BRCA1 is a key regulator of breast differentiation through activation of Notch signalling with implications for anti-endocrine treatment of breast cancers

Here, we show for the first time, that the familial breast/ovarian cancer susceptibility gene BRCA1 activates the Notch pathway in breast cells by transcriptional upregulation of Notch ligands and receptors in both normal and cancer cells. We demonstrate through chromatin immunoprecipitation assays that BRCA1 is localized to a conserved intronic enhancer region within the Notch ligand Jagged-1 (JAG1) gene, an event requiring ΔNp63. We propose that this BRCA1/ΔNp63-mediated induction of JAG1 may be important the regulation of breast stem/precursor cells, as knockdown of all three proteins resulted in increased tumoursphere growth and increased activity of stem cell markers such as Aldehyde Dehydrogenase 1 (ALDH1). Knockdown of Notch1 and JAG1 phenocopied BRCA1 knockdown resulting in the loss of Estrogen Receptor-α (ER-α) expression and other luminal markers. A Notch mimetic peptide could activate an ER-α promoter reporter in a BRCA1-dependent manner, whereas Notch inhibition using a γ-secretase inhibitor reversed this process. We demonstrate that inhibition of Notch signalling resulted in decreased sensitivity to the anti-estrogen drug Tamoxifen but increased expression of markers associated with basal-like breast cancer. Together, these findings suggest that BRCA1 transcriptional upregulation of Notch signalling is a key event in the normal differentiation process in breast tissue.

BDDT: Block-level Dynamic Dependence Analysis for Task-Based Parallelism

We present BDDT, a task-parallel runtime system that dynamically discovers and resolves dependencies among parallel tasks. BDDT allows the programmer to specify detailed task footprints on any memory address range, multidimensional array tile or dynamic region. BDDT uses a block-based dependence analysis with arbitrary granularity. The analysis is applicable to existing C programs without having to restructure object or array allocation, and provides flexibility in array layouts and tile dimensions.
We evaluate BDDT using a representative set of benchmarks, and we compare it to SMPSs (the equivalent runtime system in StarSs) and OpenMP. BDDT performs comparable to or better than SMPSs and is able to cope with task granularity as much as one order of magnitude finer than SMPSs. Compared to OpenMP, BDDT performs up to 3.9× better for benchmarks that benefit from dynamic dependence analysis. BDDT provides additional data annotations to bypass dependence analysis. Using these annotations, BDDT outperforms OpenMP also in benchmarks where dependence analysis does not discover additional parallelism, thanks to a more efficient implementation of the runtime system.

Report on Urban Settlement Upgrading in Iraq: Kurani Ainkawa, Erbil: Moving Forward, Lessons Learned

In 2009 UN-HABITAT engaged in assisting the Kurdistan Regional Government (KRG) with the design and implementation of a ‘Improving the Housing Delivery System Project in Erbil’. This initiative built upon Iraq’s National Slum Upgrading Strategy (2005) and upon Phase II of UN-HABITAT’s 'Strengthening the Capacity of the Housing Sector in Iraq' project. Key to its initiative within the KRG has been a pilot project to upgrade an informal settlement in Erbil - Kurani Ainkawa. This report reflects on the pilot project’s achievements and lessons learned from pioneering a decentralized housing strategy.

Bystander Signalling: Exploring Clinical Relevance Through New Approaches and New Models

Classical radiation biology research has centred on nuclear DNA as the main target of radiation-induced damage. Over the past two decades, this has been challenged by a significant amount of scientific evidence clearly showing radiation-induced cell signalling effects to have important roles in mediating overall radiobiological response. These effects, generally termed radiation-induced bystander effects (RIBEs) have challenged the traditional DNA targeted theory in radiation biology and highlighted an important role for cells not directly traversed by radiation. The multiplicity of experimental systems and exposure conditions in which RIBEs have been observed has hindered precise definitions of these effects. However, RIBEs have recently been classified for different relevant human radiation exposure scenarios in an attempt to clarify their role in vivo. Despite significant research efforts in this area, there is little direct evidence for their role in clinically relevant exposure scenarios. In this review, we explore the clinical relevance of RIBEs from classical experimental approaches through to novel models that have been used to further determine their potential implications in the clinic. 

Hardware Comparison of the ISO/IEC 29192-2 Block Ciphers

As ubiquitous computing becomes a reality, sensitive information is increasingly processed and transmitted by smart cards, mobile devices and various types of embedded systems. This has led to the requirement of a new class of lightweight cryptographic algorithm to ensure security in these resource constrained environments. The International Organization for Standardization (ISO) has recently standardised two low-cost block ciphers for this purpose, Clefia and Present. In this paper we provide the first comprehensive hardware architecture comparison between these ciphers, as well as a comparison with the current National Institute of Standards and Technology (NIST) standard, the Advanced Encryption Standard.

Re-analysis of microarray data reveals insights into altered transcriptional activity of TH17 and TReg signalling in psoriasis

Identifying differential expression of genes in psoriatic and healthy skin by microarray data analysis is a key approach to understand the pathogenesis of psoriasis. Analysis of more than one dataset to identify genes commonly upregulated reduces the likelihood of false positives and narrows down the possible signature genes. Genes controlling the critical balance between T helper 17 and regulatory T cells are of special interest in psoriasis. Our objectives were to identify genes that are consistently upregulated in lesional skin from three published microarray datasets. We carried out a reanalysis of gene expression data extracted from three experiments on samples from psoriatic and nonlesional skin using the same stringency threshold and software and further compared the expression levels of 92 genes related to the T helper 17 and regulatory T cell signaling pathways. We found 73 probe sets representing 57 genes commonly upregulated in lesional skin from all datasets. These included 26 probe sets representing 20 genes that have no previous link to the etiopathogenesis of psoriasis. These genes may represent novel therapeutic targets and surely need more rigorous experimental testing to be validated. Our analysis also identified 12 of 92 genes known to be related to the T helper 17 and regulatory T cell signaling pathways, and these were found to be differentially expressed in the lesional skin samples.

Orthogonal space-time block coded rate-adaptive modulation with outdated feedbasck

Abstract-Channel state information (CSI) at the transmitter can be used to adapt transmission rate or antenna gains in multi-antenna systems. We propose a rate-adaptive M-QAM scheme equipped with orthogonal space-time block coding with simple outdated, finite-rate feedback over independent flat fading channels. We obtain closed-form expressions for the average BER and throughput for our scheme, and analyze the effects of possibly delayed feedback on the performance gains. We derive optimal switching thresholds maximizing the average throughput under average and outage BER constraints with outdated feedback. Our numerical results illustrate the immunity of our optimal thresholds to delayed feedback.

Advanced glycation endproduct modified basement membrane attenuates endothelin-1 induced [Ca2+]i signalling and contraction in retinal microvascular pericytes

PURPOSE: To assess the effects of advanced glycation endproduct (AGE) modification of vascular basement membrane (BM) on endothelin-1 (Et-1) induced intracellular [Ca2+] ([Ca2+]i) homeostasis and contraction in retinal microvascular pericytes (RMP). METHODS: RMPs were isolated from bovine retinal capillaries and propagated on AGE modified BM extract (AGE-BM) or non-modified native BM. Cytosolic Ca2+ was estimated using fura-2 microfluorimetry and cellular contraction determined by measurement of planimetric cell surface area. ETA receptor mRNA and protein expression was assessed by real time RT-PCR and western blotting, respectively. RESULTS: Exogenous endothelin-1 (Et-1) evoked rises in [Ca2+]i and contraction in RMPs were found to be mediated entirely through ETA receptor (ETAR) activation. Both peak and plateau phases of the Et-1 induced [Ca2+]i response and contraction were impaired in RMPs propagated on AGE modified BM. ETAR mRNA expression remained unchanged in RMPs exposed to native or AGE-BM, but protein expression for ETAR (66 kDa) was lower in the AGE exposed cells. CONCLUSIONS: These results suggest that substrate derived AGE crosslinks can influence RMP physiology by mechanisms which include disruption of ETA receptor signalling. AGE modification of vascular BMs may contribute to the retinal hemodynamic abnormalities observed during diabetes.

A molecular photoionic AND gate based on fluorescent signalling

MOLECULES that perform logic operations are prerequisites for molecular information processing and computation. We and others have previously reported receptor molecules that can be considered to perform simple logic operations by coupling ionic bonding or more complex molecular-recognition processes with photonic (fluorescence) signals: in these systems, chemical binding (the 'input') results in a change in fluorescence intensity (the 'output') from the receptor. Here we describe a receptor (molecule (1) in Fig. 1) that operates as a logic device with two input channels: the fluorescence signal depends on whether the molecule binds hydrogen ions, sodium ions or both. The input/output characteristics of this molecular device correspond to those of an AND gate.

Modal Extraction for Wind Turbines using Moving Window Subspace Identification

This paper proposes a method for wind turbine mode identification using the multivariable output error statespace (MOESP) identification algorithm. The paper incorporates a fast moving window QR decomposition and propagator method from array signal processing, yielding a moving window subspace identification algorithm. The algorithm assumes that the system order is known as a priori and remains constant during identification. For the purpose of extracting modal information for turbines modelled as a linear parameter varying (LPV) system, the algorithm is applicable since a nonlinear system can be approximated as a piecewise time invariant system in consecutive data windows. The algorithm is exemplified using numerical simulations which show that the moving window algorithm can track the modal information. The paper also demonstrates that the low computational burden of the algorithm, compared to conventional batch subspace identification, has significant implications for online implementation.

Fast Moving Window Algorithm for QR and Cholesky Decompositions

This paper proposes a fast moving window algorithm for QR and Cholesky decompositions by simultaneously applying data updating and downdating. The developed procedure is based on inner products and entails a similar downdating to that of the Chambers’ approach. For adding and deleting one row of data from the original matrix, a detailed analysis shows that the proposed algorithm outperforms existing ones in terms or computational efficiency, if the number of columns exceeds 7. For a large number of columns, the proposed algorithm is numerically superior compared to the traditional sequential technique.