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This study makes three contributions to the debate over the effect of local land use regulations on housing prices and affordability. First, it is more geographically extensive than previous studies, encompassing 336 of the nation's 384 metropolitan areas. Second, it looks at multiple measures of regulatory stringency, not just one. Most prior studies have focused either on a single regulatory measure or index across multiple metropolitan areas, or multiple regulatory measures in a single region. Third, this paper considers the connection between regulatory stringency and housing values as a function of employment growth and per-worker payroll levels. We find that restrictive land use regulations do indeed have a pervasive effect on local home values and rents, and that these effects are magnified in faster-growing and more prosperous economies. We also find more restrictive land use regulations are not associated with faster rates of recent home value or rent growth, and that their effects on housing construction levels—that is, the degree to which they constrain supply—is uneven among different housing markets.

This article uses a series of fixed-ratio projections and scenarios to explore the potential for local residential energy conservation mandates and compact growth programs to reduce locally based CO2 emissions in eleven representative US metropolitan areas. Averaged across all eleven metros, residential energy conservation mandates could reduce residential CO2 emissions in 2030 by an average of 30 percent over and above 2010 levels. In terms of implementation, residential conservation standards were found to be goal-effective, cost-effective, scale-effective, and in the case of new construction standards, reasonably resistant to local political pushback. Local compact growth programs do not perform as well. If accompanied by aggressive efforts to get drivers out of their cars, compact growth programs could reduce auto-based 2030 CO2 emissions by as much as 25 percent over and above any emissions reductions attributable to higher fuel economy standards. Unaccompanied by modal diversion programs, the stand-alone potential for local compact growth programs to reduce auto-based CO2 emissions falls into a more modest range of 0 to 7 percent depending on the metropolitan area. Based on past performance, local compact growth programs are also likely to have problems in terms of their goal- and scale-efficiency, and their potential to incur political pushback.

Meeting forest restoration challenges relies on successful establishment of plant materials (e.g., seeds, cuttings, rooted cuttings, or seedlings, etc.; hereafter simply “seedlings”). The Target Plant Concept (TPC) provides a flexible framework that nursery managers and their clients can use to improve the survival and growth of these seedlings. The key tenets of the TPC are that (1) more emphasis is placed on how seedlings perform on the outplanting site rather than on nursery performance, (2) a partnership exists between the nursery manager and the client to determine the target plant based on site characteristics, and (3) that information gleaned from post-planting monitoring is used to improve subsequent plant materials. Through the nursery manager–client partnership, answers to a matrix of interrelated questions define a target plant to meet the reforestation or forest restoration objectives. These questions focus on project objectives; site characteristics, limiting factors, and possible mitigation efforts; species and genetic criteria; stocktype; outplanting tools and techniques; and outplanting window. We provide examples from the southeastern United States, Hawai‛i, and Lebanon on how the TPC process has improved performance of seedlings deployed for reforestation and forest restoration.

The ITER ECRH system consists of 24 gyrotrons with up to 24 MW installed millimeter wave heating power at 170 GHz, power supplies, control system, transmission lines, one Equatorial and the four Upper Launchers. With its high frequency and small beam focus the ECRH has the unique capability of driving locally current. While the Equatorial Launcher mainly acts for central heating and current profile shaping, the Upper Launchers aim on suppressing MHD instabilities, especially neoclassical tearing modes (NTM) triggering plasma disruptions. The Upper Launchers inject millimeter waves through a quasi-optical section consisting of three fixed and the front steering mirror set. The eight overlapping beams have focal points optimized for suppression of the q = 3/2 and q = 2/1 NTMs., Several project change requests required the redesign of the Upper Launchers and the connected ex-vessel system. This redesign includes a new boundary geometry of the launchers as well as a newly designed cooling system for the Blanket Shield Module (BSM), a modified flange of the BSM to the structural main frame and a refined optical design. Additionally shield blocks with integrated in-vessel waveguides were added and the closure plate with waveguide and supply line feedthroughs was adapted. Further changes, not all caused by PCRs, include newly designed ex-vessel waveguide components with a reduced aperture and redesigned ultra low-loss CVD diamond windows. Finally several components originally foreseen as off-the-shelf components have become part of the design scope. The new launcher design status is presented with selected results on numerical design validation.

Combining horizontal drilling with high volume hydraulic fracturing has increased extraction of hydrocarbons from low-permeability oil and gas (OG) formations across the United States; accompanied by increased wastewater production. Surface water discharges of OG wastewater by centralized waste treatment (CWT) plants pose risks to aquatic and human health. We evaluated the impact of surface water disposal of OG wastewater from CWT plants upstream of the Conemaugh River Lake (dam controlled reservoir) in western Pennsylvania. Regulatory compliance data were collected to calculate annual contaminant loads (Ba, Cl, total dissolved solids (TDS)) to document historical industrial activity. In this study, two CWT plants 10 and 19 km upstream of a reservoir left geochemical signatures in sediments and porewaters corresponding to peak industrial activity that occurred 5 to 10 years earlier. Sediment cores were sectioned for the collection of paired samples of sediment and porewater, and analyzed for analytes to identify unconventional OG wastewater disposal. Sediment layers corresponding to the years of maximum OG wastewater disposal contained higher concentrations of salts, alkaline earth metals, and organic chemicals. Isotopic ratios of

Purpose: Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy. Experimental Design: Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. Results: Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24−, ALDH+, and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies. Conclusions: These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. Clin Cancer Res; 19(6); 1512–24. ©2012 AACR.

One of the possible solutions to the world's rapidly increasing energy demand is the development of new photoelectrochemical cells with improved light absorption. This requires development of semiconductor materials which have appropriate bandgaps to absorb a large part of the solar spectrum at the same time as being stable in aqueous environments. Here we demonstrate an efficient, computational screening of relevant oxide and oxynitride materials based on electronic structure calculations resulting in the reduction of a vast space of 5400 different materials to only 15 promising candidates. The screening is based on an efficient and reliable way of calculating semiconductor band gaps. The outcome of the screening includes all already known successful materials of the types investigated plus some new ones which warrant further experimental investigation.

Context: Quantitative clinical measurement of heterogeneity in immunohistochemistry staining would be useful in both evaluating patient therapeutic response and identifying underlying issues in histopathology laboratory quality control. Objective: To create a heterogeneity scoring approach (HetMap) that allows the visualization of an individual patient's IHC heterogeneity in the context of a population. Design: We combined HER2 semi-quantitative analysis with the use of ecology diversity statistics to evaluate cell-level heterogeneity (consistency of protein expression within neighboring cells in a tumor nest) and tumor-level heterogeneity (differences of protein expression across a tumor as represented by a tissue section). We evaluated the approach on HER2 immunohistochemistry stained breast cancer samples, using 200 specimens across two different CLIA laboratories, with three pathologists at each laboratory each outlining regions of tumor for scoring by automatic cell-based image analysis. HetMap was evaluated using three different scoring schemes: HER2 scoring according to ASCO/CAP guidelines, H-Score and a new continuous HER2 score (HER2cont). Results: Two definitions of heterogeneity, cell-level and tumor-level, provided useful independent measures of heterogeneity. Cell-level heterogeneity, reported either as an average or the maximum area of heterogeneity across a slide, had low levels of dependency on the pathologist choice of region (coefficient of variation of 15%). Tumor-level heterogeneity measurements had more dependence on the pathologist choice of regions (coefficient of variation of 25%). Results were highly similar between the two laboratories, which is encouraging for HER2 standardization, as the labs involved different pathologists, different specimens, and different standardization procedures, although both complied with CLIA/CAP guidelines for HER2 testing. Conclusions: HetMap is a measure of heterogeneity, by which pathologists, oncologists, and drug development organizations can view cell-level and tumor-level heterogeneity for a patient for a given marker in the context of an entire patient cohort. Heterogeneity analysis can be a useful means to identify tumors with higher degrees of heterogeneity, or to highlight slides that should be rechecked for QC issues. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-17.

Obesity is thought to contribute to worse disease outcome in breast cancer as a result of increased levels of adipocyte-secreted endocrine factors, insulin, and insulin-like growth factors (IGFs) that accelerate tumor cell proliferation and impair treatment response. We examined the effects of patient obesity on primary breast tumor gene expression, by profiling transcription of a set of 103 tumors for which the patients' body mass index (BMI) was ascertained. Sample profiles were stratified according to patients' obesity phenotype defined as normal (BMI25), overweight (BMI 25-29.9), or obese (BMI ≥ 30). Widespread gene expression alterations were evident in breast tumors from obese patients as compared to other tumors, allowing us to define an obesity-associated cancer transcriptional signature of 662 genes. In multiple public expression data sets of breast cancers (representing1,500 patients), manifestation of the obesity signature patterns correlated with manifestation of a gene signature for IGF signaling and (to a lesser extent) with lower levels of estrogen receptor. In one patient cohort, manifestation of the obesity signature correlated with shorter time to metastases. A number of small molecules either induced or suppressed the obesity-associated transcriptional program in vitro; estrogens alpha-estradiol, levonorgestrel, and hexestrol induced the program, while several anti-parkinsonian agents targeting neurotransmitter receptor pathways repressed the program. Obesity in breast cancer patients appears to impact the gene expression patterns of the tumor (perhaps as a result of altered body chemistry). These results warrant further investigation of obesity-associated modifiers of breast cancer risk and disease outcome.

We evaluated the effect of so-called monitoring and treatment charts on the management of eclampsia in a referral hospital in Malawi. Baseline characteristics, clinical management, as well as overall maternal and perinatal outcome were compared by reviewing the medical files of two groups, before and after introduction of the charts in 2006. The use of the charts has resulted in improved monitoring of women with eclampsia and may have contributed to the reduction in the planned prelabour caesarean section rate from 87% to 33%, as more women underwent induction of labour after stabilisation (P = 0.020). Overall maternal and perinatal outcomes were similar.

In the same way that rural towns gave way to cities in the middle of the nineteenth century, cities gave way to metropolitan areas in the middle of the twentieth century. Today, the United States is overwhelmingly metropolitan. Using tabular and spatial data from the U.S. Census Bureau, the Department of Labor, and the U.S. Geological Survey, this article explores metropolitan population, employment, and urban settlement trends since 1990. The first part of the article compares intermetropolitan changes in population and employment in 1990, 2000, and 2007. The second part considers the changing intrametropolitan distribution of population and households between 1990 and 2000 and of employment between 1994 and 2003. Finally, the third part explores changes in density and urban land cover between 1990 (or 1992) and 2000 (or 2001). These findings are reported by geographic region, metropolitan area size, and metropolitan gateway status.

The ecological effects of roads impact about 15% of the land area of the US—an area equivalent in size to all the protected areas of the country combined. The ecological health of roadsides and road-impacted areas has not been adequately addressed. Most road projects today involve modifications to existing roads rather than new construction. As roads are modified section by section, a tremendous opportunity arises to remedy the oversights of the past, improving conditions for healthier ecosystems. The challenge is to move beyond regulation-driven mitigation approaches and into proactive environmental stewardship. Native plants are a foundation of ecological health and function. Revegetating with native plants is a key practice for managing environmental impacts. To be successful, native vegetation issues cannot be considered as an afterthought to larger road planning and construction processes. Instead, they must be an integral part of the process of designing and constructing roads. A partnership between the Federal Highway Administration and the USDA Forest Service has developed an approach to revegetation that is goal-oriented, context-sensitive, and collaborative. This is an interdisciplinary, interagency team approach with early (3-y minimum) collaboration, shared objectives, and clear guidelines. Cooperation allows time and funding for growers to produce the quality and quantity of native plant materials required. Two new publications, Roadside Revegetation: An Integrated Approach to Establishing Native Plants and A Manager’s Guide to Roadside Revegetation Using Native Plants are available.

Background Developing novel strategies against treatment-resistant triple negative breast cancer (TNBC) cells remains a significant challenge. The ErbB family, including epidermal growth factor receptor (EGFR), plays key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSC) which are believed to be responsible for tumor initiation and maintenance. Ixabepilone is a new generation microtubule-stabilizing agent, which has been expected to be more efficacious than conventional taxanes. Here we aim to investigate whether the EGFR monoclonal antibody Cetuximab, in combination with Ixabepilone, is more effective in eliminating CSC populations compared to chemotherapy alone in TNBC. Methods Representative TNBC cell lines (MDA-MB-231 and SUM159) were used to evaluate breast CSC populations. We used fluorescence-activated cell sorter analysis (CD44+ and CD24-/low, or Aldefluor+) and a self-renewal assay called mammosphere formation efficiency (MSFE) to measure CSC population size after treatment with Cetuximab, or Cetuximab plus Ixabepilone in vitro. Results Although there was no significant decrease in cell viability, Cetuximab reduced MSFE and the CSC population in breast cancer cells in vitro and in vivo through inhibition of autophagy. Also, SUM159 and MDA-MB-231 orthotopic tumors demonstrated partial response to Centuximab or Ixabepilone monotherapy; however, the effect of the combination treatment was significant only in SUM159 tumors (p

Road revegetation with native plants is both a challenge and an opportunity. A new partnership between the Western Federal Lands Highway Division of the Federal Highway Administration and the USDA Forest Service is focusing on the use of native plants for forest highway road revegetation and road obliteration projects. This emphasis is leading to new applications for many native plant species, as well as development of new stock types, innovative equipment, and monitoring techniques. The process of road planning and development has become more holistic and comprehensive, allowing engineers and biologists to work in partnerships to bring about desired results. Unique challenges of road revegetation projects include harsh conditions, high visibility, and a lack of available information and techniques. Road revegetation offers unique opportunities, including long lead times that facilitate advanced seed procurement and nursery development of native plants, as well as allowing time to evaluate different installation techniques. Two projects highlighting some innovative road revegetation strategies and native stock types are discussed: one along a scenic section of a river on steep mountainous terrain, another on a well-traveled, visually sensitive road near a ski area. Strategies included developing and testing hydroseeding mixes and application techniques with native shrub, forb, and grass species; developing seeded mats for establishing native grasses on severe sites such as gabion walls; and overcoming obstacles to obtaining and increasing high-quality local native plant seed. Because little information is available on revegetating roads with native plants, a new manual is being created to help meet the challenges ahead.

Although transesophageal echocardiography (TEE) is a well-established tool in delineating the cardiac and aortic sources of emboli in stroke patients, its reproducibility in detecting aortic atherosclerosis (AA) that may lead to stroke is not well documented. The aim of this study is to demonstrate the inter- and intra-observer agreement in diagnosing AA based on the TEE study. During the study period, 2 echocardiographers read 32 TEE studies performed on a group of stroke patients. The AA was estimated by measuring the largest atheroma thickness in millimeters (mm). The intra-observers and intraclass correlation coefficients (ICC) were 0.97 and 0.85, respectively, for the 2 TEE observers. The inter-rater ICC coefficient between TEE readers was 0.91. In conclusion, TEE detected AA and defined high proportions of the morphological characteristics of atheroma with good reproducibility among inter and intra-observers.

A FS launcher is being designed for the ITER upper port, which offers enhanced physics performance over the RS launcher. A two mirror system is used to decouple the focusing and steering aspects of the launcher and provide a relatively small beam waist ( 1.6 m from the steering mirror). The resulting NTM stabilization efficiency (maximum CD density divided by the local bootstrap current >1.6) is above marginal for the q=2 and 3/2 rational flux surfaces of the relevant ITER equilibria (scenarios 2, 3a and 5) and a factor of ~3 relative to an equivalent RS launcher. The performance of the FS launcher strongly depends on the reliability of the steering mechanism, which is used to rotate the plasma facing steering mirror. CRPP has designed a frictionless steering mechanism assembled in a compact cartridge capable of up to plusmn7deg rotation (corresponding to a poloidal steering range of up to plusmn14deg for the microwave beam around a fixed axis of rotation) that offers a high operation reliability despite the close proximity to the thermal and neutron flux coming from the ITER plasma

This article explores the effects of metropolitan industrial structure on housing market outcomes. Housing prices in new economy metropolitan areas are found to be higher, peakier, and more volatile than in old economy markets. Homeownership rates are found to be lower in new economy metropolitan areas, while crowding is higher. Although the distribution of housing values, costs, and rents was more equal in new economy markets, the cause would seem to be differences in area income levels, with poorer metropolitan statistical areas having greater inequalities. Regression analysis is used to identify the contribution of traditional supply and demand factors, such as job growth, income, and residential construction, as well as new economy indicators, to housing market outcomes. Rather than being fundamentally different, new economy housing markets are found to be faster and more extreme versions of traditional housing markets.

RHESSI is the sixth in the NASA line of Small Explorer (SMEX) missions and the first managed in the Principal Investigator mode, where the PI is responsible for all aspects of the mission except the launch vehicle. RHESSI is designed to investigate particle acceleration and energy release in solar flares, through imaging and spectroscopy of hard X-ray/gamma-ray continua emitted by energetic electrons, and of gamma-ray lines produced by energetic ions. The single instrument consists of an imager, made up of nine bi-grid rotating modulation collimators (RMCs), in front of a spectrometer with nine cryogenically-cooled germanium detectors (GeDs), one behind each RMC. It provides the first high-resolution hard X-ray imaging spectroscopy, the first high-resolution gamma-ray line spectroscopy, and the first imaging above 100 keV including the first imaging of gamma-ray lines. The spatial resolution is as fine as ~ 2.3 arc sec with a full-Sun (≳ 1°) field of view, and the spectral resolution is ~ 1–10 keV FWHM over the energy range from soft X-rays (3 keV) to gamma-rays (17 MeV). An automated shutter system allows a wide dynamic range (> 107) of flare intensities to be handled without instrument saturation. Data for every photon is stored in a solid-state memory and telemetered to the ground, thus allowing for versatile data analysis keyed to specific science objectives. The spin-stabilized (~ 15 rpm) spacecraft is Sun-pointing to within ~ 0.2° and operates autonomously. RHESSI was launched on 5 February 2002, into a nearly circular, 38° inclination, 600-km altitude orbit and began observations a week later. The mission is operated from Berkeley using a dedicated 11-m antenna for telemetry reception and command uplinks. All data and analysis software are made freely and immediately available to the scientific community.

Differences in responses by ethnic group to The Drug Abuse Problem Assessment for Primary Care (DAPA-PC) were examined. The DAPA-PC is a self-administered (via computer), internet-based screening instrument with automatic scoring, patient profile for medical reference, and unique motivational messages. Results indicate differences between blacks and whites on responses to several items in these instruments. Differences in drug use were also found between the two ethnic groups in hair/urine results. The screening criteria for the DAPA-PC instrument appear to work for both the groups in this study. Differences in responses to alcohol and drug screening instruments by ethnic group should be taken into consideration when designing screening instruments for alcohol and/or other drug use and these instruments should be adapted for different ethnic groups, when necessary. The results of this study suggest that the DAPA-PC instrument is a useful alcohol and drug abuse screening instrument for both the blacks and whites in a primary care population.

Introduction Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with no effective targeted therapy. Inducible nitric oxide synthase (iNOS) is associated with poor survival in patients with breast cancer by increasing tumor aggressiveness. This work aimed to investigate the potential of iNOS inhibitors as a targeted therapy for TNBC. We hypothesized that inhibition of endogenous iNOS would decrease TNBC aggressiveness by reducing tumor initiation and metastasis through modulation of epithelial-mesenchymal transition (EMT)-inducing factors. Methods iNOS protein levels were determined in 83 human TNBC tissues and correlated with clinical outcome. Proliferation, mammosphere-forming efficiency, migration, and EMT transcription factors were assessed in vitro after iNOS inhibition. Endogenous iNOS targeting was evaluated as a potential therapy in TNBC mouse models. Results High endogenous iNOS expression was associated with worse prognosis in patients with TNBC by gene expression as well as immunohistochemical analysis. Selective iNOS (1400 W) and pan-NOS (L-NMMA and L-NAME) inhibitors diminished cell proliferation, cancer stem cell self-renewal, and cell migration in vitro, together with inhibition of EMT transcription factors (Snail, Slug, Twist1, and Zeb1). Impairment of hypoxia-inducible factor 1α, endoplasmic reticulum stress (IRE1α/XBP1), and the crosstalk between activating transcription factor 3/activating transcription factor 4 and transforming growth factor β was observed. iNOS inhibition significantly reduced tumor growth, the number of lung metastases, tumor initiation, and self-renewal. Conclusions Considering the effectiveness of L-NMMA in decreasing tumor growth and enhancing survival rate in TNBC, we propose a targeted therapeutic clinical trial by re-purposing the pan-NOS inhibitor L-NMMA, which has been extensively investigated for cardiogenic shock as an anti-cancer therapeutic. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0527-x) contains supplementary material, which is available to authorized users.

The Drug and Alcohol Problem Assessment for Primary Care (DAPA-PC), developed under a contract from the National Institute on Drug Abuse, is a comprehensive screening system developed for quickly identifying and addressing substance abuse and related problems in a primary care setting. The DAPA-PC system includes a two-level screening instrument, resources for scoring and reporting results, motivational messages, treatment referrals, and informative links, which together address the multifaceted needs of patients dealing with addiction problems and their providers. The need for such a system, preliminary reactions to the instrument, and future course of research are discussed.

This brief introduces a partitioning algorithm, which facilitates pseudoexhaustive testing, to detect and locate faults in digital VLSI circuits. The algorithm is based on an analysis of circuit's primary input cones and fanout (PIFAN) values. An invasive approach is employed, which creates logical and physical partitions by automatically inserting reconfigurable test cells and multiplexers. The test cells are used to control and observe multiple partitioning points, while the multiplexers expand the controllability and observability provided by the test cells. The feasibility and efficiency of our algorithm are evaluated by partitioning numerous ISCAS 1985 and 1989 benchmark circuits containing up to 5597 gates. Our results show that the PIFAN algorithm offers significant reductions in overhead and test time when compared to previous partitioning algorithms.

In this paper, we present an algorithm for partitioning sequential circuits. This algorithm is based on an analysis of a circuit's primary input cones and fanout values (PIFAN), and it uses a directed acyclic graph to represent the circuit. An invasive approach is employed, which creates logical and physical partitions by automatically inserting reconfigurable test cells and multiplexers. The test cells are used to control and observe multiple partitioning points, while the multiplexers expand the controllability and observability provided by the test cells. The feasibility and efficiency of our algorithm are evaluated by partitioning numerous standard digital circuits, including some large benchmark circuits containing up to 5597 gates. Our algorithm is based upon pseudoexhaustive testing methods where fault simulation is not required for test-pattern generation and grading; hence, engineering design time and cost are further reduced.

Both modern anthropogenic emissions of mercury (Hg), primarily from artisanal and small-scale gold mining (ASGM), and preindustrial anthropogenic emissions from mining are thought to have a large impact on present-day atmospheric Hg deposition. We study the spatial distribution of Hg and its depositional history over the past ∼400 years in sediment cores from lakes located regionally proximal (∼90-150 km) to the largest ASGM in Peru and distal (400 km) to major preindustrial mining centers. Total Hg concentrations in surface sediments from fourteen lakes are typical of remote regions (10-115 ng g(-1)). Hg fluxes in cores from four lakes demonstrate preindustrial Hg deposition in southeastern Peru was spatially variable and at least an order of magnitude lower than previously reported fluxes in lakes located closer to mining centers. Average modern (A.D. 2000-2011) Hg fluxes in these cores are 3.4-6.9 μg m(-2) a(-1), compared to average preindustrial (A.D. 1800-1850) fluxes of 0.8-2.5 μg m(-2) a(-1). Modern Hg fluxes determined from the four lakes are on average 3.3 (±1.5) times greater than their preindustrial fluxes, similar to those determined in other remote lakes around the world. This agreement suggests that Hg emissions from ASGM are likely not significantly deposited in nearby down-wind regions.

The California Urban Futures Model (or CUF Model) is the first of a new generation of metropolitan planning models designed to help planners, elected officials, and citizen groups create and compare alternative land-use policies. This article explains how the CUF Model works and then demonstrates its use in simulating realistic alternatives for regional and subregional growth policy/planning. Part One explains the design principles and logic of the CUF Model. Part Two presents CUF Model simulation results of three alternatives for growth policy/land-use planning alternatives for the San Franciso Bay and Sacramento areas. Part Three demonstrates the use of the CUF Model for evaluating alternative agricultural protection and zoning policies at the county, or sub-regional, level.

Quantitative clinical measurement of heterogeneity in immunohistochemistry staining would be useful in evaluating patient therapeutic response and in identifying underlying issues in histopathology laboratory quality control. A heterogeneity scoring approach (HetMap) was designed to visualize a individual patient's immunohistochemistry heterogeneity in the context of a patient population. HER2 semiquantitative analysis was combined with ecology diversity statistics to evaluate cell-level heterogeneity (consistency of protein expression within neighboring cells in a tumor nest) and tumor-level heterogeneity (differences of protein expression across a tumor as represented by a tissue section). This approach was evaluated on HER2 immunohistochemistry-stained breast cancer samples using 200 specimens across two different laboratories with three pathologists per laboratory, each outlining regions of tumor for scoring by automatic cell-based image analysis. HetMap was evaluated using three different scoring schemes: HER2 scoring according to American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) guidelines, H-score, and a new continuous HER2 score (HER2(cont)). Two definitions of heterogeneity, cell-level and tumor-level, provided useful independent measures of heterogeneity. Cases where pathologists had disagreement over reads in the area of clinical importance (+1 and +2) had statistically significantly higher levels of tumor-level heterogeneity. Cell-level heterogeneity, reported either as an average or the maximum area of heterogeneity across a slide, had low levels of dependency on the pathologist choice of region, while tumor-level heterogeneity measurements had more dependence on the pathologist choice of regions. HetMap is a measure of heterogeneity, by which pathologists, oncologists, and drug development organizations can view cell-level and tumor-level heterogeneity for a patient for a given marker in the context of an entire patient cohort. Heterogeneity analysis can be used to identify tumors with differing degrees of heterogeneity, or to highlight slides that should be rechecked for QC issues. Tumor heterogeneity plays a significant role in disconcordant reads between pathologists.

• To connect activity projections (population and jobs) to locations. • Work forward to explore the spatial impacts of near-term strategic planning interventions, particularly infrastructure investments and land use and environmental regulations. Work backward to connect desirable future outcomes to contemporary policy interventions and projects. • Identify key drivers of urban growth and change patterns. • Generate scenarios as inputs into local and regional impact assessment models: • Transportation system use and congestion • Air and water quality • Habitat and biodiversity impacts • Local public finance • Energy use and climate change

In recent years, a debate has brewed over whether the decentralization of employment has been beneficial from a regional standpoint. This article focuses on one aspect of the debate: how the relocation of office workers from a downtown to a suburban location affects commuting patterns and mode choice. From a survey of 320 former downtown San Francisco workers who now work in the suburbs, it was found that the average travel distance remained essentially unchanged and that the average commuting speed increased. The most dramatic change, however, was the switch from public transit to drive-alone commuting. In the aggregate, it can be estimated that the change in job location was associated with nearly a threefold increase in vehicle miles traveled to work. While from a personal standpoint, employees should be better off since they got to work faster and more comfortably, from a larger social and environmental perspective, the costs could be significant. More detailed analyses of commuter submarkets revealed that the transportation impacts vary considerably depending on whether the original residence was in the suburbs or central city and whether relocated workers had moved their residences in recent years. In general, those who remained in San Francisco and became reverse commuters were worst off whereas those who moved their residences out of the city were much better off in terms of job access. The article concludes that road pricing would be the best way to force motorists to internalize the external costs of increased drive-alone commuting. Second-best options would be to introduce development impact fees or employer-based trip reduction regulations.

Four of the 16 ITER upper port plugs will be devoted to electron cyclotron resonance heating (ECRH) in order to control the magneto-hydrodynamic (MHD) instabilities.

In our x-ray calorimetry effort, we have developed several techniques which may be helpful to other groups working in this field. We are studying several different monolithic and composite calorimeter designs. In our readout configuration, the preamplifier circuit employs negative voltage feedback which allows us to accurately measure the temporal profile of the thermal pulse produced by an x-ray absorbed in a micro-calorimeter. Rise times of less than two microseconds have been observed in monolithic devices operating at .3 K. Furthermore, the feedback preamplifier can be configured for either positive or negative electro-thermal feedback. This preamplifier system is followed by an analog pulse shaping amplifier with a frequency response that can be adjusted to yield the maximum signal to noise ratio for a given thermal response of the calorimeter. In addition, we have developed several diagnostic procedures which have been useful in determining the operating and noise characteristics of our devices. These include an infrared light-emitting diode which flashes a discrete amount of energy on to the calorimeter, and a capacitively coupled test input to the preamplifier which allows us to directly determine the total noise in the thermal detection system. Finally, we are developing an adiabatic demagnetization refrigerator with a temperature control system that is designed to stabilize the 0.1 K cold stage to better than 8 μK. This is required for a resistive thermal detector with resolving power of 1000.

The ITER ECH upper launcher is devoted to directing up to eight 2-MW beams per port plug over half of the plasma cross section. A focusing mirror is used to achieve a very narrow deposition profile to stabilize MHD activity such as the neoclassical tearing modes (NTMs) and the sawtooth oscillation. The beam deposition location is changed via a steering mirror with up to plusmn7 deg (plusmn14 deg beam), which allows access from inside mid radius out to nearly the plasma edge. The steering mechanism uses a frictionless backlash free system to avoid sticking, thus increasing the reliability. A small percentage (

The ITER ECRH upper port antenna (or launcher) will be used to drive current locally for stabilising the neoclassical tearing mode (NTM) by depositing ram-wave power inside of the island which forms on the q=3/2 or 2 rational magnetic flux surfaces and control the sawtooth instability by driving current near the q=l surface. This requires the launcher to be capable of steering the focused beam deposition location across the resonant flux surface over the range where the q=l, 3/2 and 2 surfaces are expected to be found (roughly the outer half of the plasma). ITER'S present reference design uses a front steering (FS) concept, which uses a moveable mirror close to the plasma. Two separate mirrors are used to decouple the focusing and steering aspects resulting in an optimized optical configuration providing a well focused beam over a large steering range. The steering mechanism providing the mirror rotation uses a frictionless and backlash free mechanical system based on the elastically compliant deformation of structural components to avoid the in vessel tribological difficulties. Traditional designs are based on push-pull rods acting on a mirror which rotates with ball bearings, they present the risk of gripping or result in stick-slip movements. The ball bearings are replaced with a set of flexure pivots while the classic actuation through a push-pull rod scheme is replaced by a directly acting pneumatic system consisting on a fast feed line, bellows and springs, in which the pressure acting on the bellows pushes the mirror against the compressive springs. The rotation of the mirror is thus produced by the counteraction between the forces exerced by the springs and the bellows, themselves piloted by the pressure of the system. A servovalve placed outside of the port plug and connected to the bellows by a small tube will control this pressure. The system also includes flexible water cooling pipes which allow the removal of heat generated by the ohmic surface losses of the reflected mm-wave beams and the nuclear and radiation volumic heating of the rotating mirror components. This paper will give an overview of the engineering and design issues and their solutions, and provide the development status of the different components of the mechanism. Special attention will be given to the engineering analysis performed to ensure compliance of the steering mechanism with the various ITER requirements.

Triple negative breast cancer is characterized by its aggressive clinical behavior with high incidence of metastasis to the lungs and brain. These patients do not respond to hormonal therapy and show intrinsic resistance to conventional chemotherapy. Robust evidence indicates that treatment-resistance and metastases may arise from a subpopulation of cells with tumor-initiating capacity called breast cancer stem cells (BCSC). We are one of the first groups to demonstrate that residual tumors after exposure to chemotherapy are enriched for BCSC. We have previously described a treatment-resistant gene signature of 493 genes derived from patient biopsies.This finding narrowed down the possible cancer stem cell growth related genes from genome wide to only 493 genes and provided candidate genes for screening potential targets that affect BCSC self-renewal. Re-evaluation of the candidate genes determined a previously unidentified cancer gene, Hematological and Neurological Expressed 1-Like (HN1L) as the target of cancer stem cell self-renewal. The objective of this study was to investigate the role of HN1L in regulating BCSC and metastasis in TNBC, and to determine the mechanism of action of HN1L in BCSC. Knocking down HN1L by shRNA in SUM159 and MDAMB231 cell lines significantly decreased mammosphere forming efficiency (MSFE) and CD44+/CD24low/- population. To assess the contribution of HN1L to BCSC and tumor growth, a patient derived human-cancer-in-mouse xenograft model and two cancer cell line xenograft models were employed. To ensure targeted delivery, siRNA was packaged into DOPC liposomes and delivered into mice via intraperitoneal injection. Results showed that silencing HN1L alone or in combination with chemotherapy in xenografts reduced tumor volume and BCSC population as measured by MSFE, CD44+/CD24low/- markers, ALDF+ cell population and limiting dilution assay. Liposomal HN1L siRNA treated mice also showed lower level of lung metastasis. A gene signature obtained from microarray analysis on HN1L siRNA treated tumor tissues highly correlated with better prognosis in TNBC patients. Overexpression of HN1L in TNBC cell lines activated STAT3 signaling, induced CD44+/CD24low/- population and cancer cell migration. Moreover, chemoresistance were also observed with HN1L overexpression. HN1L colocalized with CNTFR and STAT3 in cytoplasm and nucleus by immunofluorescence staining. Changes in HN1L expression level resulted in corresponding changes in phospho-STAT3. Furthermore, CNTFR knockdown compromised the effect of HN1L overexpression in activating STAT3.These results suggest that the HN1L gene plays an important role in BCSC through regulating CNTFR-STAT3 signaling pathway, and is associated with poor prognosis. Taken together, the results from our study demonstrate for the first time that HN1L is a novel target for TNBC. Targeting HN1L and/or CNTFR-STAT3 pathway might provide an alternative therapeutic strategy for TNBC. Citation Format: Yi Liu, Dong Soon Choi, Sergio Grandos-Principal, Wei Qian, Lacey Burey, Helen Wong, Crisitian Rodriguez-Aguayo, Anil Sood, Zheng Li, Stephen Wong, Heidi Weiss, Bhuvanesh Dave, Melissa Landis, Jenny C. Chang. Identifying novel cancer stem cell target for triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2312. doi:10.1158/1538-7445.AM2015-2312

The success of new system-on-a-chip (SoC) initiatives depends on the availability of well-trained SoC designers who are able to bridge the gap between software centric system specification and hardware-software implementation in novel architectures. The Pittsburgh Digital Greenhouse is working with its member Universities to facilitate the education of such designers-those capable of bridging all the key competence areas required to bring about this integration. We are cooperating in the creation of an MS Certificate program in SoC Design that will be collaboratively developed and jointly coordinated. This paper briefly describes our educational initiative, and the resulting collaboratively defined SoC Skill set.

This paper deals with the Sandbox design experience course which was conceived to provide students with an ambitious team project experience in the context of modern ASIC design. The goal of the course is to design and verify a decoder for low-density parity check (LDPC) code using the latest commercial EDA tools in an industrial 0.16 micron process technology.

The Pittsburgh Digital Greenhouse is sponsoring an educational support program to facilitate student IC design projects and laboratories at Carnegie Mellon University, the Pennsylvania State University, and the University of Pittsburgh. Students who have access to industry standard IC design tools that are integrated in a commercial design flow will be better prepared to enter the workforce. However, these capabilities are expensive to support and not generally available within Universities. The "Digital Sandbox" program described in this paper is facilitating education by providing and supporting modern VLSI/SoC CAD tools and industry standard design libraries.

A contract between Pittsburgh digital greenhouse and the university of Pittsburgh called for the development of a set of three(3) continuing education courses. The original objectives, anticipated student background,schedule of each course are briefly described.

Continuing improvements in semiconductor fabrication density are enabling new classes of system-on-a-chip architectures that combine extensive processing logic and high-density memory. Many of the capabilities of these new architectures can be custom tailored to the demands of real-time digital image processing. This paper evaluates several candidate designs, using the criteria of image processing performance, flexibility, manufacturability, and fabrication cost.

Electronic technologies are evolving more rapidly than any other aspect of commercial and military systems. This pace can lead to waste and inefficiency when perfectly serviceable systems must be scrapped because spare assemblies and replacement parts are no longer available. While rapid prototyping methods offer the means to quickly go from concept to prototype, they lack the ability to easily include good concepts from old designs. This paper describes preliminary work to develop methods that allow legacy design information to be incorporated into a top-down language-based rapid prototyping methodology. This will allow rapid re-engineering and replacement of obsolete legacy system components, as well as offering a new design re-use path for system upgrades.

Commercial and military systems may contain a mix of legacy and state-of-the-art electronic equipment. With time, the older legacy equipment becomes difficult to support, due to increasing costs of spare parts and/or non-existent procurement sources. The technical documentation needed to re-manufacture replacement parts is often insufficient or non-existent, and valuable systems may be retired early as a result. In such cases, rapid prototyping and reverse engineering procedures offer a cost-effective method to replicate the missing part(s). This paper describes a step-by-step semi-automated method for rapidly reproducing electronic systems through reverse engineering of printed circuit boards (PCBs).

Faults in digital circuits are primarily the results of various random defects which can occur during manufacturing. These random defects can introduce DC (stuck-at) faults as well as AC (delay) faults. Previous work on statistical modeling and analysis for delay fault testing assumes that at most a single delay fault can occur along any given path in the circuit under test. In this paper, we study the statistical effect of multiple delay faults along any path in the circuit under test. We present a statistical model for path delay faults in VLSI circuits which takes into account multiple delay faults occurring along any given signal. We also show how to compute path delay fault probabilities for all paths in a given circuit. Furthermore, we describe how this statistical model could be used to predict important information such as the maximum number of path delay faults in a given circuit.

The authors describe the programmable systolic data processor (PSDP). The PSDP will enhance US Department of Defense (DoD) mission capabilities by extending signal and data processing speed/performance while reducing system size, weight, and power consumption. The characteristics of this architecture which make it opportune for building as a wafer-scale system include broad homogeneity, ease of redundancy, and limited physical interconnect bandwidth of wafer-scale integration (WSI) using a robust programmable systolic array processing architecture. Thus, it will provide unique onboard processing capabilities for DoD missions. >

A Microcontroller Compensated Crystal Oscillator (MCXO) is described which employs varactor compensation using a high precision digital to analog converter (DAC) and analog to digital converter (ADC). A proven analog Temperature Compensated Crystal Oscillator (TCXO) design was enhanced by adding a state-of-the-art microcontroller subsystem. The resulting design maintains low cost while preserving the high density packaging of the parent TCXO design. Development is on going, with a currently achievable temperature stability of plus or minus 0.5 ppm from minus 40 to plus 85 degrees C using an AT cut crystal. MCXO's are calibrated after all packaging is completed, thus reducing manufacturing costs. Recalibration, to compensate for effects such as aging, can be performed at any time through one of the four device pins. The complete MCXO is assembled in a 1/spl times/1 inch footprint package. Typical power consumption is 125 milliwatts from a single 5 volt supply.

The hallmarks of Neutron Transmutation Doped (NTD) germanium cryogenic thermistors include high reliability, reproducibility, and long term stability of bulk carrier transport properties. Using micro-machined NTD Ge thermistors with integral “flying” leads, we can now fabricate two-dimensional arrays that are built up from a series of stacked linear arrays. We believe that this modular approach of building, assembling, and perhaps replacing individual modules of detectors is essential to the successful fabrication and testing of large multi-element spectrometers. Details of construction are presented.

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with no effective targeted therapy. Inducible nitric oxide synthase (iNOS) is associated with poor survival in breast cancer patients by increasing tumor aggressiveness. This work aimed to investigate the potential of iNOS inhibitors as a targeted therapy for TNBC. We hypothesized that inhibition of endogenous iNOS would decrease TNBC aggressiveness by reducing metastasis through modulation of epithelial-mesenchymal transition (EMT)-inducing factors. We also propose an effective clinically relevant-targeted therapeutic regimen by re-purposing the iNOS inhibitor L-NMMA which has been extensively investigated in thousands of patients with cardiogenic shock. Cell migration was determined in confluent MDA-MB-231 cells with a “wound healing assay” treated with different concentrations of the specific iNOS inhibitor 1400W (0, 0.0001, 0.001, 0.01, 0.1, 1, 2, 4 mM) in low serum conditions (1%) for 72h. EMT-inducing factors (Snail, Slug, Twist1, and Zeb1) were determined by Western blot in MDA-MB-231 cells. For in vivo studies, 3x106 MDA-MB-231 and SUM159 cells were injected in the right mammary fat pad of female SCID Beige mice (n=10/group). The clinically relevant dose regimen consisted on two cycles of docetaxel (20mg/kg, i.p, on day 0) twelve hours before being combined with L-NMMA (400mg/kg on day 1, and 200mg/kg for 4 additional days by oral gavage) and amlodipine on day 0 (10mg/kg, i.p, daily, for 6 days). Docetaxel alone, as well as saline (i.p) + sterile water (oral gavage) were used as controls. Our results show that the specific iNOS inhibitor 1400W was able to diminish cell migration in vitro for all concentrations tested. Importantly, impact of iNOS inhibition on cell migration was further correlated with a dose-dependent decrease of the EMT transcription factors- Snail, Slug, and Twist1. Zeb1 was mainly affected at millimolar concentrations. In vivo, the combination of L-NMMA and docetaxel was able to decrease tumor growth in a MDA-MB-231 and SUM159 orthotopic models. Additionally, the combination with amlodipine did significantly prevent the L-NMMA-dependent increase of blood pressure. More importantly, this dose regimen also improved survival compared to docetaxel alone. In conclusion, targeted therapy with iNOS inhibitor impacts cell migration and changes in epithelial-mesenchymal transition might influence metastatic events. Based on these findings, we have planned a phase Ib/II targeted therapeutic trial by re-purposing L-NMMA as an anti-cancer indication. Targeting TNBC with L-NMMA could significantly alter clinical practice for treatment of breast cancer in the near future. Citation Format: Sergio M. Granados, Yi Liu, Bhuvanesh Dave, Melissa D. Landis, Steven S. Gross, Jenny C. Chang. iNOS inhibition increases survival in triple negative breast cancer by targeting metastasis and epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4024. doi:10.1158/1538-7445.AM2014-4024

Meeting abstracts In recent years, the tumor microenvironment (TME) has been identified as an important factor influencing the growth and metastasis of the tumor. In the TME, different classes of inflammatory cells have been found to exert either a pro- or anti-tumor effect. This has resulted in a