Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244)

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.

Speaker verification using I-vector features

This PhD research has provided novel solutions to three major challenges which have prevented the wide spread deployment of speaker recognition technology: (1) combating enrolment/ verification mismatch, (2) reducing the large amount of development and training data that is required and (3) reducing the duration of speech required to verify a speaker. A range of applications of speaker recognition technology from forensics in criminal investigations to secure access in banking will benefit from the research outcomes.

Higher order spectra based support vector machine for arrhythmia classification

Heart rate variability (HRV) refers to the regulation of the sinoatrial node, the natural pacemaker of the heart by the sympathetic and parasympathetic branches of the autonomic nervous system. HRV analysis is an important tool to observe the heart’s ability to respond to normal regulatory impulses that affect its rhythm. Like many bio-signals, HRV signals are non-linear in nature. Higher order spectral analysis (HOS) is known to be a good tool for the analysis of non-linear systems and provides good noise immunity. A computer-based arrhythmia detection system of cardiac states is very useful in diagnostics and disease management. In this work, we studied the identification of the HRV signals using features derived from HOS. These features were fed to the support vector machine (SVM) for classification. Our proposed system can classify the normal and other four classes of arrhythmia with an average accuracy of more than 85%.

Classification of echolocation calls from 14 species of bat by Support Vector Machines and Ensembles of Neural Networks

Calls from 14 species of bat were classified to genus and species using discriminant function analysis (DFA), support vector machines (SVM) and ensembles of neural networks (ENN). Both SVMs and ENNs outperformed DFA for every species while ENNs (mean identification rate – 97%) consistently outperformed SVMs (mean identification rate – 87%). Correct classification rates produced by the ENNs varied from 91% to 100%; calls from six species were correctly identified with 100% accuracy. Calls from the five species of Myotis, a genus whose species are considered difficult to distinguish acoustically, had correct identification rates that varied from 91 – 100%. Five parameters were most important for classifying calls correctly while seven others contributed little to classification performance.

Reliable Fault Diagnosis for Low-Speed Bearings Using Individually Trained Support Vector Machines With Kernel Discriminative Feature Analysis

This paper proposes a highly reliable fault diagnosis approach for low-speed bearings. The proposed approach first extracts wavelet-based fault features that represent diverse symptoms of multiple low-speed bearing defects. The most useful fault features for diagnosis are then selected by utilizing a genetic algorithm (GA)-based kernel discriminative feature analysis cooperating with one-against-all multicategory support vector machines (OAA MCSVMs). Finally, each support vector machine is individually trained with its own feature vector that includes the most discriminative fault features, offering the highest classification performance. In this study, the effectiveness of the proposed GA-based kernel discriminative feature analysis and the classification ability of individually trained OAA MCSVMs are addressed in terms of average classification accuracy. In addition, the proposedGA- based kernel discriminative feature analysis is compared with four other state-of-the-art feature analysis approaches. Experimental results indicate that the proposed approach is superior to other feature analysis methodologies, yielding an average classification accuracy of 98.06% and 94.49% under rotational speeds of 50 revolutions-per-minute (RPM) and 80 RPM, respectively. Furthermore, the individually trained MCSVMs with their own optimal fault features based on the proposed GA-based kernel discriminative feature analysis outperform the standard OAA MCSVMs, showing an average accuracy of 98.66% and 95.01% for bearings under rotational speeds of 50 RPM and 80 RPM, respectively.

Security Analysis of Randomize-Hash-then-Sign Digital Signatures

At CRYPTO 2006, Halevi and Krawczyk proposed two randomized hash function modes and analyzed the security of digital signature algorithms based on these constructions. They showed that the security of signature schemes based on the two randomized hash function modes relies on properties similar to the second preimage resistance rather than on the collision resistance property of the hash functions. One of the randomized hash function modes was named the RMX hash function mode and was recommended for practical purposes. The National Institute of Standards and Technology (NIST), USA standardized a variant of the RMX hash function mode and published this standard in the Special Publication (SP) 800-106. In this article, we first discuss a generic online birthday existential forgery attack of Dang and Perlner on the RMX-hash-then-sign schemes. We show that a variant of this attack can be applied to forge the other randomize-hash-then-sign schemes. We point out practical limitations of the generic forgery attack on the RMX-hash-then-sign schemes. We then show that these limitations can be overcome for the RMX-hash-then-sign schemes if it is easy to find fixed points for the underlying compression functions, such as for the Davies-Meyer construction used in the popular hash functions such as MD5 designed by Rivest and the SHA family of hash functions designed by the National Security Agency (NSA), USA and published by NIST in the Federal Information Processing Standards (FIPS). We show an online birthday forgery attack on this class of signatures by using a variant of Dean’s method of finding fixed point expandable messages for hash functions based on the Davies-Meyer construction. This forgery attack is also applicable to signature schemes based on the variant of RMX standardized by NIST in SP 800-106. We discuss some important applications of our attacks and discuss their applicability on signature schemes based on hash functions with ‘built-in’ randomization. Finally, we compare our attacks on randomize-hash-then-sign schemes with the generic forgery attacks on the standard hash-based message authentication code (HMAC).

On Randomizing Hash Functions to Strengthen the Security of Digital Signatures

Halevi and Krawczyk proposed a message randomization algorithm called RMX as a front-end tool to the hash-then-sign digital signature schemes such as DSS and RSA in order to free their reliance on the collision resistance property of the hash functions. They have shown that to forge a RMX-hash-then-sign signature scheme, one has to solve a cryptanalytical task which is related to finding second preimages for the hash function. In this article, we will show how to use Dean’s method of finding expandable messages for finding a second preimage in the Merkle-Damgård hash function to existentially forge a signature scheme based on a t-bit RMX-hash function which uses the Davies-Meyer compression functions (e.g., MD4, MD5, SHA family) in 2 t/2 chosen messages plus 2 t/2 + 1 off-line operations of the compression function and similar amount of memory. This forgery attack also works on the signature schemes that use Davies-Meyer schemes and a variant of RMX published by NIST in its Draft Special Publication (SP) 800-106. We discuss some important applications of our attack.

The origin of cyclical high- and low-Cr basalts with continental crust trace element signatures in the Kalkarindji Large Igneous Province

The 510 million year old Kalkarindji Large Igneous Province correlates in time with the first major extinction event after the Cambrian explosion of life. Large igneous provinces correlate with all major mass extinction events in the last 500 million years. The genetic link between large igneous provinces and mass extinction remains unclear. My work is a contribution towards understanding magmatic processes involved in the generation of Large Igneous Provinces. I concentrate on the origin of variation in Cr in magmas and have developed a model in which high temperature melts intrude into and assimilate large amounts of upper continental crust.

DS-VBF : dual sink vector-based routing protocol for underwater wireless sensor network

Underwater wireless sensor networks (UWSNs) have become the seat of researchers' attention recently due to their proficiency to explore underwater areas and design different applications for marine discovery and oceanic surveillance. One of the main objectives of each deployed underwater network is discovering the optimized path over sensor nodes to transmit the monitored data to onshore station. The process of transmitting data consumes energy of each node, while energy is limited in UWSNs. So energy efficiency is a challenge in underwater wireless sensor network. Dual sinks vector based forwarding (DS-VBF) takes both residual energy and location information into consideration as priority factors to discover an optimized routing path to save energy in underwater networks. The modified routing protocol employs dual sinks on the water surface which improves network lifetime. According to deployment of dual sinks, packet delivery ratio and the average end to end delay are enhanced. Based on our simulation results in comparison with VBF, average end to end delay reduced more than 80%, remaining energy increased 10%, and the increment of packet reception ratio was about 70%.

GPU accelerated algorithms for computing matrix function vector products with applications to exponential integrators and fractional diffusion

The efficient computation of matrix function vector products has become an important area of research in recent times, driven in particular by two important applications: the numerical solution of fractional partial differential equations and the integration of large systems of ordinary differential equations. In this work we consider a problem that combines these two applications, in the form of a numerical solution algorithm for fractional reaction diffusion equations that after spatial discretisation, is advanced in time using the exponential Euler method. We focus on the efficient implementation of the algorithm on Graphics Processing Units (GPU), as we wish to make use of the increased computational power available with this hardware. We compute the matrix function vector products using the contour integration method in [N. Hale, N. Higham, and L. Trefethen. Computing Aα, log(A), and related matrix functions by contour integrals. SIAM J. Numer. Anal., 46(5):2505–2523, 2008]. Multiple levels of preconditioning are applied to reduce the GPU memory footprint and to further accelerate convergence. We also derive an error bound for the convergence of the contour integral method that allows us to pre-determine the appropriate number of quadrature points. Results are presented that demonstrate the effectiveness of the method for large two-dimensional problems, showing a speedup of more than an order of magnitude compared to a CPU-only implementation.

High connectivity in rastrelliger kanagurta: Influence of historical signatures and migratory behaviour inferred from mtDNA Cytochrome b

Phylogeographic patterns and population structure of the pelagic Indian mackerel, Rastrelliger kanagurta were examined in 23 populations collected from the Indonesian-Malaysian Archipelago (IMA) and the West Indian Ocean (WIO). Despite the vast expanse of the IMA and neighbouring seas, no evidence for geographical structure was evident. An indication that R. kanagurta populations across this region are essentially panmictic. This study also revealed that historical isolation was insufficient for R. kanagurta to attain migration drift equilibrium. Two distinct subpopulations were detected between the WIO and the IMA (and adjacent populations); interpopulation genetic variation was high. A plausible explanation for the genetic differentiation observed between the IMA and WIO regions suggest historical isolation as a result of fluctuations in sea levels during the late Pleistocene. This occurrence resulted in the evolution of a phylogeographic break for this species to the north of the Andaman Sea.

Role of enhanced vector transmission of a new West Nile virus strain in an outbreak of equine disease in Australia in 2011

Background In 2011, a variant of West Nile virus Kunjin strain (WNVKUN) caused an unprecedented epidemic of neurological disease in horses in southeast Australia, resulting in almost 1,000 cases and a 9% fatality rate. We investigated whether increased fitness of the virus in the primary vector, Culex annulirostris, and another potential vector, Culex australicus, contributed to the widespread nature of the outbreak. Methods Mosquitoes were exposed to infectious blood meals containing either the virus strain responsible for the outbreak, designated WNVKUN2011, or WNVKUN2009, a strain of low virulence that is typical of historical strains of this virus. WNVKUN infection in mosquito samples was detected using a fixed cell culture enzyme immunoassay and a WNVKUN- specific monoclonal antibody. Probit analysis was used to determine mosquito susceptibility to infection. Infection, dissemination and transmission rates for selected days post-exposure were compared using Fisher’s exact test. Virus titers in bodies and saliva expectorates were compared using t-tests. Results There were few significant differences between the two virus strains in the susceptibility of Cx. annulirostris to infection, the kinetics of virus replication and the ability of this mosquito species to transmit either strain. Both strains were transmitted by Cx. annulirostris for the first time on day 5 post-exposure. The highest transmission rates (proportion of mosquitoes with virus detected in saliva) observed were 68% for WNVKUN2011 on day 12 and 72% for WNVKUN2009 on day 14. On days 12 and 14 post-exposure, significantly more WNVKUN2011 than WNVKUN2009 was expectorated by infected mosquitoes. Infection, dissemination and transmission rates of the two strains were not significantly different in Culex australicus. However, transmission rates and the amount of virus expectorated were significantly lower in Cx. australicus than Cx. annulirostris. Conclusions The higher amount of WNVKUN2011 expectorated by infected mosquitoes may be an indication that this virus strain is transmitted more efficiently by Cx. annulirostris compared to other WNVKUN strains. Combined with other factors, such as a convergence of abundant mosquito and wading bird populations, and mammalian and avian feeding behaviour by Cx. annulirostris, this may have contributed to the scale of the 2011 equine epidemic.

VIP Barcoding: Composition vector-based software for rapid species identification based on DNA barcoding

Species identification based on short sequences of DNA markers, that is, DNA barcoding, has emerged as an integral part of modern taxonomy. However, software for the analysis of large and multilocus barcoding data sets is scarce. The Basic Local Alignment Search Tool (BLAST) is currently the fastest tool capable of handling large databases (e.g. >5000 sequences), but its accuracy is a concern and has been criticized for its local optimization. However, current more accurate software requires sequence alignment or complex calculations, which are time-consuming when dealing with large data sets during data preprocessing or during the search stage. Therefore, it is imperative to develop a practical program for both accurate and scalable species identification for DNA barcoding. In this context, we present VIP Barcoding: a user-friendly software in graphical user interface for rapid DNA barcoding. It adopts a hybrid, two-stage algorithm. First, an alignment-free composition vector (CV) method is utilized to reduce searching space by screening a reference database. The alignment-based K2P distance nearest-neighbour method is then employed to analyse the smaller data set generated in the first stage. In comparison with other software, we demonstrate that VIP Barcoding has (i) higher accuracy than Blastn and several alignment-free methods and (ii) higher scalability than alignment-based distance methods and character-based methods. These results suggest that this platform is able to deal with both large-scale and multilocus barcoding data with accuracy and can contribute to DNA barcoding for modern taxonomy. VIP Barcoding is free and available at http://msl.sls.cuhk.edu.hk/vipbarcoding/.