The Arctic as a test case for an assessment of climate impacts on national security.

The Arctic region is rapidly changing in a way that will affect the rest of the world. Parts of Alaska, western Canada, and Siberia are currently warming at twice the global rate. This warming trend is accelerating permafrost deterioration, coastal erosion, snow and ice loss, and other changes that are a direct consequence of climate change. Climatologists have long understood that changes in the Arctic would be faster and more intense than elsewhere on the planet, but the degree and speed of the changes were underestimated compared to recent observations. Policy makers have not yet had time to examine the latest evidence or appreciate the nature of the consequences. Thus, the abruptness and severity of an unfolding Arctic climate crisis has not been incorporated into long-range planning. The purpose of this report is to briefly review the physical basis for global climate change and Arctic amplification, summarize the ongoing observations, discuss the potential consequences, explain the need for an objective risk assessment, develop scenarios for future change, review existing modeling capabilities and the need for better regional models, and finally to make recommendations for Sandia's future role in preparing our leaders to deal with impacts of Arctic climate change on national security. Accurate and credible regional-scale climate models are still several years in the future, and those models are essential for estimating climate impacts around the globe. This study demonstrates how a scenario-based method may be used to give insights into climate impacts on a regional scale and possible mitigation. Because of our experience in the Arctic and widespread recognition of the Arctic's importance in the Earth climate system we chose the Arctic as a test case for an assessment of climate impacts on national security. Sandia can make a swift and significant contribution by applying modeling and simulation tools with internal collaborations as well as with outside organizations. Because changes in the Arctic environment are happening so rapidly, a successful program will be one that can adapt very quickly to new information as it becomes available, and can provide decision makers with projections on the 1-5 year time scale over which the most disruptive, high-consequence changes are likely to occur. The greatest short-term impact would be to initiate exploratory simulations to discover new emergent and robust phenomena associated with one or more of the following changing systems: Arctic hydrological cycle, sea ice extent, ocean and atmospheric circulation, permafrost deterioration, carbon mobilization, Greenland ice sheet stability, and coastal erosion. Sandia can also contribute to new technology solutions for improved observations in the Arctic, which is currently a data-sparse region. Sensitivity analyses have the potential to identify thresholds which would enable the collaborative development of 'early warning' sensor systems to seek predicted phenomena that might be precursory to major, high-consequence changes. Much of this work will require improved regional climate models and advanced computing capabilities. Socio-economic modeling tools can help define human and national security consequences. Formal uncertainty quantification must be an integral part of any results that emerge from this work

Preliminary systems engineering evaluations for the National Ecological Observatory Network.

The National Ecological Observatory Network (NEON) is an ambitious National Science Foundation sponsored project intended to accumulate and disseminate ecologically informative sensor data from sites among 20 distinct biomes found within the United States and Puerto Rico over a period of at least 30 years. These data are expected to provide valuable insights into the ecological impacts of climate change, land-use change, and invasive species in these various biomes, and thereby provide a scientific foundation for the decisions of future national, regional, and local policy makers. NEON's objectives are of substantial national and international importance, yet they must be achieved with limited resources. Sandia National Laboratories was therefore contracted to examine four areas of significant systems engineering concern; specifically, alternatives to commercial electrical utility power for remote operations, approaches to data acquisition and local data handling, protocols for secure long-distance data transmission, and processes and procedures for the introduction of new instruments and continuous improvement of the sensor network. The results of these preliminary systems engineering evaluations are presented, with a series of recommendations intended to optimize the efficiency and probability of long-term success for the NEON enterprise

Response to sunitinib in combination with proton beam radiation in a patient with chondrosarcoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Chondrosarcoma is well-known to be primarily resistant to conventional radiation and chemotherapy.</p> <p>Case presentation</p> <p>We present the case of a 32-year-old Caucasian man with clear cell chondrosarcoma who presented with symptomatic recurrence in his pelvis and metastases to his skull and lungs. Our patient underwent systemic therapy with sunitinib and then consolidation with proton beam radiation to his symptomatic site. He achieved complete symptomatic relief with a significantly improved performance status and had an almost complete and durable metabolic response on fluorine-18-fluorodeoxyglucose positron emission tomography.</p> <p>Conclusions</p> <p>Our findings have important clinical implications and suggest novel clinical trials for this difficult to treat disease.</p

Identification of Kinases Regulating Prostate Cancer Cell Growth Using an RNAi Phenotypic Screen

As prostate cancer progresses to castration-resistant disease, there is an increase in signal transduction activity. Most castration-resistant prostate tumors continue to express the androgen receptor (AR) as well as androgen-responsive genes, despite the near absence of circulating androgen in these patients. The AR is regulated not only by its cognate steroid hormone, but also by interactions with a constellation of co-regulatory and signaling molecules. Thus, the elevated signaling activity that occurs during progression to castration resistance can affect prostate cancer cell growth either through the AR or independent of the AR. In order to identify signaling pathways that regulate prostate cancer cell growth, we screened a panel of shRNAs targeting 673 human kinases against LNCaP prostate cancer cells grown in the presence and absence of hormone. The screen identified multiple shRNA clones against known and novel gene targets that regulate prostate cancer cell growth. Based on the magnitude of effect on growth, we selected six kinases for further study: MAP3K11, DGKD, ICK, CIT, GALK2, and PSKH1. Knockdown of these kinases decreased cell growth in both androgen-dependent and castration-resistant prostate cancer cells. However, these kinases had different effects on basal or androgen-induced transcriptional activity of AR target genes. MAP3K11 knockdown most consistently altered transcription of AR target genes, suggesting that MAP3K11 affected its growth inhibitory effect by modulating the AR transcriptional program. Consistent with MAP3K11 acting on the AR, knockdown of MAP3K11 inhibited AR Ser 650 phosphorylation, further supporting stress kinase regulation of AR phosphorylation. This study demonstrates the applicability of lentiviral-based shRNA for conducting phenotypic screens and identifies MAP3K11, DGKD, ICK, CIT, GALK2, and PSKH1 as regulators of prostate cancer cell growth. The thorough evaluation of these kinase targets will pave the way for developing more effective treatments for castration-resistant prostate cancer

Atmospheric observations made at Oliktok Point, Alaska, as part of the Profiling at Oliktok Point to Enhance YOPP Experiments (POPEYE) campaign

Between 1 July and 30 September 2018, small unmanned aircraft systems (sUAS), tethered balloon systems (TBSs), and additional radiosondes were deployed at Oliktok Point, Alaska, to measure the atmosphere in support of the second special observing period for the Year of Polar Prediction (YOPP). These measurements, collected as part of the Profiling at Oliktok Point to Enhance YOPP Experiments (POPEYE) campaign, targeted quantities related to enhancing our understanding of boundary layer structure, cloud and aerosol properties and surface&ndash;atmosphere exchange and providing extra information for model evaluation and improvement work. Over the 3-month campaign, a total of 59 DataHawk2 sUAS flights, 52 TBS flights, and 238 radiosonde launches were completed as part of POPEYE. The data from these coordinated activities provide a comprehensive three-dimensional data set of the atmospheric state (air temperature, humidity, pressure, and wind), surface skin temperature, aerosol properties, and cloud microphysical information over Oliktok Point. These data sets have been checked for quality and submitted to the US Department of Energy (DOE) Atmospheric Radiation Measurement (ARM) program data archive (http://www.archive.arm.gov/discovery/, last access: July 2019) and are accessible at no cost by all registered users. The primary dataset DOIs are https://doi.org/10.5439/1418259 (DataHawk2 measurements; Atmospheric Radiation Measurement Program, 2016), https://doi.org/10.5439/1426242 (TBS measurements; Atmospheric Radiation Measurement Program, 2017) and https://doi.org/10.5439/1021460 (radiosonde measurements; Atmospheric Radiation Measurement Program, 2013a).</p

Alternative Splicing in the Differentiation of Human Embryonic Stem Cells into Cardiac Precursors

The role of alternative splicing in self-renewal, pluripotency and tissue lineage specification of human embryonic stem cells (hESCs) is largely unknown. To better define these regulatory cues, we modified the H9 hESC line to allow selection of pluripotent hESCs by neomycin resistance and cardiac progenitors by puromycin resistance. Exon-level microarray expression data from undifferentiated hESCs and cardiac and neural precursors were used to identify splice isoforms with cardiac-restricted or common cardiac/neural differentiation expression patterns. Splice events for these groups corresponded to the pathways of cytoskeletal remodeling, RNA splicing, muscle specification, and cell cycle checkpoint control as well as genes with serine/threonine kinase and helicase activity. Using a new program named AltAnalyze (http://www.AltAnalyze.org), we identified novel changes in protein domain and microRNA binding site architecture that were predicted to affect protein function and expression. These included an enrichment of splice isoforms that oppose cell-cycle arrest in hESCs and that promote calcium signaling and cardiac development in cardiac precursors. By combining genome-wide predictions of alternative splicing with new functional annotations, our data suggest potential mechanisms that may influence lineage commitment and hESC maintenance at the level of specific splice isoforms and microRNA regulation

MicroRNA profiling of the pubertal mouse mammary gland identifies miR-184 as a candidate breast tumour suppressor gene

INTRODUCTION: The study of mammalian development has offered many insights into the molecular aetiology of cancer. We previously used analysis of mammary morphogenesis to discover a critical role for GATA-3 in mammary developmental and carcinogenesis. In recent years an important role for microRNAs (miRNAs) in a myriad of cellular processes in development and in oncogenesis has emerged. METHODS: microRNA profiling was conducted on stromal and epithelial cellular subsets microdissected from the pubertal mouse mammary gland. miR-184 was reactivated by transient or stable overexpression in breast cancer cell lines and examined using a series of in vitro (proliferation, tumour-sphere and protein synthesis) assays. Orthotopic xenografts of breast cancer cells were used to assess the effect of miR-184 on tumourigenesis as well as distant metastasis. Interactions between miR-184 and its putative targets were assessed by quantitative PCR, microarray, bioinformatics and 3' untranslated region Luciferase reporter assay. The methylation status of primary patient samples was determined by MBD-Cap sequencing. Lastly, the clinical prognostic significance of miR-184 putative targets was assessed using publicly available datasets. RESULTS: A large number of microRNA were restricted in their expression to specific tissue subsets. MicroRNA-184 (miR-184) was exclusively expressed in epithelial cells and markedly upregulated during differentiation of the proliferative, invasive cells of the pubertal terminal end bud (TEB) into ductal epithelial cells in vivo. miR-184 expression was silenced in mouse tumour models compared to non-transformed epithelium and in a majority of breast cancer cell line models. Ectopic reactivation of miR-184 inhibited the proliferation and self-renewal of triple negative breast cancer (TNBC) cell lines in vitro and delayed primary tumour formation and reduced metastatic burden in vivo. Gene expression studies uncovered multi-factorial regulation of genes in the AKT/mTORC1 pathway by miR-184. In clinical breast cancer tissues, expression of miR-184 is lost in primary TNBCs while the miR-184 promoter is methylated in a subset of lymph node metastases from TNBC patients. CONCLUSIONS: These studies elucidate a new layer of regulation in the PI3K/AKT/mTOR pathway with relevance to mammary development and tumour progression and identify miR-184 as a putative breast tumour suppressor

New Mexico cloud super cooled liquid water survey final report 2009.

Los Alamos and Sandia National Laboratories are partners in an effort to survey the super-cooled liquid water in clouds over the state of New Mexico in a project sponsored by the New Mexico Small Business Assistance Program. This report summarizes the scientific work performed at Sandia National Laboratories during the 2009. In this second year of the project a practical methodology for estimating cloud super-cooled liquid water was created. This was accomplished through the analysis of certain MODIS sensor satellite derived cloud products and vetted parameterizations techniques. A software code was developed to analyze multiple cases automatically. The eighty-one storm events identified in the previous year effort from 2006-2007 were again the focus. Six derived MODIS products were obtained first through careful MODIS image evaluation. Both cloud and clear-sky properties from this dataset were determined over New Mexico. Sensitivity studies were performed that identified the parameters which most influenced the estimation of cloud super-cooled liquid water. Limited validation was undertaken to ensure the soundness of the cloud super-cooled estimates. Finally, a path forward was formulized to insure the successful completion of the initial scientific goals which include analyzing different of annual datasets, validation of the developed algorithm, and the creation of a user-friendly and interactive tool for estimating cloud super-cooled liquid water

WINTER DISTRIBUTION OF GREATER SANDHILL CRANES MARKED AT BREEDING AREAS IN CALIFORNIA, OREGON, AND WASHINGTON

Large numbers of greater sandhill cranes (Grus canadensis tabida) have been banded and color-marked at several important breeding sites in the western U.S. since the late 1960s. Crane color-marking began in the late 1960s at Malheur National Wildlife Refuge (NWR) in eastern Oregon. Crane marking programs were initiated at Sycan Marsh, Summer Lake Wildlife Area (both in south-central Oregon), as well as at Modoc NWR in the mid-1980s. In the mid-1990s, a marking program was initiated at Conboy Lake NWR in south-central Washington. This paper reviews winter records and distribution of marked birds from these sites within the Central Valley of California, reviews their movements between wintering areas, assesses their fidelity to wintering sites and discusses conservation implications of this information