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The cellular heterogeneity and complex tissue architecture of most tumor samples is a major obstacle in image analysis on standard hematoxylin and eosin-stained (H&E) tissue sections. A mixture of cancer and normal cells complicates the interpretation of their cytological profiles. Furthermore, spatial arrangement and architectural organization of cells are generally not reflected in cellular characteristics analysis. To address these challenges, first we describe an automatic nuclei segmentation of H&E tissue sections. In the task of deconvoluting cellular heterogeneity, we adopt Landmark based Spectral Clustering (LSC) to group individual nuclei in such a way that nuclei in the same group are more similar. We next devise spatial statistics for analyzing spatial arrangement and organization, which are not detectable by individual cellular characteristics. Our quantitative, spatial statistics analysis could benefit H&E section analysis by refining and complementing cellular characteristics analysis.

All materials and devices tend to degrade with time. For this reason, reliability physics is of great theoretical and practical importance. Reliability investigations generally start with measuring the degradation rate for a material/device under stress and then a modeling of the time-to-failure versus the applied stress. The term stress, as used here, is very general: stress will refer to any external agent (electrical, mechanical, chemical, thermal, electrochemical, etc.) that is capable of producing material/device degradation. Time-to-failure occurs when the amount of degradation reaches some critical threshold level. Since devices often require different levels of degradation to induce failure, time-to-failure becomes statistical in nature and two common failure distributions are discussed: Weibull and Lognormal. Time-to-failure (TF) modeling generally assumes either a power law or exponential stress-dependence with either an Arrhenius or Eyring-like activation energy. From these TF models, acceleration factors can be deduced and these tend to serve as the foundation for accelerated testing. During this presentation, several semiconductor failure mechanisms will be reviewed: Electromigration (EM), Stress Migration (SM), Time-Dependent Dielectric Breakdown (TDDB), Hot-Carrier Injection (HCI), Negative-Biased Temperature Instability (NBTI), Plasma-Induced Damage (PID), Single-Event Upsets (SEU), Surface Inversion, Thermal Cycling Fatigue, and Corrosion. This tutorial should provide the attendee with a solid foundation for a better understanding of the papers presented at the IRPS.

Recently, with the growth of high-throughput proteomic data, in particular time series gene expression data from various perturbations, a general question that has arisen is how to extract meaningful structure from inherently heterogeneous data. Little is known about exactly how these gene regulatory networks (GRNs) operate under different stimuli. Challenges due to the lack of knowledge may cause bias or uncertainty in identifying parameters or inferring the GRN structure. We propose a new algorithm which enables us to estimate bias error due to the effect of perturbations, and correctly identify the common graph structure among biased inferred graph structures. To do this, we retrieve common dynamics of the GRN subject to various perturbations inspired by “image repairing” in computer vision [1].

Breast cancer tumors have inherently heterogeneous cell types that respond differently to treatments. Although there is a wealth of studies describing canonical cell signaling networks, little is known about how these networks operate in different cancer cells and treatments. This paper proposes a method to split a set of responses gathered from experiments on different cancer cells up into common and specific components. The key to this retrieval is the derivation of a linear timevarying model of the shared dynamics among the different cell lines. A convex optimization problem is derived that retrieves both the model and the common and specific responses without a priori information. The method is tested on synthetic data, and verifies known facts when tested on a biological data set with protein expression data from breast cancer experiments. The technique can be used to analyze specific responses to understand what treatments can be combined to persistently treat a heterogeneous cancer tumor. The linear time-varying model sheds light on how proteins interact over time.

We present a novel method for automated learning of features from unlabeled image patches for classification of tumor architecture. In contrast to previous manually-designed feature detectors (e.g., Gabor basis function), the proposed method utilizes inexpensive un-labeled data to construct features. The algorithm, also known as reconstruction independent subspace analysis, can be described as a two-layer network with non-linear responses, where the second layer represents subspace structures. The technique is applied to tissue sections for characterizing necrosis, apoptotic, and viable regions of Glioblastoma Multifrome (GBM) from TCGA dataset. Experimental results show that this method outperforms more complex expert-designed approaches. The fact that our approach learns features automatically from unlabeled data promises a wider application of self-learning strategies for tissue characterization.

We evaluated the functional support currently existing University of Washington clinical systems provide to execute approximate pharmacogenomic decision support rules. In addition, we evaluated proposed clinical decision support system user interface features with use scenarios to provide contextual information. Based on results from these evaluations, we derived a conceptual model for incorporating pharmacogenomic knowledge into the electronic health record that supports the functional and user interface requirements for pharmacogenomic clinical decision support.

A yield ramp methodology for Field-Programmable Gate Array (FPGA) in advanced technologies has been presented. By optimizing design based defect inspection setups, we can use defect-to-bit overlay mapping method more effectively and more reliably in product failure debug [1]. This is complimentary to the manufacturing fab's test vehicles, electrical tests and physical failure analysis for faster wafer failure root cause analysis. With integrating the critical area analysis and defect criticality calculation, this proven methodology provides fab-less and fab-lit companies more tools in their efforts of design for yield, design for manufacturing and design for tests.

Simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) can provide both functional and structural information about disease. However, for quantitative PET measurements all sources of scatter and absorption that photons undergo on their trajectory between source and detector must be assessed. In simultaneous PET/MR, this includes the scatter and absorption undergone in MR radio frequency (RF) coils that lie directly in the field of view (FOV). This work quantifies the sensitivity and resolution impact of various coil arrangements in the PET FOV using Monte Carlo simulations for a preclinical system. The sensitivity and resolution impact of five typical RF coils has been simulated by tracking γ-ray scatter locations and by reconstructing 18F and 68Ge sources with activity in the range 0.1MBq to 1MBq. The majority of scattering is found to be from coil support structures, with sensitivity loss up to 25% and spatial resolution loss up to 0.6mm. Subsequently six common supporting polymers were compared for their scattering effect. Typically for 5mm thick material the probability of a true can be reduced by ∼10%. The effect of misaligning a surface coil on scatter location is also demonstrated, and having dense electronic materials between 2mm and 6mm from the source is shown to result in a spatial resolution loss ∼5% and a sensitivity loss up to 17%.

Targeted drug therapies have proven very useful as cancer treatments, but some still demonstrate very little antitumor activity in certain cancers. A class of tyrosine kinase inhibitors (TKIs) that are unexpectedly inefficient in some cancers are those that target the human epidermal growth factor receptor (HER) family. This paper proposes a mathematical model of the HER signaling pathway for the study and treatment of cancers that overexpress. The goals of this paper are threefold. The first is to introduce an ODE model that agrees with the existing data over large time intervals, and the second is to use this model to understand the effects of applying certain drugs to such cancers. We finally use this model to determine a “steering-based” treatment scheme for cancers that overexpress HER2.

A panel of cell lines of diverse molecular background offers an improved model system for high-content screening, comparative analysis, and cell systems biology. A computational pipeline has been developed to collect images from cell-based assays, segment individual cells and colonies, represent segmented objects in a multidimensional space, and cluster them for identifying distinct subpopulations. While each segmentation strategy can vary for different imaging assays, representation and subpopulation analysis share a common thread. Application of this pipeline to a library of 41 breast cancer cell lines is demonstrated. These cell lines are grown in 2D and imaged through immunofluorescence microscopy. Subpopulations in this panel are identified and shown to correlate with previous subtyping literature that was derived from transcript data.

Resolution of important outstanding questions in air quality, climate change and ozone layer stability demands global observations of multiple chemical species with high horizontal and vertical resolution from the boundary layer to the stratopause. We present a mission concept that delivers the needed atmospheric composition observations, along with cloud ice and water vapor data needed for improvements in climate and weather forecasting models. The mission comprises ultraviolet and infrared nadir and microwave limb viewing instruments observing wide swaths each orbit. We review the scientific goals of the mission and the measurement capabilities this concept will deliver. We describe how precessing orbits offer significant improvements in temporal resolution and diurnal coverage compared to sun-synchronous orbits. Such improvements are needed to quantify the impact of critical "fast processes" such as deep convection on the composition and radiative properties of the upper troposphere, a region where water vapor and ozone are strong but poorly understood greenhouse gases. This concept can serve as the "Global Atmospheric Composition Mission" (GACM) recently recommended by the National Academy of Sciences decadal survey as one of 17 priority earth science missions for the coming decade. ©2008 IEEE. U7 - Export Date: 2 August 2010 U7 - Source: Scopus U7 - Art. No.: 4526243

Advanced microelectronics interconnect systems can have metal leads several hundred meters long with minimum metal to metal spacing of

Time-dependent dielectric breakdown (TDDB) of low-k dielectrics is reported for fully integrated carbon-doped silica dielectric (SiOC, keff=2.9) at wafer level over a wide range of area and electric-field test conditions at 105degC. In addition, long-term package level TDDB data were taken at 105degC for over 2 years on integrated comb-serpent test structures. The field acceleration parameter (gamma=4.5 plusmn 0.5 cm/MV) was found to be approximately independent of area (over 4 decades of area) and over a wide range of field (1.5-6.0 MV/cm), respectively. TDDB data, taken over long periods, agree well with predictions based on more rapid wafer-level TDDB testing. The low-k TDDB data suggest that, while the time-to-failure is a strong function of area and field, the time-to-failure physics does not vary greatly for fully integrated SiOC films as both the area and field are scaled. Furthermore, the fact that gamma is approximately constant (independent of area and applied E-field) indicates that silica-based low-k dielectric TDDB follows closely a thermochemical E-model for all areas and fields examined.

Many dynamical processes can be represented as directed attributed graphs or Petri nets where relationships between various entities are explicitly expressed. Signaling networks modeled as Petri nets are one class of such graphical modeling and representations. These networks encode how different protein in specific compartments, interact to create new protein products. Initially, the proteins and rules governing their interactions are curated from literature and then refined with experimental data. Variation in these networks occurs in topological structure, size, and weights associated on edges. Collectively, these variations are quite significant for manual and interactive analysis. Furthermore, as new information is added to these networks, the emergence of new computational models becomes paramount. From this perspective, hierarchical spectral methods are proposed and applied for inferring similarities and dissimilarities from an ensemble of graphs that corresponds to reaction networks. The technique has been implemented and tested on curated signaling networks that are derived for breast cancer cell lines

Using a generalized Mie-Gruneisen bonding potential, a quantum mechanical treatment (WKB method) for Si-O bond breakage in silica is presented under the conditions of high electric field, hole injection and hydrogen release. The full spectrum of bound-state energy eigenvalues is used to calculate the transmission probability whereby bond breakage occurs when the Si-ion goes from 4-fold to 3-fold coordination. When this full spectrum of bound-state energy eigenvalues is considered, it is shown that, due to the mass of the Si-ion and the width of the potential energy barrier separating the 4-fold and 3-fold coordinated bonding positions, the tunneling probability is relatively small and thus the transmission probability is described well by thermionic emission. It is further shown that stretched bonds, hole capture and hydrogen release can all have a significant impact on the barrier height and thus greatly impact the transmission probability.

Aa new method of measuring blood pressure (BP) is presented. This technique involves automatic analysis of the wideband external pulse (WEP) recorded by a pressure sensor positioned over the brachial artery during standard BP cuff deflation. Three distinct components of this "K" or "WEP" signal can be defined: K1, K2, and K3 [1]. Each component has a different shape and "appearance/disappearance property. K1 is a low frequency inaudible signal present with cuff pressure above systolic. The K2 signal appears at SP and disappears at Dp (K2-algorithm) and can be used to measure BP. Using this property, the "K2-algorithm" has been shown to be more accurate than the auscultatory technique [1]. To implement an automatic measurement using the K2-algorithm, signal processing techniques are applied to K signals.

Adult-derived stem cells have recently been found to respond in vivo to inductive signals from the microenvironment and to differentiate into a phenotype that is characteristic of cells in that microenvironment. We examined the differentiation potential of an adult liver stem cell line (WBF344) in a cardiac microenvironment in vitro. WBF344 cells were established from a single cloned non-parenchymal epithelial cell isolated from a normal male adult rat liver. Genetically modified, WBF344 cells that express �� - galactosidase, green fluorescent protein (GFP) or mitochondrial red fluorescent protein (DsRed) were co- cultured with rat neonatal cardiac cells. After 4 -14 days, we identified WBF344-derived cardiomyocytes that were elongated, binucleated and expressed the cardiac specific proteins cardiac troponin T, cardiac troponin I and N cadherin. These WBF344-derived cardiomyocytes also exhibited myofibrils, sarcomeres, and a nascent sarcoplasmic reticulum. Furthermore, rhythmically beating WBF344-derived cardiomyocytes displayed "cardiac-like" calcium transients similar to the surrounding neonatal cardiomyocytes. Fluorescent recovery after photobleaching demonstrated that WBF344-derived cardiomyocytes were electrically coupled with adjacent neonatal cardiomyocytes through gap junctions (GJs). Collectively, these results support the conclusion that these adult-derived liver stem cells respond to signals generated in a cardiac microenvironment in vitro acquiring a cardiomyocyte phenotype and function. The identification of micro- environmental signals that appear to cross germ layer and species specificities should prove valuable in understanding the regulation of normal development and stem cell differentiation in vivo.

This paper addresses a modified localization scheme of a wheeled mobile robot. When it navigates in a square given by the operator, the position error of a robot accumulates and it never ends up with the goal position where the robot intends to go to initially. The objective of localization is to estimate the position of a robot precisely. Many algorithms were developed and still are being researched for localization of a mobile robot at present. Among them, a localization algorithm named continuous localization proposed by Schultz (Schultz and Adams, 1998) has some merits on real-time navigation and is easy to be implemented compared to other schemes. Continuous localization (CL) is based on map-matching algorithm with global and local maps using only ultrasonic sensors for making grid maps following a given path by us (e.g. squares). In addition to CL, we here propose systematic error correction and fast powerful map-matching algorithm for localization of a mobile robot by experiments

Extensive time-dependent dielectric breakdown (TDDB) data were taken for several silica-based low-k interconnect dielectrics so that the full statistical-distribution for the field acceleration parameter (gamma) could be determined. The low-k materials tested during this study included: SiOF (k=3.6), SiOCl (k=2.9), SiOC2 (k=2.6) and MSQ (k=2.3). While a strong material-dependence was found for the breakdown strength and time-to-failure, all of these silica-based materials tested at 105degC were observed to have a similar field acceleration parameter of gamma = 4.13 +/- 0.85 cm/MV

Future CMOS technology generations may implement multi-gate architectures according to S. M. Kim et al. (2004), D Ha et al. (2004), S.-Y. Kim et al. (2005), W.-S. Liao et al. (2005), S. Maeda et al. (2004), N. Collaert et al. (2005),and C. Jahan et al. (2005), together with a change from SiO2-based to high-k gate dielectrics and a change from poly-silicon to metal gate. The purpose of this work is to identify the influences of multi-gate architecture and metal gate on gate dielectric reliability and to demonstrate the dielectric reliability trend along the road map towards a CMOS process using triple gate architecture, metal gate, and HfSiON gate dielectric

UARS MLS observations of stratospheric ozone and chlorine monoxide are described. Enhanced concentrations of ClO, the predominant form of reactive chlorine responsible for ozone depletion, are seen within both the northern and southern winter polar vortices. In the southern hemisphere, this leads directly to the development of the annual Antarctic ozone hole. While ozone depletion is also observed in the north, it is less severe and there is considerable interannual variability. >

The Microwave Limb Sounder was designed to map the concentrations of trace gases from the stratosphere to the lower thermosphere, to improve understanding of the photochemical reactions which take place in this part of the atmosphere. The instrument will measure the intensity of thermal radiation from molecules in the atmosphere at frequencies corresponding to rotational absorption bands of chlorine monoxide, ozone, and water vapor. Molecular concentration profiles will be determined over a height range of 15 to 80 km (20 to 45 km for C10). The 57 deg inclination orbit proposed for the Upper Atmosphere Research Satellite will allow global coverage.

Describes pre-launch radiometric and spectral calibrations of the Microwave Limb Sounder (MLS) on the Upper Atmosphere Research Satellite (UARS). Use of in-flight data for validation or refinement of calibration is described. The estimated uncertainty in calibrated radiance from pre-launch radiometric and spectral calibration data is better than 2% in most bands. >

Microwave limb sounding can provide important measurements for understanding global change and processes in earth's stratosphere, mesosphere, and lower thermosphere. An experiment for this purpose operating at millimeter wavelengths is now ready for launch on the NASA Upper Atmosphere Research Satellite (UARS). An enhanced experiment at submillimeter wavelengths is also being studied for the future NASA Earth Observing System (EOS).

The shrinking of line-to-line spacing in interconnect systems for advanced IC technology and the use of new lower dielectric constant materials create the need for tools to evaluate the interconnect dielectric reliability. A multi-temperature, dual ramp-rate voltage-ramp to breakdown methodology is presented and used here to extract important dielectric breakdown parameters accurately for minimum spaced metal-lines. It is demonstrated that correction for the true minimum line-to-line spacing distributions become critically important and that the minimum spacing can be extracted electrically and compares favorably to electron microscopy cross sections. The spacing-corrected breakdown field distributions, at various temperatures, for the organo-silicate materials tested, indicated a very low apparent zero-field activation energy (0.14/spl plusmn/0.02 eV) and an apparent field acceleration parameter /spl gamma/ = 4.1/spl plusmn/0.3 cm/MV that has little or no temperature dependence. Constant-voltage time-dependent-dielectric-breakdown (TDDB) measurements were found to agree well with these observations.

Charge trapping in HfSiON and HfO/sub 2/ gate dielectrics was studied using both DC and pulsed I/sub D/-V/sub G/ characterization techniques. The data shows a significant amount of hysteresis in HfO/sub 2/ but negligible instability in HfSiON. Constant voltage stress measurements of HfO/sub 2/ and HfSiON films show that the threshold voltage shift in HfO/sub 2/ films is as much as 10 times higher than that of HfSiON. Further, modeling of the time dependence of the threshold voltage shows that the trap capture cross section responsible for the instability of HfO/sub 2/ films is 10 times higher than the trap capture cross section of HfSiON. Our data indicate that amorphous HfSiON has better electrical stability than HfO/sub 2/.

Electrical instability due to charge trapping in high-k materials is a primary concern for the usefulness of these films in future CMOS devices. This paper reports the effect of charge trapping on the threshold voltage and transistor drive current of devices made with HfSiON gate dielectric. Our results show that the physics of the charge trapping in HfSiON is unique and follows logarithmic dependence with time rather than usual exponential dependence. NMOS devices fabricated with HfSiON films show acceptable electrical stability for 10 years without substantial degradation of either the threshold voltage or the drive current.

The reliability physics of low-k interconnect dielectrics is of great interest. Leakage, breakdown and TDDB data are presented for fluorinated silica, porous carbon-doped silica, and very porous carbon-doped silica. The breakdown and TDDB performance of the dielectrics are observed to degrade with the degree of porosity but the failure kinetics (field acceleration parameter and activation energy) seem to rather insensitive to porosity. A percolation model has been developed whereby the pores are treated as defects. The percolation model seems to describe well the observed breakdown and TDDB behavior.

Dielectrics with high dielectric constant k will likely be required for future replacement of conventional SiO/sub 2/ gate dielectric. Physical models are needed which describe the reliability tradeoffs associated with the high-k material selection. In this paper we report on a fundamental relationship existing between the dielectric breakdown E/sub bd/ and dielectric constant k. An approximate E/sub bd/ /spl sim/ (k )/sup -1/2/ relation is found and seems to be universal, i.e., the relation holds over nearly two decades of dielectric constant. A physics-based model has been developed to understand this critically important relationship. The good fit of the physical model (with no adjustable parameters) to the experimental data suggests that the local electric field (Lorentz-relation/Mossotti-field) in these high-k materials plays a very important role in the observed E/sub bd/ /spl sim/ (k)/sup -1/2/ behavior. The very high local electric field (in high-k materials) tends to distort/weaken polar molecular-bonds thereby lowering the enthalpy of activation required for bond breakage by standard Boltzmann processes.

Stress-induced voiding is observed in Cu-based, deep-submicron, dual-damascene technologies where voids are formed under the via when the via connects to a wide metal lead below it. The voiding results from the supersaturation of vacancies that develops due to grain growth when the Cu is not properly annealed prior to being fully constrained. The driving force for voiding is shown to be stress migration with a maximum in voiding rate observed at /spl sim/190/spl deg/C. A diffusional model is presented which shows that the voiding mechanism is an issue primarily for vias connected to wide Cu leads. A thermomechanical stress exponent of 3.2 and a diffusional activation energy of 0.74 eV were determined for this stress-induced voiding mechanism.

Switched polarization fatigue was investigated for CVD PZT ferroelectric films of thickness

The susceptibility to chlorine-induced corrosion of Al-Cu and Al-Cu-Si films has been measured. The adverse impact of Cu on the corrosion susceptibility of unsintered films is clearly evident at 0.3% and increases sharply between 1.0% and 2.0% with the latter being 6 times more corrosive than the former. Adding 1.0% Si to the Al-Cu (2%) alloys tends to lower the corrosion susceptibility of unannealed films by a factor of 9. This effect is shown to be caused by higher quality native aluminum oxide resulting in a delay in the onset of the corrosion rather than a slower rate once corrosion has begun. Annealing (30 min at 450 degrees C) the copper containing films also has a beneficial effect on corrosion susceptibility. >

It is noted that remote sensing by submillimeter-wave heterodyne spectroscopy can provide measurements for studying global change and processes in the Earth's atmosphere. The characteristics of stratospheric submillimeter spectra are discussed, and the planned submillimeter Microwave Limb Sounder experiment for the Earth Observing System is briefly considered. >

Alternate gate-dielectric films are required for future replacement of conventional SiO/sub 2/. Replacement is needed to reduce gate-leakage while still maintaining good reliability and a high-level of transistor performance. One such candidate is HfSiON dielectric film. In this paper we report for the first time, IV and CV characteristics, stability and reliability results for amorphous HfSiON dielectric films scaled below 13 /spl Aring/. Our results show that leakage current through this material is reduced by two orders of magnitude versus an equivalent SiO/sub 2/ film, while the interface and TDDB stability remains good. The positive leakage, stability and reliability results indicate that HfSiON may be a suitable candidate for gate-oxide replacement in CMOS applications where an effective hyper-thin gate-oxide is required for performance reasons and a reduced gate-leakage for low-power applications.

Leakage and breakdown characteristics of low-k dielectrics are becoming increasingly important reliability issues for interconnects as they are scaled to 0.18 um and below. Several of the low-k dielectrics, integrated into a dual-damascene Cu process flow, are quite leaky and have difficulty in meeting a leakage spec of 1E-8 A/cm/sup 2/ at 25/spl deg/C. Time-dependent dielectric breakdown (TDDB) for some of the low-k candidate films is also an issue because of generally low breakdown strengths

A temperature-independent field acceleration parameter /spl gamma/ and a field-independent activation energy /spl Delta/Ho can result when different types of disturbed bonding states are mixed during time-dependent dielectric breakdown (TDDB) testing of SiO/sub 2/ thin films. While /spl gamma/ for each defect type alone has the expected 1/T dependence and /spl Delta/Ho shows a linear decrease with electric field, a nearly temperature-independent /spl gamma/ and a field-independent /spl Delta/Ho can result when two or more disturbed bonding states are mixed. These observations suggest strongly that the oxygen vacancy is an important intrinsic defect for breakdown and that field, not current, is the cause of TDDB under low-field conditions.

The system soft error rate (SSER) of 4M/16M DRAMs has been shown to be dependent on the cosmic ray neutron flux. A simple model and accelerated soft error rate (ASER) measurements made with an intense, high energy neutron beam support this result. The model predicts that cosmic ray neutron induced soft errors will become important at the 64M DRAM generation and beyond.

The electromigration (Er) performance of layered Al-0.5%Cu and Al-1%Si-0.5%Cu metallization systems was investigated, including leads with refractory barrier and capping layers, and tungsten-filled via holes. While the W-plugs exhibited a lifetime shorter than the leads, a dramatic improvement in EM performance of the vias was achieved by incorporating a thin layer of titanium between the aluminum and its cap. Among the most likely explanations for this observation is that the aluminum is protected from physical damage during via etch by the continuous TiAl/sub 3/ layer which forms by reaction between the titanium and the aluminum. Current flow simulations show complex crowding effects at the bottom of the vias. The role of grain boundaries and the effects of dopants on early via failure modes are also discussed. >