Lung microvascular and arterial endothelial cells differ in their responses to intercellular adhesion molecule-1 ligation

Neutrophil adherence to tumor necrosis factor-α (TNF-α)-treated human pulmonary microvascular endothelial cells (PMECs) induces cytoskeletal changes in endothelial cells that require intercellular adhesion molecule-1 (ICAM-1)-dependent signaling events. This study determined whether similar changes occurred in rat PMECs and whether rat pulmonary arterial endothelial cells (PAECs) responded differently. Neutrophil adherence induced an increase in the formation of F-actin and in the apparent stiffness of TNF-α-treated rat PMECs. These responses, however, were absent in PAECs. To determine the mechanisms underlying these differences, ICAM-1-mediated signaling events were compared. Upregulation of ICAM-1 by TNF-α and redistribution of ICAM-1 induced by cross-linking antibodies were similar in both cell types. However, neutrophil adherence induced production of reactive oxygen species only in PMECs and not in PAECs. Moreover, phosphorylation of p38 mitogen-activated protein kinase induced by ICAM-1 cross-linking occurred only in PMECs and not in PAECs. This increase in p38 phosphorylation in PMECs was inhibited by allopurinol, a xanthine oxidase inhibitor. These data demonstrated that whereas TNF-α upregulated ICAM-1 and ICAM-1 cross-linking induced a similar redistribution of ICAM-1 on the endothelial cell surface, ICAM-1 ligation initiated p38 activation and cytoskeletal rearrangements only in PMECs and not in PAECs. Thus, neutrophil adhesion through ICAM-1 induced signaling events leading to cytoskeletal changes only in PMECs, the site of neutrophil emigration and edema formation, and not in PAECs

Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma

In vivo fiber optic raman spectroscopy of muscle in preclinical models of amyotrophic lateral sclerosis and Duchenne muscular dystrophy

Neuromuscular diseases result in muscle weakness, disability, and, in many instances, death. Preclinical models form the bedrock of research into these disorders, and the development of in vivo and potentially translational biomarkers for the accurate identification of disease is crucial. Spontaneous Raman spectroscopy can provide a rapid, label-free, and highly specific molecular fingerprint of tissue, making it an attractive potential biomarker. In this study, we have developed and tested an in vivo intramuscular fiber optic Raman technique in two mouse models of devastating human neuromuscular diseases, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy (SOD1G93A and mdx, respectively). The method identified diseased and healthy muscle with high classification accuracies (area under the receiver operating characteristic curves (AUROC): 0.76–0.92). In addition, changes in diseased muscle over time were also identified (AUROCs 0.89–0.97). Key spectral changes related to proteins and the loss of α-helix protein structure. Importantly, in vivo recording did not cause functional motor impairment and only a limited, resolving tissue injury was seen on high-resolution magnetic resonance imaging. Lastly, we demonstrate that ex vivo muscle from human patients with these conditions produced similar spectra to those observed in mice. We conclude that spontaneous Raman spectroscopy of muscle shows promise as a translational research tool

Promised Land? Immigration, Religiosity, and Space in Southern California

This article looks at how immigrants and their supporters appropriate and use religious space and other public spaces for religious and socio-political purposes in Southern California. While the everyday living conditions of many immigrants, particularly the unauthorized Latino immigrants, force unto them an embodied disciplinarity that maintains spatialities of restricted citizenship, the public appropriations of space for and through religious practices allow for them -even if only momentarily -to express an embodied transgression. This practice in public space helps realize spaces of freedom and hope, however ephemerally. Potentially, these rehearsing exercises can help revert internalized disempowering subjectivities and create social empowerment. Negative stereotypes about immigrants held by the larger public can also be challenged through these spatial practices, as the public demonstrations make visible the invisible. We focus on “Posadas Without Borders” and “the New Sanctuary Movement,” considering both the role of progressive civic and religious institutions in supporting immigrants and the agency of the immigrants themselves. The theoretical analysis builds on concepts drawn from a conversation between geography and religious and theological studies. We use a triangulated methodological approach that includes observation and participant observation, content-analysis of multimedia, interviews, and intellectual advocacy for the immigrant movement. The cases discussed here show that progressive religious groups and coalitions can be important allies to progressive planners, geographers, and policy makers in advancing social and environmental justice for the disenfranchised. They also show that the theological underpinnings of such groups share a lot in common with planning epistemologies for the just city

Origins of the Ambient Solar Wind: Implications for Space Weather

The Sun's outer atmosphere is heated to temperatures of millions of degrees, and solar plasma flows out into interplanetary space at supersonic speeds. This paper reviews our current understanding of these interrelated problems: coronal heating and the acceleration of the ambient solar wind. We also discuss where the community stands in its ability to forecast how variations in the solar wind (i.e., fast and slow wind streams) impact the Earth. Although the last few decades have seen significant progress in observations and modeling, we still do not have a complete understanding of the relevant physical processes, nor do we have a quantitatively precise census of which coronal structures contribute to specific types of solar wind. Fast streams are known to be connected to the central regions of large coronal holes. Slow streams, however, appear to come from a wide range of sources, including streamers, pseudostreamers, coronal loops, active regions, and coronal hole boundaries. Complicating our understanding even more is the fact that processes such as turbulence, stream-stream interactions, and Coulomb collisions can make it difficult to unambiguously map a parcel measured at 1 AU back down to its coronal source. We also review recent progress -- in theoretical modeling, observational data analysis, and forecasting techniques that sit at the interface between data and theory -- that gives us hope that the above problems are indeed solvable.Comment: Accepted for publication in Space Science Reviews. Special issue connected with a 2016 ISSI workshop on "The Scientific Foundations of Space Weather." 44 pages, 9 figure

The evolutionary history of wild, domesticated, and feral brassica oleracea (Brassicaceae)

Understanding the evolutionary history of crops, including identifying wild relatives, helps to provide insight for conservation and crop breeding efforts. Cultivated Brassica oleracea has intrigued researchers for centuries due to its wide diversity in forms, which include cabbage, broccoli, cauliflower, kale, kohlrabi, and Brussels sprouts. Yet, the evolutionary history of this species remains understudied. With such different vegetables produced from a single species, B. oleracea is a model organism for understanding the power of artificial selection. Persistent challenges in the study of B. oleracea include conflicting hypotheses regarding domestication and the identity of the closest living wild relative. Using newly generated RNA-seq data for a diversity panel of 224 accessions, which represents 14 different B. oleracea crop types and nine potential wild progenitor species, we integrate phylogenetic and population genetic techniques with ecological niche modeling, archaeological, and literary evidence to examine relationships among cultivars and wild relatives to clarify the origin of this horticulturally important species. Our analyses point to the Aegean endemic B. cretica as the closest living relative of cultivated B. oleracea, supporting an origin of cultivation in the Eastern Mediterranean region. Additionally, we identify several feral lineages, suggesting that cultivated plants of this species can revert to a wild-like state with relative ease. By expanding our understanding of the evolutionary history in B. oleracea, these results contribute to a growing body of knowledge on crop domestication that will facilitate continued breeding efforts including adaptation to changing environmental conditions