develop the intellectual skills, creativity, and wellbeing required to become healthy and productive adults. In this paper, the first in a three part Series on early childhood development, we examine recent scientific progress and global commitments to early childhood development. Research, programmes, and policies have advanced substantially since 2000, with new neuroscientific evidence linking early adversity and nurturing care with brain development and function throughout the life course.

The warm and saline Atlantic Water has long been recognized as being subjected to substantial heat loss during its transit towards the polar regions. In particular, the Lofoten Basin, a subpolar sea with energetic eddy activity and strong air-sea interactions, plays a crucial role in the transformation of Atlantic Water. Vertical heat transport at submesoscales (0.1-10 km) in the Lofoten Basin is potentially a key link in the heat transfer to the atmosphere. Here, based on multi-year Seaglider observations augmented by satellite altimeters, radiometers, and high-resolution numerical model results, we evaluate the oceanic vertical heat transport in the Lofoten Basin and demonstrate how geostrophic strain enhances heat transport. The enhancement is found to be associated with submesoscale ageostrophic motions along the mesoscale eddy edges, occurring on spatial scales smaller than 10 km and below the mixed layer depth. These strain-induced submesoscale vertical motions transport heat from the ocean interior to the surface, leading to a 0.4 °C increase in sea surface temperature and the formation of “warm ring” structures in both cyclones and anticyclones. The dominant role of submesoscale heat transport likely represents the primary mechanism for substantial heat loss from Atlantic Water in the Lofoten Basin. The authors use data from underwater gliders, satellites and numerical simulations and show that submesoscale motions at ocean eddy edges pump heat upward, forming “warm rings” and a ~ 0.4 °C warming in the Lofoten Basin—a key pathway for Atlantic water heat loss.

An NCI-sponsored, randomized clinical trial tested whether patients with relapsed ovarian cancer might benefit from surgical debulking of tumors followed by chemotherapy, as compared with chemotherapy alone. No significant outcome differences were noted between the patients who underwent surgery and those treated with chemotherapy alone.

Findings of polymerase chain reaction (PCR) studies of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) and breast cancer vary, making it difficult to determine whether either, both, or neither virus is causally associated with breast cancer. We investigated CMV and EBV in paired samples of breast cancer and normal breast tissue from 70 women using quantitative PCR. A serum sample from each woman was tested for CMV and EBV IgG. To place our results in context, we reviewed the existing literature and performed a meta-analysis of our results together with previous PCR studies of EBV, CMV, and breast cancer. Of the serology samples, 67 of 70 (96%) were EBV IgG positive and 49 of 70 (70%) were CMV IgG positive. QPCR detected EBV in 24 (34%) of the tumour and 9 (13%) of the paired normal specimens and CMV in 0 (0%) of the tumour and 2 (3%) of the paired normal specimens. Our findings, together with earlier results summarised in the meta-analysis, suggest several possibilities: variable findings may be due to limitations of molecular analyses; 'hit and run' oncogenesis may lead to inconsistent results; one or both viruses has a role at a later stage in breast cancer development; infection with multiple viruses increases breast cancer risk; or neither virus has a role. Future studies should focus on ways to investigate these possibilities, and should include comparisons of breast cancer tissue samples with appropriate normal tissue samples.

The concept of resilience has evolved considerably since Holling’s (1973) seminal paper. Different interpretations of what is meant by resilience, however, cause confusion. Resilience of a system needs to be considered in terms of the attributes that govern the system’s dynamics. Three related attributes of social–ecological systems (SESs) determine their future trajectories: resilience, adaptability, and transformability. Resilience (the capacity of a system to absorb disturbance and reorganize while undergoing change so as to still retain essentially the same function, structure, identity, and feedbacks) has four components—latitude, resistance, precariousness, and panarchy—most readily portrayed using the metaphor of a stability landscape. Adaptability is the capacity of actors in the system to influence resilience (in a SES, essentially to manage it). There are four general ways in which this can be done, corresponding to the four aspects of resilience. Transformability is the capacity to create a fundamentally new system when ecological, economic, or social structures make the existing system untenable. The implications of this interpretation of SES dynamics for sustainability science include changing the focus from seeking optimal states and the determinants of maximum sustainable yield (the MSY paradigm), to resilience analysis, adaptive resource management, and adaptive governance.

Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor α (ERα) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression. In accordance with these findings, nuclear ERα protein levels are altered by stress in male and female mice. Further, overexpression of ERα in the NAc promotes stress resilience in both sexes. Subsequent RNA-sequencing reveals that ERα overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ERα is an important regulator of pro-resilient transcriptional changes, but with sex-specific downstream targets. Stress resilience is accompanied by broad changes in gene expression. This study shows that estrogen receptor α (ERα) is a key upstream regulator of these changes in the nucleus accumbens, and that overexpression of ERα increases behavioral resilience via a sex-specific transcriptional mechanism.