University of Glasgow (qirdcsuog) at TREC Crowdsourcing 2011 : TurkRank-network-based worker ranking in crowdsourcing

For TREC Crowdsourcing 2011 (Stage 2) we propose a networkbased approach for assigning an indicative measure of worker trustworthiness in crowdsourced labelling tasks. Workers, the gold standard and worker/gold standard agreements are modelled as a network. For the purpose of worker trustworthiness assignment, a variant of the PageRank algorithm, named TurkRank, is used to adaptively combine evidence that suggests worker trustworthiness, i.e., agreement with other trustworthy co-workers and agreement with the gold standard. A single parameter controls the importance of co-worker agreement versus gold standard agreement. The TurkRank score calculated for each worker is incorporated with a worker-weighted mean label aggregation.

NTRUCCA : how to strengthen NTRUEncrypt to chosen-ciphertext security in the standard model

NTRUEncrypt is a fast and practical lattice-based public-key encryption scheme, which has been standardized by IEEE, but until recently, its security analysis relied only on heuristic arguments. Recently, Stehlé and Steinfeld showed that a slight variant (that we call pNE) could be proven to be secure under chosen-plaintext attack (IND-CPA), assuming the hardness of worst-case problems in ideal lattices. We present a variant of pNE called NTRUCCA, that is IND-CCA2 secure in the standard model assuming the hardness of worst-case problems in ideal lattices, and only incurs a constant factor overhead in ciphertext and key length over the pNE scheme. To our knowledge, our result gives the first IND-CCA2 secure variant of NTRUEncrypt in the standard model, based on standard cryptographic assumptions. As an intermediate step, we present a construction for an All-But-One (ABO) lossy trapdoor function from pNE, which may be of independent interest. Our scheme uses the lossy trapdoor function framework of Peikert and Waters, which we generalize to the case of (k − 1)-of-k-correlated input distributions.

Controlled automated discovery of collections of business process models

Automated process discovery techniques aim at extracting process models from information system logs. Existing techniques in this space are effective when applied to relatively small or regular logs, but generate spaghetti-like and sometimes inaccurate models when confronted to logs with high variability. In previous work, trace clustering has been applied in an attempt to reduce the size and complexity of automatically discovered process models. The idea is to split the log into clusters and to discover one model per cluster. This leads to a collection of process models – each one representing a variant of the business process – as opposed to an all-encompassing model. Still, models produced in this way may exhibit unacceptably high complexity and low fitness. In this setting, this paper presents a two-way divide-and-conquer process discovery technique, wherein the discovered process models are split on the one hand by variants and on the other hand hierarchically using subprocess extraction. Splitting is performed in a controlled manner in order to achieve user-defined complexity or fitness thresholds. Experiments on real-life logs show that the technique produces collections of models substantially smaller than those extracted by applying existing trace clustering techniques, while allowing the user to control the fitness of the resulting models.

Mechanism‐based selection of a potent kallikrein‐related peptidase 7 inhibitor from a versatile library based on the sunflower trypsin inhibitor SFTI‐1

Potent and specific enzyme inhibition is a key goal in the development of therapeutic inhibitors targeting proteolytic activity. The backbone-cyclized peptide, Sunflower Trypsin Inhibitor (SFTI-1) affords a scaffold that can be engineered to achieve both these aims. SFTI-1's mechanism of inhibition is unusual in that it shows fast-on/slow-off kinetics driven by cleavage and religation of a scissile bond. This phenomenon was used to select a nanomolar inhibitor of kallikrein-related peptidase 7 (KLK7) from a versatile library of SFTI variants with diversity tailored to exploit distinctive surfaces present in the active site of serine proteases. Inhibitor selection was achieved through the use of size exclusion chromatography to separate protease/inhibitor complexes from unbound inhibitors followed by inhibitor identification according to molecular mass ascertained by mass spectrometry. This approach identified a single dominant inhibitor species with molecular weight of 1562.4 Da, which is consistent with the SFTI variant SFTI-WCTF. Once synthesized individually this inhibitor showed an IC50 of 173.9 ± 7.6 nM against chromogenic substrates and could block protein proteolysis. Molecular modeling analysis suggested that selection of SFTI-WCTF was driven by specific aromatic interactions and stabilized by an enhanced internal hydrogen bonding network. This approach provides a robust and rapid route to inhibitor selection and design.

Prediction with limited advice and multiarmed bandits with paid observations

We study two problems of online learning under restricted information access. In the first problem, prediction with limited advice, we consider a game of prediction with expert advice, where on each round of the game we query the advice of a subset of M out of N experts. We present an algorithm that achieves O(√(N/M)TlnN ) regret on T rounds of this game. The second problem, the multiarmed bandit with paid observations, is a variant of the adversarial N-armed bandit game, where on round t of the game we can observe the reward of any number of arms, but each observation has a cost c. We present an algorithm that achieves O((cNlnN) 1/3 T2/3+√TlnN ) regret on T rounds of this game in the worst case. Furthermore, we present a number of refinements that treat arm- and time-dependent observation costs and achieve lower regret under benign conditions. We present lower bounds that show that, apart from the logarithmic factors, the worst-case regret bounds cannot be improved.

Rapid identification of cytochrome P450cam variants by in vivo screening of active site libraries

The selection of cytochrome P450 enzymes from large variant libraries, and the subsequent use of these enzymes in preparative scale biotransformations, remains a formidable challenge due to the complexities of the associated electron transport systems. Here, a powerful approach for the generation and screening of P450cam libraries for new function is presented that is both flexible and robust. A targeted library was generated wherein only the P450cam active-site amino acids Y96 and F98 were fully randomized and biotransformations, using a novel P450cam whole-cell system, were screened by GC–MS for the hydroxylation of diphenylmethane. One in 50 of the reactions screened, including 16 different variants, produced 4-hydroxydiphenylmethane with up to 92% conversion observed in the case of the Y96A variant. These results demonstrate a primary example of the screening of P450cam libraries in a format that is compatible with extension to preparative scale reactions.

Direct repression of MYB by ZEB1 suppresses proliferation and epithelial gene expression during epithelial-to-mesenchymal transition of breast cancer cells

Introduction Epithelial-to-mesenchymal transition (EMT) promotes cell migration and is important in metastasis. Cellular proliferation is often downregulated during EMT, and the reverse transition (MET) in metastases appears to be required for restoration of proliferation in secondary tumors. We studied the interplay between EMT and proliferation control by MYB in breast cancer cells. Methods MYB, ZEB1, and CDH1 expression levels were manipulated by lentiviral small-hairpin RNA (shRNA)-mediated knockdown/overexpression, and verified with Western blotting, immunocytochemistry, and qRT-PCR. Proliferation was assessed with bromodeoxyuridine pulse labeling and flow cytometry, and sulforhodamine B assays. EMT was induced with epidermal growth factor for 9 days or by exposure to hypoxia (1% oxygen) for up to 5 days, and assessed with qRT-PCR, cell morphology, and colony morphology. Protein expression in human breast cancers was assessed with immunohistochemistry. ZEB1-MYB promoter binding and repression were determined with Chromatin Immunoprecipitation Assay and a luciferase reporter assay, respectively. Student paired t tests, Mann–Whitney, and repeated measures two-way ANOVA tests determined statistical significance (P < 0.05). Results Parental PMC42-ET cells displayed higher expression of ZEB1 and lower expression of MYB than did the PMC42-LA epithelial variant. Knockdown of ZEB1 in PMC42-ET and MDA-MB-231 cells caused increased expression of MYB and a transition to a more epithelial phenotype, which in PMC42-ET cells was coupled with increased proliferation. Indeed, we observed an inverse relation between MYB and ZEB1 expression in two in vitro EMT cell models, in matched human breast tumors and lymph node metastases, and in human breast cancer cell lines. Knockdown of MYB in PMC42-LA cells (MYBsh-LA) led to morphologic changes and protein expression consistent with an EMT. ZEB1 expression was raised in MYBsh-LA cells and significantly repressed in MYB-overexpressing MDA-MB-231 cells, which also showed reduced random migration and a shift from mesenchymal to epithelial colony morphology in two dimensional monolayer cultures. Finally, we detected binding of ZEB1 to MYB promoter in PMC42-ET cells, and ZEB1 overexpression repressed MYB promoter activity. Conclusions This work identifies ZEB1 as a transcriptional repressor of MYB and suggests a reciprocal MYB-ZEB1 repressive relation, providing a mechanism through which proliferation and the epithelial phenotype may be coordinately modulated in breast cancer cells.

Kiwifruit floral gene APETALA2 is alternatively spliced and accumulates in aberrant indeterminate flowers in the absence of miR172

In Arabidopsis, the identity of perianth and reproductive organs are specified by antagonistic action of two floral homeotic genes, APETALA2 (AP2) and AGAMOUS (AG). AP2 is also negatively regulated by an evolutionary conserved interaction with a microRNA, miR172, and has additional roles in general plant development. A kiwifruit gene with high levels of homology to AP2 and AP2-like genes from other plant species was identified. The transcript was abundant in the kiwifruit flower, particularly petal, suggesting a role in floral organ identity. Splice variants were identified, all containing both AP2 domains, including a variant that potentially produces a shorter transcript without the miRNA172 targeting site. Increased AP2 transcript accumulation was detected in the aberrant flowers of the mutant 'Pukekohe dwarf' with multiple perianth whorls and extended petaloid features. In contrast to normal kiwifruit flowers, the aberrant flowers failed to accumulate miR172 in the developing whorls, although accumulation was detected at the base of the flower. An additional role during dormancy in kiwifruit was proposed based on AP2 transcript accumulation in axillary buds before and after budbreak.

Mendel, 150 years on

Mendel's paper 'Versuche über Pflanzen-Hybriden' is the best known in a series of studies published in the late 18th and 19th centuries that built our understanding of the mechanism of inheritance. Mendel investigated the segregation of seven gene characters of pea (Pisum sativum), of which four have been identified. Here, we review what is known about the molecular nature of these genes, which encode enzymes (R and Le), a biochemical regulator (I) and a transcription factor (A). The mutations are: a transposon insertion (r), an amino acid insertion (i), a splice variant (a) and a missense mutation (le-1). The nature of the three remaining uncharacterized characters (green versus yellow pods, inflated versus constricted pods, and axial versus terminal flowers) is discussed.

Hormonal carcinogenesis in breast cancer : cellular and molecular studies of malignant progression

We have established and characterized a series of variant cell lines in which to identify the critical factors associated with E2-induced malignant progression, and the acquisition to tamoxifen resistance in human breast cancer. Sublines of the hormone-dependent MCF-7 cell line (MCF7/MIII and MCF7/LCC1) form stable, invasive, estrogen independent tumors in the mammary fat pads of ovariectomized athymic nude mice. These cells retain expression of both estrogen (ER) and progesterone receptors (PGR), but retain sensitivity to each of the major structural classes of antiestrogens. The tamoxifen-resistant MCF7/LCC2 cells retain sensitivity to the inhibitory effects of the steroidal antiestrogen ICI 182780. By comparing the parental hormone-dependent and variant hormone-independent cells, we have demonstrated an altered expression of some estrogen regulated genes (PGR, pS2, cathepsin D) in the hormone-independent variants. Other genes remain normally estrogen regulated (ER, laminin receptor, EGF-receptor). These data strongly implicate the altered regulation of a specific subset or network of estrogen regulated genes in the malignant progression of human breast cancer. Some of the primary response genes in this network may exhibit dose-response and induction kinetics similar to pS2, which is constitutively upregulated in the MCF7/MIII, MCF7/LCC1 and MCF7/LCC2 cells.

ICI 164,384, a pure antagonist of estrogen-stimulated MCF-7 cell proliferation and invasiveness

Estrogen is known to stimulate the proliferation and basement membrane invasiveness of the MCF-7 human breast cancer cell line. We have compared the new steroidal antiestrogen ICI 164,384, the triphenylethylene 4-hydroxytamoxifen (OHT), and the benzothiophene LY 117018, for their effects on the proliferation and invasiveness of the MCF-7 cell line and its antiestrogen-resistant variant LY-2. While all three antiestrogens blocked the proliferative effects of 17β-estradiol on MCF-7 cells, OHT and LY 117018, but not ICI 164,384 stimulated their proliferation in the absence of estrogen. The proliferative effects of OHT and LY 117018 were blocked by ICI 164,384. Basement membrane invasiveness of MCF-7 cells was stimulated by 17β-estradiol and OHT, but not LY 117018 or ICI 164,384. Both ICI 164,384 and Ly 117018 were able to block the invasiveness induced by either 17β-estradiol or OHT. The LY-2 antiestrogen-resistant variant of the MCF-7 cell line showed increased basal proliferation, and responded only slightly to estrogen. ICI 164,384, but not OHT or LY 117018 antagonized the effects of 17β-estradiol, but did not reduce proliferation below control levels. The LY-2 line was not resistant to the antiestrogenic effects of LY 117018 or ICI 164,384 on invasiveness, and was stimulated by LY 117018 for this parameter. Thus, ICI 164,384 is a pure antiestrogen for MCF-7 cell proliferation and invasiveness, and may offer clinical advantage over nonsteroidal antiestrogens which can stimulate these activities in tumor models in vitro.

Tyrosine phosphorylation mediates ConA-induced membrane type 1-matrix metalloproteinase expression and matrix metalloproteinase-2 activation in MDA-MB-231 human breast carcinoma cells

ConA-induced cell surface activation of pro-matrix metalloproteinase-2 (pro-MMP-2) by MDA-MB-231 human breast cancer cells is apparently mediated by up-regulation of membrane type 1 MMP (MT1-MMP) through transcriptional and posttranscriptional mechanisms. Here, we have explored the respective roles of cell surface clustering and protein tyrosine phosphorylation in the ConA- induction effects. Treatment with succinyl-ConA, a variant lacking significant clusterability, partially stimulated MT1-MMP mRNA and protein levels but did not induce MMP-2 activation, suggesting that clustering contributes to the transcriptional regulation by ConA but appears to be critical for the nontranscriptional component. We further found that genistein, an inhibitor of tyrosine phosphorylation, blocked ConA-induced pro-MMP-2 activation and ConA-induced MT1-MMP mRNA level in a dose-dependent manner, implicating tyrosine phosphorylation in the transcriptional aspect. This was confirmed by the dose-dependent promotion of pro-MMP-2 activation by sodium orthovanadate in the presence of suboptimal concentrations of ConA (7.5 μg/ml), with optimal effects seen at 25 μg/g orthovanadate. Genistein did not inhibit the ConA potentiation of MMP-2 activation in MCF-7 cells, in which transfected MT1-MMP is driven by a heterologous promoter, supporting the major implication of phosphotyrosine in the transcriptional component of ConA regulation. These data describe a major signaling event upstream of MT1- MMP induction by ConA and set the stage for further analysis of the nontranscriptional component.

A mass spectrometry study of XCO+, X = Si, Ge : Is SiCO+ a main group carbonyl? Comments on the bonding in ground state SiCO and the Si,C,O (+) potential energy surface

The cation\[Si,C,O](+) has been generated by 1) the electron ionisation (EI) of tetramethoxysilane and 2) chemical ionisation (CI) of a mixture of silane and carbon monoxide. Collisional activation (CA) experiments performed for mass-selected \[Si,C,O](+), generated by using both methods, indicate that the structure is not inserted OSiC+; however, a definitive structural assignment as Si+-CO, Si+-OC or some cyclic variant is impossible based on these results alone. Neutralisation-reionisation (+NR+) experiments for EI-generated \[Si,C,O](+) reveal a small peak corresponding to SiC+, but no detectable SiO+ signal, and thus establishes the existence of the Si+-CO isomer. CCSD(T)//B3LYP calculations employing a triple-zeta basis set have been used to explore the doublet and quartet potential-energy surfaces of the cation, as well as some important neutral states The results suggest that both Si+-CO and Si+ - OC isomers are feasible; however, the global minimum is (2)Pi SiCO+. Isomeric (2)Pi SiOC+ is 12.1 kcal mol(-1) less stable than (2)Pi SiCO+, and all quartet isomers are much higher in energy. The corresponding neutrals Si-CO and Si-OC are also feasible, but the lowest energy Si - OC isomer ((3)A") is bound by only 1.5 kcal mol(-1). We attribute most, if nor all, of the recovery signal in the +NR' experiment to SiCO+ survivor ions. The nature of the bonding in the lowest energy isomers of Si+ -(CO,OC) is interpreted with the aid of natural bond order analyses, and the ground stale bonding of SiCO+ is discussed in relation to classical analogues such as metal carbonyls and ketenes.

Combined analysis of categorical and numerical descriptors of Australian groundnut accessions using nonlinear principal component analysis

For users of germplasm collections, the purpose of measuring characterization and evaluation descriptors, and subsequently using statistical methodology to summarize the data, is not only to interpret the relationships between the descriptors, but also to characterize the differences and similarities between accessions in relation to their phenotypic variability for each of the measured descriptors. The set of descriptors for the accessions of most germplasm collections consists of both numerical and categorical descriptors. This poses problems for a combined analysis of all descriptors because few statistical techniques deal with mixtures of measurement types. In this article, nonlinear principal component analysis was used to analyze the descriptors of the accessions in the Australian groundnut collection. It was demonstrated that the nonlinear variant of ordinary principal component analysis is an appropriate analytical tool because subspecies and botanical varieties could be identified on the basis of the analysis and characterized in terms of all descriptors. Moreover, outlying accessions could be easily spotted and their characteristics established. The statistical results and their interpretations provide users with a more efficient way to identify accessions of potential relevance for their plant improvement programs and encourage and improve the usefulness and utilization of germplasm collections.

Authentication of concast communication

In this paper we tackle the problem of finding an efficient signature verification scheme when the number of signatures is signi.- cantly large and the verifier is relatively weak. In particular, we tackle the problem of message authentication in many-to-one communication networks known as concast communication. The paper presents three signature screening algorithms for a variant of ElGamal-type digital signatures. The cost for these schemes is n applications of hash functions, 2n modular multiplications, and n modular additions plus the verification of one digital signature, where n is the number of signatures. The paper also presents a solution to the open problem of finding a fast screening signature for non-RSA digital signature schemes.