Data Perturbation Independent Diagnosis and Validation of Breast Cancer Subtypes Using Clustering and Patterns

Molecular stratification of disease based on expression levels of sets of genes can help guide therapeutic decisions if such classifications can be shown to be stable against variations in sample source and data perturbation. Classifications inferred from one set of samples in one lab should be able to consistently stratify a different set of samples in another lab. We present a method for assessing such stability and apply it to the breast cancer (BCA) datasets of Sorlie et al. 2003 and Ma et al. 2003. We find that within the now commonly accepted BCA categories identified by Sorlie et al. Luminal A and Basal are robust, but Luminal B and ERBB2+ are not. In particular, 36% of the samples identified as Luminal B and 55% identified as ERBB2+ cannot be assigned an accurate category because the classification is sensitive to data perturbation. We identify a “core cluster” of samples for each category, and from these we determine “patterns” of gene expression that distinguish the core clusters from each other. We find that the best markers for Luminal A and Basal are (ESR1, LIV1, GATA-3) and (CCNE1, LAD1, KRT5), respectively. Pathways enriched in the patterns regulate apoptosis, tissue remodeling and the immune response. We use a different dataset (Ma et al. 2003) to test the accuracy with which samples can be allocated to the four disease subtypes. We find, as expected, that the classification of samples identified as Luminal A and Basal is robust but classification into the other two subtypes is not

Role of domain walls in the abnormal photovoltaic effect in BiFeO3

Recently, the anomalous photovoltaic (PV) effect in BiFeO3 (BFO) thin films, which resulted in open circuit voltages (V-oc) considerably larger than the band gap of the material, has generated a revival of the entire field of photoferroelectrics. Here, via temperature-dependent PV studies, we prove that the bulk photovoltaic (BPV) effect, which has been studied in the past for many non-centrosymmetric materials, is at the origin of the anomalous PV effect in BFO films. Moreover, we show that irrespective of the measurement geometry, V-oc as high as 50V can be achieved by controlling the conductivity of domain walls (DW). We also show that photoconductivity of the DW is markedly higher than in the bulk of BFO

A Diagram Is Worth A Dozen Images

Diagrams are common tools for representing complex concepts, relationships and events, often when it would be difficult to portray the same information with natural images. Understanding natural images has been extensively studied in computer vision, while diagram understanding has received little attention. In this paper, we study the problem of diagram interpretation and reasoning, the challenging task of identifying the structure of a diagram and the semantics of its constituents and their relationships. We introduce Diagram Parse Graphs (DPG) as our representation to model the structure of diagrams. We define syntactic parsing of diagrams as learning to infer DPGs for diagrams and study semantic interpretation and reasoning of diagrams in the context of diagram question answering. We devise an LSTM-based method for syntactic parsing of diagrams and introduce a DPG-based attention model for diagram question answering. We compile a new dataset of diagrams with exhaustive annotations of constituents and relationships for over 5,000 diagrams and 15,000 questions and answers. Our results show the significance of our models for syntactic parsing and question answering in diagrams using DPGs

Contrast Mechanisms for the Detection of Ferroelectric Domains with Scanning Force Microscopy

We present a full analysis of the contrast mechanisms for the detection of ferroelectric domains on all faces of bulk single crystals using scanning force microscopy exemplified on hexagonally poled lithium niobate. The domain contrast can be attributed to three different mechanisms: i) the thickness change of the sample due to an out-of-plane piezoelectric response (standard piezoresponse force microscopy), ii) the lateral displacement of the sample surface due to an in-plane piezoresponse, and iii) the electrostatic tip-sample interaction at the domain boundaries caused by surface charges on the crystallographic y- and z-faces. A careful analysis of the movement of the cantilever with respect to its orientation relative to the crystallographic axes of the sample allows a clear attribution of the observed domain contrast to the driving forces respectively.Comment: 8 pages, 8 figure

Polarization curling and flux closures in multiferroic tunnel junctions

Formation of domain walls in ferroelectrics is not energetically favourable in low-dimensional systems. Instead, vortex-type structures are formed that are driven by depolarization fields occurring in such systems. Consequently, polarization vortices have only been experimentally found in systems in which these fields are deliberately maximized, that is, in films between insulating layers. As such configurations are devoid of screening charges provided by metal electrodes, commonly used in electronic devices, it is wise to investigate if curling polarization structures are innate to ferroelectricity or induced by the absence of electrodes. Here we show that in unpoled Co/PbTiO3/(La,Sr)MnO3 ferroelectric tunnel junctions, the polarization in active PbTiO3 layers 9 unit cells thick forms Kittel-like domains, while at 6 unit cells there is a complex flux-closure curling behaviour resembling an incommensurate phase. Reducing the thickness to 3 unit cells, there is an almost complete loss of switchable polarization associated with an internal gradient

Identifying mRNA targets of microRNA dysregulated in cancer: with application to clear cell Renal Cell Carcinoma

BACKGROUND. MicroRNA regulate mRNA levels in a tissue specific way, either by inducing degradation of the transcript or by inhibiting translation or transcription. Putative mRNA targets of microRNA identified from seed sequence matches are available in many databases. However, such matches have a high false positive rate and cannot identify tissue specificity of regulation. RESULTS. We describe a simple method to identify direct mRNA targets of microRNA dysregulated in cancers from expression level measurements in patient matched tumor/normal samples. The word "direct" is used here in a strict sense to: a) represent mRNA which have an exact seed sequence match to the microRNA in their 3'UTR, b) the seed sequence match is strictly conserved across mouse, human, rat and dog genomes, c) the mRNA and microRNA expression levels can distinguish tumor from normal with high significance and d) the microRNA/mRNA expression levels are strongly and significantly anti-correlated in tumor and/or normal samples. We apply and validate the method using clear cell Renal Cell Carcinoma (ccRCC) and matched normal kidney samples, limiting our analysis to mRNA targets which undergo degradation of the mRNA transcript because of a perfect seed sequence match. Dysregulated microRNA and mRNA are first identified by comparing their expression levels in tumor vs normal samples. Putative dysregulated microRNA/mRNA pairs are identified from these using seed sequence matches, requiring that the seed sequence be conserved in human/dog/rat/mouse genomes. These are further pruned by requiring a strong anti-correlation signature in tumor and/or normal samples. The method revealed many new regulations in ccRCC. For instance, loss of miR-149, miR-200c and mir-141 causes gain of function of oncogenes (KCNMA1, LOX), VEGFA and SEMA6A respectively and increased levels of miR-142-3p, miR-185, mir-34a, miR-224, miR-21 cause loss of function of tumor suppressors LRRC2, PTPN13, SFRP1, ERBB4, and (SLC12A1, TCF21) respectively. We also found strong anti-correlation between VEGFA and the miR-200 family of microRNA: miR-200a*, 200b, 200c and miR-141. Several identified microRNA/mRNA pairs were validated on an independent set of matched ccRCC/normal samples. The regulation of SEMA6A by miR-141 was verified by a transfection assay. CONCLUSIONS. We describe a simple and reliable method to identify direct gene targets of microRNA in any cancer. The constraints we impose (strong dysregulation signature for microRNA and mRNA levels between tumor/normal samples, evolutionary conservation of seed sequence and strong anti-correlation of expression levels) remove spurious matches and identify a subset of robust, tissue specific, functional mRNA targets of dysregulated microRNA.Cancer Institute of New Jersy; New Jersey Commission for Cacner Research; Lineberger Comprehensive Cancer Center Tissue Procurement and Genomics Core Facility; Crawford Fun

Metal-Ferroelectric-Metal structures with Schottky contacts: II. Analysis of the experimental current-voltage and capacitance-voltage characteristics of Pb(Zr,Ti)O3 thin films

A modified model of metal-semiconductor contacts is applied to analyze the capacitance-voltage and current-voltage characteristics of metal-ferroelectric-metal structures. The ferroelectric polarization is considered as a sheet of surface charge situated at a fixed distance from the interface. The presumable high concentration of structural defects acting as active electric traps is taken into account by introducing a deep acceptor-like level. The model is applied on a set of metal-PZT--metal samples with different Zr/Ti ratios, deposited by different methods, and having different thickness, electrode materials, and electrode areas. The concentration of the free carriers, the fixed charge density in the depletion region, the distance between polarization charge and the physical interface, the potential barrier were estimated.Comment: 16 pages with 11 figure

Ferroelectric Nanotubes

We report the independent invention of ferroelectric nanotubes from groups in several countries. Devices have been made with three different materials: lead zirconate-titanate PbZr1-xTixO3 (PZT); barium titanate BaTiO3; and strontium bismuth tantalate SrBi2Ta2O9 (SBT). Several different deposition techniques have been used successfully, including misted CSD (chemical solution deposition) and pore wetting. Ferroelectric hysteresis and high optical nonlinearity have been demonstrated. The structures are analyzed via SEM, TEM, XRD, AFM (piezo-mode), and SHG. Applications to trenching in Si dynamic random access memories, ink-jet printers, and photonic devices are discussed. Ferroelectric filled pores as small as 20 nm in diameter have been studied