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This paper presents an extension of stochastic gradient descent for the minimization of Lipschitz continuous loss functions. Our motivation is for use in non-smooth non-convex stochastic optimization problems, which are frequently encountered in applications such as machine learning. Using the Clarke ϵ -subdifferential, we prove the non-asymptotic convergence to an approximate stationary point in expectation for the proposed method. From this result, a method with non-asymptotic convergence with high probability, as well as a method with asymptotic convergence to a Clarke stationary point almost surely are developed. Our results hold under the assumption that the stochastic loss function is a Carathéodory function which is almost everywhere Lipschitz continuous in the decision variables. To the best of our knowledge, this is the first non-asymptotic convergence analysis under these minimal assumptions. [ABSTRACT FROM AUTHOR]

We propose a new first-order method for minimizing nonconvex functions with Lipschitz continuous gradients and Hölder continuous Hessians. The proposed algorithm is a heavy-ball method equipped with two particular restart mechanisms. It finds a solution where the gradient norm is less than ε\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\varepsilon $$\end{document} in O(Hν12+2νε-4+3ν2+2ν)\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$O(H_{\nu }^{\frac{1}{2 + 2 \nu }} \varepsilon ^{- \frac{4 + 3 \nu }{2 + 2 \nu }})$$\end{document} function and gradient evaluations, where ν∈[0,1]\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\nu \in [0, 1]$$\end{document} and Hν\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$H_{\nu }$$\end{document} are the Hölder exponent and constant, respectively. This complexity result covers the classical bound of O(ε-2)\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$O(\varepsilon ^{-2})$$\end{document} for ν=0\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\nu = 0$$\end{document} and the state-of-the-art bound of O(ε-7/4)\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$O(\varepsilon ^{-7/4})$$\end{document} for ν=1\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\nu = 1$$\end{document}. Our algorithm is ν\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\nu $$\end{document}-independent and thus universal; it automatically achieves the above complexity bound with the optimal ν∈[0,1]\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\nu \in [0, 1]$$\end{document} without knowledge of Hν\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$H_{\nu }$$\end{document}. In addition, the algorithm does not require other problem-dependent parameters as input, including the gradient’s Lipschitz constant or the target accuracy ε\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\varepsilon $$\end{document}. Numerical results illustrate that the proposed method is promising. [ABSTRACT FROM AUTHOR]

This paper focuses on stochastic proximal gradient methods for optimizing a smooth nonconvex loss function with a non-smooth non-convex regularizer and convex constraints. To the best of our knowledge we present the rst non-asymptotic convergence bounds for this class of problem. We present two simple stochastic proximal gradient algorithms, for general stochastic and nite-sum optimization problems. In a numerical experiment we compare our algorithms with the current state-of-the-art deterministic algorithm and nd our algorithms to exhibit superior convergence. [ABSTRACT FROM AUTHOR]

We propose a DC (Difference of two Convex functions) formulation approach for sparse optimization problems having a cardinality or rank constraint. With the largest-k norm, an exact DC representation of the cardinality constraint is provided. We then transform the cardinality-constrained problem into a penalty function form and derive exact penalty parameter values for some optimization problems, especially for quadratic minimization problems which often appear in practice. A DC Algorithm (DCA) is presented, where the dual step at each iteration can be efficiently carried out due to the accessible subgradient of the largest-k norm. Furthermore, we can solve each DCA subproblem in linear time via a soft thresholding operation if there are no additional constraints. The framework is extended to the rank-constrained problem as well as the cardinality- and the rank-minimization problems. Numerical experiments demonstrate the efficiency of the proposed DCA in comparison with existing methods which have other penalty terms. [ABSTRACT FROM AUTHOR]

Financial risk measures have been used recently in machine learning. For example, v-support vector machine (v-SVM) minimizes the conditional value at risk (CVaR) of margin distribution. The measure is popular in finance because of the subadditivity property, but it is very sensitive to a few outliers in the tail of the distribution. We propose a new classification method, extended robust SVM (ER-SVM), which minimizes an intermediate risk measure between the CVaR and value at risk (VaR) by expecting that the resulting model becomes less sensitive than v - S V M to outliers. We can regard ER-SVM as an extension of robust SVM, which uses a truncated hinge loss. Numerical experiments imply the ER-SVM's possibility of achieving a better prediction performance with proper parameter setting. [ABSTRACT FROM AUTHOR]

Hematologic malignancies are often associated with chromosomal rearrangements that lead to the expression of chimeric fusion proteins. Rearrangements of the genes encoding two nucleoporins, NUP98 and NUP214, have been implicated in the pathogenesis of several types of hematologic malignancies, particularly acute myeloid leukemia. NUP98 rearrangements result in fusion of an N-terminal portion of NUP98 to one of numerous proteins. These rearrangements often follow treatment with topoisomerase II inhibitors and tend to occur in younger patients. They have been shown to induce leukemia in mice and to enhance proliferation and disrupt differentiation in primary human hematopoietic precursors. NUP214 has only a few fusion partners. DEK-NUP214 is the most common NUP214 fusion in AML; it tends to occur in younger patients and is usually associated with FLT3 internal tandem duplications. The leukemogenic activity of NUP214 fusions is less well characterized. Normal nucleoporins, including NUP98 and NUP214, have important functions in nucleocytoplasmic transport, transcription, and mitosis. These functions and their disruptions by oncogenic nucleoporin fusions are discussed. [ABSTRACT FROM AUTHOR]

A wide variety of machine learning algorithms such as the support vector machine (SVM), minimax probability machine (MPM), and Fisher discriminant analysis (FDA) exist for binary classification. The purpose of this letter is to provide a unified classification model that includes these models through a robust optimization approach. This unified model has several benefits. One is that the extensions and improvements intended for SVMs become applicable to MPM and FDA, and vice versa. For example, we can obtain nonconvex variants of MPM and FDA by mimicking Perez-Cruz, Weston, Hermann, and Schölkopf's (2003) extension from convex v-SVM to nonconvex Ev-SVM. Another benefit is to provide theoretical results concerning these learning methods at once by dealing with the unified model. We give a statistical interpretation of the unified classification model and prove that the model is a good approximation for the worst-case minimization of an expected loss with respect to the uncertain probability distribution. We also propose a nonconvex optimization algorithm that can be applied to nonconvex variants of existing learning methods and show promising numerical results. [ABSTRACT FROM AUTHOR]

The Johnson-Lindenstrauss Lemma states that there exist linear maps that project a set of points of a vector space into a space of much lower dimension such that the Euclidean distance between these points is approximately preserved. This lemma has been previously used to prove that we can randomly aggregate, using a random matrix whose entries are drawn from a zero-mean sub-Gaussian distribution, the equality constraints of an Linear Program (LP) while preserving approximately the value of the problem. In this paper we extend these results to the inequality case by introducing a random matrix with non-negative entries that allows to randomly aggregate inequality constraints of an LP while preserving approximately the value of the problem. By duality, the approach we propose allows to reduce both the number of constraints and the dimension of the problem while obtaining some theoretical guarantees on the optimal value. We will also show an extension of our results to certain semidefinite programming instances. [ABSTRACT FROM AUTHOR]

A deterministic approach called robust optimization has been recently proposed to deal with optimization problems including inexact data, i.e., uncertainty. The basic idea of robust optimization is to seek a solution that is guaranteed to perform well in terms of feasibility and near-optimality for all possible realizations of the uncertain input data. To solve robust optimization problems, Calafiore and Campi have proposed a randomized approach based on sampling of constraints, where the number of samples is determined so that only a small portion of the original constraints is violated by the randomized solution. Our main concern is not only the probability of violation, but also the degree of violation, i.e., the worst-case violation. We derive an upper bound of the worst-case violation for the sampled convex programs and consider the relation between the probability of violation and the worst-case violation. The probability of violation and the degree of violation are simultaneously bounded by a prescribed value when the number of random samples is large enough. In addition, a confidence interval of the optimal value is obtained when the objective function includes uncertainty. Our method is applicable to not only a bounded uncertainty set but also an unbounded one. Hence, the scope of our method includes random sampling following an unbounded distribution such as the normal distribution. [ABSTRACT FROM AUTHOR]

Background/Aims: Although protein kinase C-γ (PKC-γ) is a target for the effects of volatile anesthetics, the molecular mechanisms of the kinase function during their action remain unclear. We examined the effects of different types of anesthetics on PKC-γ knockout mice. Furthermore, we investigated the dynamics of the kinase in brain cells obtained from mice anesthetized with these anesthetics. Methods: We measured the required times for loss of righting reflex (rtfLORR) after administration of isoflurane, sevoflurane, or propofol on PKC-γ knockout mice and compared the times with those of wild-type mice. We also used immunoblotting to investigate the intracellular distribution of PKC-γ and phosphorylated PKC-γ (p-PKC-γ) in brain cell fractions obtained from wild-type mice during the loss of righting reflex induced by these anesthetics. Results: Isoflurane (2.6%) and sevoflurane (3.4%) used at twice the minimum alveolar concentration significantly prolonged the rtfLORRs in PKC-γ knockout mice compared to those in wild-type mice. On the other hand, no significant difference was observed between knockout and wild-type mice treated with propofol (200 mg/kg). Examination of the cellular fractions isolated from volatile anesthetic-treated mouse brains showed that PKC-γ was significantly decreased in the synaptic membrane fraction (P2), whereas p-PKC-γ was significantly increased in P2. There was no significant change in the supernatant fraction (S). In propofol-treated mice, PKC-γ and p-PKC-γ showed no significant changes in P2 or S. Conclusion: Our results provide new evidence to support the possibility of the involvement of PKC-γ in the actions of volatile anesthetics. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

NUP98 is a nucleoporin that plays complex roles in the nucleocytoplasmic trafficking of macromolecules. Rearrangements of the NUP98 gene in human leukemia result in the expression of numerous fusion oncoproteins whose effect on nucleocytoplasmic trafficking is poorly understood. The present study was undertaken to determine the effects of leukemogenic NUP98 fusion proteins on CRM1-mediated nuclear export. NUP98-HOXA9, a prototypic NUP98 fusion, inhibited the nuclear export of two known CRM1 substrates: mutated cytoplasmic nucleophosmin and HIV-1 Rev. In vitro binding assays revealed that NUP98-HOXA9 binds CRM1 through the FG repeat motif in a Ran-GTP-dependent manner similar to but stronger than the interaction between CRM1 and its export substrates. Two NUP98 fusions, NUP98-HOXA9 and NUP98-DDX10, whose fusion partners are structurally and functionally unrelated, interacted with endogenous CRM1 in myeloid cells as shown by co-immunoprecipitation. These leukemogenic NUP98 fusion proteins interacted with CRM1, Ran, and the nucleoporin NUP214 in a manner fundamentally different from that of wild-type NUP98. NUP98-HOXA9 and NUP98-DDX10 formed characteristic aggregates within the nuclei of a myeloid cell line and primary human CD34+ cells and caused aberrant localization of CRM1 to these aggregates. These NUP98 fusions caused nuclear accumulation of two transcription factors, NFAT and NFκB, that are regulated by CRM1-mediated export. The nuclear entrapment of NFAT and NFκB correlated with enhanced transcription from promoters responsive to these transcription factors. Taken together, the results suggest a new mechanism by which NUP98 fusions dysregulate transcription and cause leukemia, namely, inhibition of CRM1-mediated nuclear export with aberrant nuclear retention of transcriptional regulators. [ABSTRACT FROM AUTHOR]

In this research, a petrological and mineralogical examination was carried out for the first time to examine the ground layers of urushi works. The examined samples were two pieces of urushi coating from Chusonji Konjikido, a building representative of twelfth-century AD Japan. Also examined were two samples from a dish excavated from the Yanaginogosho site. Chusonji Konjikido and the Yanaginogosho government building were built by the Oshu Fujiwara Family, a powerful family who controlled the entire Oshu area. The examination revealed that the admixture of the ground layers of the Konjikido samples consisted mainly of pumice tuff. The dish had ground layers composed mainly of plagioclase and volcanic glass. It was discovered that pumice tuff distributed within the precincts of the Chusonji Temple was used to make the ground layers of the examined urushi works, based on a comparison of the chemical composition of the volcanic glass contained in the urushi works. This material is not used in the modern lacquer-ware industry. The technique for making the ground coating used in the production of Konjikido and the dish is a lost technology. [ABSTRACT FROM AUTHOR]

Despite many efforts to develop AIDS vaccines eliciting virus-specific T-cell responses, whether induction of these memory T cells by vaccination before human immunodeficiency virus (HIV) exposure can actually contribute to effective T-cell responses postinfection remains unclear. In particular, induction of HIV-specific memory CD4+ T cells may increase the target cell pool for HIV infection because the virus preferentially infects HIV-specific CD4+ T cells. However, virus-specific CD4+ helper T-cell responses are thought to be important for functional CD8+ cytotoxic-T-lymphocyte (CTL) induction in HIV infection, and it has remained unknown whether HIV-specific memory CD8+ T cells induced by vaccination without HIV-specific CD4+ T-cell help can exert effective responses after virus exposure. Here we show the impact of CD8+ T-cell memory induction without virus-specific CD4+ T-cell help on the control of a simian immunodeficiency virus (SIV) challenge in rhesus macaques. We developed a prophylactic vaccine by using a Sendai virus (SeV) vector expressing a single SIV Gag241-249 CTL epitope fused with enhanced green fluorescent protein (EGFP). Vaccination resulted in induction of SeV-EGFP-specific CD4+ T-cell and Gag241-249-specific CD8+ T-cell responses. After a SIV challenge, the vaccinees showed dominant Gag241-249-specific CD8+ T-cell responses with higher effector memory frequencies in the acute phase and exhibited significantly reduced viral loads. These results demonstrate that virus-specific memory CD8+ T cells induced by vaccination without virus-specific CD4+ T-cell help could indeed facilitate SIV control after virus exposure, indicating the benefit of prophylactic vaccination eliciting virus-specific CTL memory with non-virus-specific CD4+ T-cell responses for HIV control. [ABSTRACT FROM AUTHOR]

The υ-support vector classification (υ-SVC) algorithm was shown to work well and provide intuitive interpretations, e.g., the parameter v roughly specifies the fraction of support vectors. Although ii corresponds to a fraction, it cannot take the entire range between 0 and 1 in its original form. This problem was settled by a non-convex extension of υ-SVC and the extended method was experimentally shown to generalize better than original υ-SVC. However, its good generalization performance and convergence properties of the optimization algorithm have not been studied yet. In this paper, we provide new theoretical insights into these issues and propose a novel υ-SVC algorithm that has guaranteed generalization performance and convergence properties. [ABSTRACT FROM AUTHOR]

Abstract: We extend the conditional geometric score (CGS) classifier of Gotoh and Takeda for binary linear classification to a nonlinear one, which we call the -support vector classifier (SVC), and investigate the equivalence between the -SVC and the (extended) -SVC. The CGS classifier has recently been found to be equivalent to the extended -SVC of Perez-Cruz et al. and, especially in the convex case, equivalent to the -SVC of Schölkopf et al. The CGS problem is to minimize a risk measure known as the conditional value-at-risk (-CVaR). In this paper, we discuss theoretical aspects, mainly generalization performance, of the -SVC. The formula of a generalization error bound includes the -CVaR or a related quantity. It implies that the minimum -CVaR leads to a small generalization error bound of the -SVC. The viewpoint of CVaR minimization is useful to ensure the validity of not only the -SVC but also the (extended) -SVC. [Copyright &y& Elsevier]

Abstract: Viral vectors are promising vaccine tools for eliciting antigen-specific T-cell responses. We previously showed the potential of recombinant Sendai virus (SeV) vectors to induce virus-specific T-cell responses in macaque AIDS models. Here, we have evaluated the immunogenicity of replication-competent V-knocked-out and replication-defective F-deleted SeV vectors in macaques. Intranasal replication-competent and replication-defective SeV immunizations both elicited robust systemic antigen-specific T-cell responses, whereas the responses induced by the former were more durable than those by the latter. However, even the latter-induced T-cell responses remained detectable in a local, retropharyngeal lymph node two months after the immunization. These findings are useful for establishment of a vaccine protocol using SeV vectors. [Copyright &y& Elsevier]

Abstract: Fv-4 is a mouse gene that confers resistance against ecotropic murine leukemia virus (MLV) infection on mice. While receptor interference by the Fv-4 env gene product, Fv-4 Env, that can bind to the ecotropic MLV receptor has been shown to play an important role in the resistance, other mechanisms have also been suggested because it confers extremely efficient, complete resistance in vivo. Here, we have examined the effect of Fv-4 Env on infectious MLV production. Infectious MLV titers in supernatants obtained after transfection with a Friend MLV (FMLV) Env-expressing plasmid from MLV gag–pol producer cells harboring a retroviral vector were largely reduced by coexpression of Fv-4 Env. Syncytia formation mediated by R-peptide-deleted FMLV Env in NIH 3T3 cells was impaired by Fv-4 Env coexpression. Similarly, Fv-4 Env inhibited infectious amphotropic MLV production and syncytia formation mediated by R-peptide-deleted amphotropic MLV Env. Immunoprecipitation analysis revealed interaction of Fv-4 Env with amphotropic MLV Env as well as FMLV Env. These results indicate that Fv-4 Env inhibits infectious ecotropic and amphotropic MLV production by exerting dominant negative effect on MLV Env, suggesting contribution of this inhibitory effect to the resistance against ecotropic MLV infection in Fv-4-expressing mice. [Copyright &y& Elsevier]

PU.1 is a transcription factor of the Ets family with important functions in hematopoietic cell differentiation. Using green fluorescent protein-PU.1 fusions, we show that the Ets DNA binding domain of PU.1 is necessary and sufficient for its nuclear localization. Fluorescence and ultrastructural nuclear import assays showed that PU.1 nuclear import requires energy but not soluble carriers. PU.1 interacted directly with two nucleoporins, Nup62 and Nup153. The binding of PU.1 to Nup153, but not to Nup62, increased dramatically in the presence of RanGMPPNP, indicating the formation of a PU.1-RanGTPNup153 complex. The Ets domain accounted for the bulk of the interaction of PU.1 with Nup153 and RanGMPPNP. Because Nup62 is located close to the midplane of the nuclear pore complex whereas Nup153 is at its nuclear side, these findings suggest a model whereby RanGTP propels PU.1 toward the nuclear side of the nuclear pore complex by increasing its affinity for Nup153. This notion was confirmed by ultrastructural studies using gold-labeled PU.1 in permeabilized cells. [ABSTRACT FROM AUTHOR]

Describes the mechanisms by which the oncogene Nup98-HOXA9 induces gene transcription in myeloid cells. DNA binding domains; Homeodomain transcription factor; Oligonucleotide microarrays; Transcriptional activation factor; Gene expression; Cell proliferation and survival; Drug metabolism.

We previously demonstrated the excellent protective efficacy of DNA priming followed by Gag-expressing Sendai virus (SeV) boosting (DNA prime/SeV-Gag boost vaccine) against a pathogenic simian-human immunodeficiency virus (SHIV89.6PD) infection in macaques. Here we show that we established a practical, safer AIDS vaccine protocol, a single DNA priming followed by a single booster with a recently developed replication defective F deletion SeV-expressing Gag, and show its protective efficacy against SHIV89.6PD infections. [ABSTRACT FROM AUTHOR]

Minimizing the sum of a convex function and a composite function appears in various fields. The generalized Levenberg–Marquardt (LM) method, also known as the prox-linear method, has been developed for such optimization problems. The method iteratively solves strongly convex subproblems with a damping term. This study proposes a new generalized LM method for solving the problem with a smooth composite function. The method enjoys three theoretical guarantees: iteration complexity bound, oracle complexity bound, and local convergence under a Hölderian growth condition. The local convergence results include local quadratic convergence under the quadratic growth condition; this is the first to extend the classical result for least-squares problems to a general smooth composite function. In addition, this is the first LM method with both an oracle complexity bound and local quadratic convergence under standard assumptions. These results are achieved by carefully controlling the damping parameter and solving the subproblems by the accelerated proximal gradient method equipped with a particular termination condition. Experimental results show that the proposed method performs well in practice for several instances, including classification with a neural network and nonnegative matrix factorization. [ABSTRACT FROM AUTHOR]

Examines the reaction of hydrogen peroxide with protohemin in aqueous solution at pH 5-10 with potassium ferrocyanide as a substrate. Initial rates; Effects of bases on kapp; Base binding to ferric hemin; pH dependency.

The article discusses the technique for the ground coating used in tsuishu jikiro lacquerware, a historical Chinese food storage container. Topics include details on the damage from the 2011 Eastern Japan Natural Disaster to a jikiro exhibited at a nonprofit organization in Yamagata City, Japan, details on the hikimage technique of making cuts into wood, details on the kentai technique of wrapping strips of wood, details on the mineral admixture used as the surface preparation, and details on conservation and preservation techniques for lacquers.

Extracellular vesicles (EVs) have attracted much attention as potential diagnostic biomarkers for human diseases. Although both plasma and serum are utilized as a source of blood EVs, it remains unclear whether, how and to what extent the choice of plasma and serum affects the experimental results. To address this issue, in this study, we performed comprehensive characterization of EV fractions derived from plasma and serum, and investigated the differences between these blood EVs. We demonstrated by nanoparticle tracking analysis that EV fractions derived from serum contain more particles than those from plasma of mice. Proteomic analysis demonstrated that platelet-associated proteins are selectively enriched in serum EV fractions from both mice and humans. A literature review of proteomic data of human blood EVs reported by other groups further confirmed that selective enrichment of platelet-associated proteins is commonly observed in serum EVs, and confers different proteome profiles to plasma EVs. Our data provide experimental evidence that EV fractions derived from serum generally contain additional EVs that are released from platelets, which may qualitatively and quantitatively alter EV profiles when using serum as a source of blood EVs. [ABSTRACT FROM AUTHOR]

We consider a class of nonconvex nonsmooth optimization problems whose objective is the sum of a smooth function and a finite number of nonnegative proper closed possibly nonsmooth functions (whose proximal mappings are easy to compute), some of which are further composed with linear maps. This kind of problems arises naturally in various applications when different regularizers are introduced for inducing simultaneous structures in the solutions. Solving these problems, however, can be challenging because of the coupled nonsmooth functions: the corresponding proximal mapping can be hard to compute so that standard first-order methods such as the proximal gradient algorithm cannot be applied efficiently. In this paper, we propose a successive difference-of-convex approximation method for solving this kind of problems. In this algorithm, we approximate the nonsmooth functions by their Moreau envelopes in each iteration. Making use of the simple observation that Moreau envelopes of nonnegative proper closed functions are continuous difference-of-convex functions, we can then approximately minimize the approximation function by first-order methods with suitable majorization techniques. These first-order methods can be implemented efficiently thanks to the fact that the proximal mapping of each nonsmooth function is easy to compute. Under suitable assumptions, we prove that the sequence generated by our method is bounded and any accumulation point is a stationary point of the objective. We also discuss how our method can be applied to concrete applications such as nonconvex fused regularized optimization problems and simultaneously structured matrix optimization problems, and illustrate the performance numerically for these two specific applications. [ABSTRACT FROM AUTHOR]

A substantial body of evidence points to the heritability of dietary preferences. While vegetarianism has been practiced for millennia in various societies, its practitioners remain a small minority of people worldwide, and the role of genetics in choosing a vegetarian diet is not well understood. Dietary choices involve an interplay between the physiologic effects of dietary items, their metabolism, and taste perception, all of which are strongly influenced by genetics. In this study, we used a genome-wide association study (GWAS) to identify loci associated with strict vegetarianism in UK Biobank participants. Comparing 5,324 strict vegetarians to 329,455 controls, we identified one SNP on chromosome 18 that is associated with vegetarianism at the genome-wide significant level (rs72884519, β = -0.11, P = 4.997 x 10−8), and an additional 201 suggestively significant variants. Four genes are associated with rs72884519: TMEM241, RIOK3, NPC1, and RMC1. Using the Functional Mapping and Annotation (FUMA) platform and the Multi-marker Analysis of GenoMic Annotation (MAGMA) tool, we identified 34 genes with a possible role in vegetarianism, 3 of which are GWAS-significant based on gene-level analysis: RIOK3, RMC1, and NPC1. Several of the genes associated with vegetarianism, including TMEM241, NPC1, and RMC1, have important functions in lipid metabolism and brain function, raising the possibility that differences in lipid metabolism and their effects on the brain may underlie the ability to subsist on a vegetarian diet. These results support a role for genetics in choosing a vegetarian diet and open the door to future studies aimed at further elucidating the physiologic pathways involved in vegetarianism. [ABSTRACT FROM AUTHOR]

This paper describes how Machine Learning and Robust Optimization techniques can greatly improve cash logistics operations. Specifically, we seek to optimize the logistics followed by the different branches of a given bank. Machine Learning is used to forecast cash demands for each of the branches, taking into account past demands and calendar effects. These demand predictions are forwarded to a Robust Optimization model, whose outputs are the cash transports that each branch should request. These transports guarantee that demand is fulfilled up to the desired confidence level, while also satisfying additional constraints arising in this particular domain. [ABSTRACT FROM AUTHOR]

We propose a unified formulation of robust learning methods for classification and regression problems. In the learning methods, the hinge loss is used with outlier indicators in order to detect outliers in the observed data. To analyze the robustness property, we evaluate the breakdown point of the learning methods in the situation that the outlier ratio is not necessarily small. Although minimization of the hinge loss with outlier indicators is a non-convex optimization problem, we prove that any local optimal solution of our learning algorithms has the robustness property. The theoretical findings are confirmed in numerical experiments. [ABSTRACT FROM AUTHOR]

Strongly motivated from applications in various fields including machine learning, the methodology of sparse optimization has been developed intensively so far. Especially, the advancement of algorithms for solving problems with nonsmooth regularizers has been remarkable. However, those algorithms suppose that weight parameters of regularizers, called hyperparameters hereafter, are pre-fixed, but it is a crucial matter how the best hyperparameter should be selected. In this paper, we focus on the hyperparameter selection of regularizers related to the ℓp\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\ell _p$$\end{document} function with 0

The conditional value-at-risk (CVaR) has gained growing popularity in financial risk management due to the coherence property and tractability in its optimization. However, optimal solutions to the CVaR minimization are highly susceptible to estimation error of the risk measure because the estimate depends only on a small portion of sampled scenarios. The same is equally true of the other coherent measures. In this paper, by employing robust optimization modelling for minimizing coherent risk measures, we present a simple and practical way for making the solution robust over a certain range of estimation errors. More specifically, we show that a worst-case coherent risk minimization leads to a penalized minimization of the empirical risk estimate. The worst-case risk measure developed in this paper is different from the distributionally worst-case CVaR in Zhu and Fukushima's work of 2009, but these two worst-case risk measures can be simultaneously minimized. Additionally, inspired by Konno, Waki and Yuuki's work of 2002, we examine the use of factor models in coherent risk minimization. We see that, in general, factor model-based coherent risk minimization along the lines of that pursued by Goldfarb and Iyengar in 2003 becomes computationally intractable. Therefore, we apply a simplified version to the factor model-based CVaR minimization, and see that it improves on the performance, achieving better CVaR, turnover, standard deviation and Sharpe ratio than the empirical CVaR minimization and market benchmarks. [ABSTRACT FROM PUBLISHER]

Abstract: A current promising AIDS vaccine strategy is to elicit CD8+ cytotoxic T lymphocyte (CTL) responses that broadly recognize highly-diversified HIVs. In our previous vaccine trial eliciting simian immunodeficiency virus (SIV) mac239 Gag-specific CTL responses, a group of Burmese rhesus macaques possessing a major histocompatibility complex haplotype 90-120-Ia have shown vaccine-based viral control against a homologous SIVmac239 challenge. Vaccine-induced Gag206–216 epitope-specific CTL responses exerted strong selective pressure on the virus in this control. Here, we have evaluated in vivo efficacy of vaccine-induced Gag206–216-specific CTL responses in two 90-120-Ia-positive macaques against challenge with a heterologous SIVsmE543-3 that has the same Gag206–216 epitope sequence with SIVmac239. Despite efficient Gag206–216-specific CTL induction by vaccination, both vaccinees failed to control SIVsmE543-3 replication and neither of them showed mutations within the Gag206–216 epitope. Further analysis indicated that Gag206–216-specific CTLs failed to show responses against SIVsmE543-3 infection due to a change from aspartate to glutamate at Gag residue 205 immediately preceding the amino terminus of Gag206–216 epitope. Our results suggest that even vaccine-induced CTL efficacy can be abrogated by a single amino acid change in viral epitope flanking region, underlining the influence of viral epitope flanking sequences on CTL-based AIDS vaccine efficacy. [Copyright &y& Elsevier]

Cytotoxic T-lymphocyte (CTL) responses are crucial for the control of immunodeficiency virus replication. Possible involvement of a dominant single epitope-specific CTL in control of viral replication has recently been indicated in preclinical AIDS vaccine trials, but it has remained unclear if multiple epitope-specific CTLs can be involved in the vaccine-based control. Here, by following up five rhesus macaques that showed vaccine-based control of primary replication of a simian immunodeficiency virus, SIVmac239, we present evidence indicating involvement of multiple epitope-specific CTL responses in this control. Three macaques maintained control for more than 2 years without additional mutations in the provirus. However, in the other two that shared a major histocompatibility complex haplotype, viral mutations were accumulated in a similar order, leading to viral evasion from three epitope-specific CTL responses with viral fitness costs. Accumulation of these multiple escape mutations resulted in the reappearance of plasma viremia around week 60 after challenge. Our results implicate multiple epitope-specific CTL responses in control of immunodeficiency virus replication and furthermore suggest that sequential accumulation of multiple CTL escape mutations, if allowed, can result in viral evasion from this control. [ABSTRACT FROM AUTHOR]

Vaccine-based control of the replication of a simian immunodeficiency virus (SIV), SIVmac239, in macaques has recently been shown. In the process of the control, a mutant virus escaping from epitope-specific cytotoxic-T-lymphocyte (CTL) responses was rapidly selected and contained. In this study, we show that the wild-type virus appeared and became predominant in the absence of the epitope-specific CTL after inoculation of naive macaques with a molecular clone DNA of the CTL escape mutant SIV. This is the first report describing reversion in vivo from an inoculated, molecular proviral DNA clone of immunodeficiency virus with a CTL escape mutation. [ABSTRACT FROM AUTHOR]

Abstract: Recent prophylactic vaccine trials inducing virus-specific CD8+ T-cell responses have shown control of primary infections of a pathogenic simian-human immunodeficiency virus (SHIV) in macaques. In the chronic phase, therapeutic immunization replenishing virus-specific CD8+ T-cells is likely to contribute to sustained control of virus replication. In this study, we have administered a recombinant Sendai virus (SeV) vector into five rhesus macaques that had received prophylactic vaccinations and had controlled SHIV replication for more than 1 year after challenge. Our results indicate that virus-specific CD8+ T-cell responses can be expanded and broadened by therapeutic immunization with SeV vectors in the chronic phase after prophylactic vaccine-based control of primary immunodeficiency virus infections. [Copyright &y& Elsevier]

We propose a new formulation of multiple-instance learning (MIL), in which a unit of data consists of a set of instances called a bag. The goal is to find a good classifier of bags based on the similarity with a "shapelet" (or pattern), where the similarity of a bag with a shapelet is the maximum similarity of instances in the bag. In previous work, some of the training instances have been chosen as shapelets with no theoretical justification. In our formulation, we use all possible, and thus infinitely many, shapelets, resulting in a richer class of classifiers. We show that the formulation is tractable, that is, it can be reduced through linear programming boosting (LPBoost) to difference of convex (DC) programs of finite (actually polynomial) size. Our theoretical result also gives justification to the heuristics of some previous work. The time complexity of the proposed algorithm highly depends on the size of the set of all instances in the training sample. To apply to the data containing a large number of instances, we also propose a heuristic option of the algorithm without the loss of the theoretical guarantee. Our empirical study demonstrates that our algorithm uniformly works for shapelet learning tasks on time-series classification and various MIL tasks with comparable accuracy to the existing methods. Moreover, we show that the proposed heuristics allow us to achieve the result in reasonable computational time. [ABSTRACT FROM AUTHOR]

The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases that include Huntington's disease, various spinocerebellar ataxias, spinal and bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. They are caused by the abnormal expansion of a CAG repeat coding for the polyQ stretch in the causative gene of each disease. The expanded polyQ stretches trigger abnormal β-sheet conformational transition and oligomerization followed by aggregation of the polyQ proteins in the affected neurons, leading to neuronal toxicity and neurodegeneration. Disease-modifying therapies that attenuate both symptoms and molecular pathogenesis of polyQ diseases remain an unmet clinical need. Here we identified arginine, a chemical chaperone that facilitates proper protein folding, as a novel compound that targets the upstream processes of polyQ protein aggregation by stabilizing the polyQ protein conformation. We first screened representative chemical chaperones using an in vitro polyQ aggregation assay, and identified arginine as a potent polyQ aggregation inhibitor. Our in vitro and cellular assays revealed that arginine exerts its anti-aggregation property by inhibiting the toxic β-sheet conformational transition and oligomerization of polyQ proteins before the formation of insoluble aggregates. Arginine exhibited therapeutic effects on neurological symptoms and protein aggregation pathology in Caenorhabditis elegans, Drosophila, and two different mouse models of polyQ diseases. Arginine was also effective in a polyQ mouse model when administered after symptom onset. As arginine has been safely used for urea cycle defects and for mitochondrial myopathy, encephalopathy, lactic acid and stroke syndrome patients, and efficiently crosses the blood-brain barrier, a drug-repositioning approach for arginine would enable prompt clinical application as a promising disease-modifier drug for the polyQ diseases. [ABSTRACT FROM AUTHOR]

The software package BBCPOP is a MATLAB implementation of a hierarchy of sparse doubly nonnegative relaxations of a class of polynomial optimization (minimization) problems (POPs) with binary, box, and complementarity (BBC) constraints. Given a POP in the class and a relaxation order, BBCPOP constructs a simple conic optimization problem (COP), which serves as a doubly nonnegative relaxation of the POP, and then solves the COP by applying the bisection and projection method. The COP is expressed with a linear objective function and constraints described as a single hyperplane and two cones, which are the Cartesian product of positive semidefinite cones and a polyhedral cone induced from the BBC constraints. BBCPOP aims to compute a tight lower bound for the optimal value of a large-scale POP in the class that is beyond the comfort zone of existing software packages. The robustness, reliability, and efficiency of BBCPOP are demonstrated in comparison to the state-of-the-art software SDP package SDPNAL+ on randomly generated sparse POPs of degree 2 and 3 with up to a few thousands variables, and ones of degree from 5 to 8 with up to a few hundred variables. Numerical results on BBC-constrained POPs that arise from quadratic assignment problems are also reported. The software package BBCPOP is available at https://sites.google.com/site/bbcpop1/. [ABSTRACT FROM AUTHOR]

• Spherical hydrous Ta 2 O 5 particles were prepared using hydrolyzing Ta alkoxide. • Hydrous Ta 2 O 5 particles became porous after being soaked in 2-propanol. • Hydrothermal treatment crystallized porous hydrous Ta 2 O 5 particles. • The Ta 2 O 5 particles had urchin-like shapes with high specific surface areas. Tantalum oxide (Ta 2 O 5) particles with defined structures and high specific surface areas are highly desirable for diverse applications. Herein, hydrous Ta 2 O 5 particles with porous structures were prepared by hydrolyzing tantalum alkoxide and partially dissolving the particle surfaces by soaking in alcohol. To obtain crystallized Ta 2 O 5 , these particles were subjected to heat treatment or hydrothermal treatment. Heat treatment produced particles that retained the original porous structure to some extent, while hydrothermal treatment caused dried hydrous Ta 2 O 5 particles to disintegrate. In contrast, hydrothermal crystallization of nondried hydrous Ta 2 O 5 particles produced an urchin-like structure, with Ta 2 O 5 spines grown on the original spherical core. The urchin-like particles had a mesoporous structure with a specific surface area of about 75 m2 g−1. [ABSTRACT FROM AUTHOR]

Several major histocompatibility complex class I (MHC-I) alleles are associated with lower viral loads and slower disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. Immune-correlates analyses in these MHC-I-related HIV/SIV controllers would lead to elucidation of the mechanism for viral control. Viral control associated with some protective MHC-I alleles is attributed to CD8+ T-cell responses targeting Gag epitopes. We have been trying to know the mechanism of SIV control in multiple groups of Burmese rhesus macaques sharing MHC-I genotypes at the haplotype level. Here, we found a protective MHC-I haplotype, 90-010-Id (D), which is not associated with dominant Gag-specific CD8+ T-cell responses. Viral loads in five D+ animals became significantly lower than those in our previous cohorts after 6 months. Most D+ animals showed predominant Nef-specific but not Gag-specific CD8+ T-cell responses after SIV challenge. Further analyses suggested two Nef-epitope-specific CD8+ T-cell responses exerting strong suppressive pressure on SIV replication. Another set of five D+ animals that received a prophylactic vaccine using a Gag-expressing Sendai virus vector showed significantly reduced viral loads compared to unvaccinated D+ animals at 3 months, suggesting rapid SIV control by Gag-specific CD8+ T-cell responses in addition to Nef-specific ones. These results present a pattern of SIV control with involvement of non-Gag antigen-specific CD8+ T-cell responses. [ABSTRACT FROM AUTHOR]

Cytotoxic T-lymphocyte (CTL) responses frequently select for immunodeficiency virus mutations that result in escape from CTL recognition with viral fitness costs. The replication in vivo of such viruses carrying not single but multiple escape mutations in the absence of the CTL pressure has remained undetermined. Here, we have examined the replication of simian immunodeficiency virus (SIV) with five gag mutations selected in a macaque possessing the major histocompatibility complex haplotype 90-120-Ia after its transmission into 90-120-Ia-negative macaques. Our results showed that even such a "crippled" SIV infection can result in persistent viral replication, multiple reversions, and AIDS progression. [ABSTRACT FROM AUTHOR]

Nonhuman primate AIDS models are essential for the analysis of AIDS pathogenesis and the evaluation of vaccine efficacy. Multiple studies on human immunodeficiency virus and simian immunodeficiency virus (SIV) infection have indicated the association of major histocompatibility complex class I (MHC-I) genotypes with rapid or slow AIDS progression. The accumulation of macaque groups that share not only a single MHC-I allele but also an MHC-I haplotype consisting of multiple polymorphic MHC-I loci would greatly contribute to the progress of AIDS research. Here, we investigated SIVmac239 infections in four groups of Burmese rhesus macaques sharing individual MHC-I haplotypes, referred to as A, E, B, and J. Out of 20 macaques belonging to A+ (n = 6), E+ (n = 6), B+ (n = 4), and J+ (n = 4) groups, 18 showed persistent viremia. Fifteen of them developed AIDS in 0.5 to 4 years, with the remaining three at 1 or 2 years under observation. A+ animals, including two controllers, showed slower disease progression, whereas J+ animals exhibited rapid progression. E+ and B+ animals showed intermediate plasma viral loads and survival periods. Gag-specific CD8+ T-cell responses were efficiently induced in A+ animals, while Nef-specific CD8+ T-cell responses were in A+, E+, and B+ animals. Multiple comparisons among these groups revealed significant differences in survival periods, peripheral CD4+ T-cell decline, and SIV-specific CD4+ T-cell polyfunctionality in the chronic phase. This study indicates the association of MHC-I haplotypes with AIDS progression and presents an AIDS model facilitating the analysis of virus-host immune interaction. [ABSTRACT FROM AUTHOR]

Abstract: Cytotoxic T lymphocyte (CTL) responses are crucial for the control of human and simian immunodeficiency virus (HIV and SIV) replication. A promising AIDS vaccine strategy is to induce CTL memory resulting in more effective CTL responses post-viral exposure compared to those in natural HIV infections. We previously developed a CTL-inducing vaccine and showed SIV control in some vaccinated rhesus macaques. These vaccine-based SIV controllers elicited vaccine antigen-specific CTL responses dominantly in the acute phase post-challenge. Here, we examined CTL responses post-challenge in those vaccinated animals that failed to control SIV replication. Unvaccinated rhesus macaques possessing the major histocompatibility complex class I haplotype 90-088-Ij dominantly elicited SIV non-Gag antigen-specific CTL responses after SIV challenge, while those induced with Gag-specific CTL memory by prophylactic vaccination failed to control SIV replication with dominant Gag-specific CTL responses in the acute phase, indicating dominant induction of vaccine antigen-specific CTL responses post-challenge even in non-controllers. Further analysis suggested that prophylactic vaccination results in dominant induction of vaccine antigen-specific CTL responses post-viral exposure but delays SIV non-vaccine antigen-specific CTL responses. These results imply a significant influence of prophylactic vaccination on CTL immunodominance post-viral exposure, providing insights into antigen design in development of a CTL-inducing AIDS vaccine. [Copyright &y& Elsevier]

NUP98-HOXA9 is the prototype of a group of oncoproteins associated with acute myeloid leukemia. It consists of an N-terminal portion of NUP98 fused to the homeodomain of HOXA9 and is believed to act as an aberrant transcription factor that binds DNA through the homeodomain. Here we show that NUP98-HOXA9 can regulate transcription without binding to DNA. In order to determine the relative contributions of the NUP98 and HOXA9 portions to the transforming ability of NUP98-HOXA9, the effects of NUP98-HOXA9 on primary human CD34+ cells were dissected and compared to those of wild-type HOXA9. In contrast to previous findings in mouse cells, HOXA9 had only mild effects on the differentiation and proliferation of primary human hematopoietic cells. The ability of NUP98-HOXA9 to disrupt the differentiation of primary human CD34+ cells was found to depend primarily on the NUP98 portion, whereas induction of long-term proliferation required both the NUP98 moiety and an intact homeodomain. Using oligonucleotide microarrays in primary human CD34+ cells, a group of genes was identified whose dysregulation by NUP98-HOXA9 is attributable primarily to the NUP98 portion. These include RAP1A, HEY1, and PTGS2 (COX-2). Their functions may reflect the contribution of the NUP98 moiety of NUP98-HOXA9 to leukemic transformation. Taken together, these results suggest that the effects of NUP98-HOXA9 on gene transcription and cell transformation are mediated by at least two distinct mechanisms: one that involves promoter binding through the homeodomain with direct transcriptional activation, and another that depends predominantly on the NUP98 moiety and does not involve direct DNA binding. [ABSTRACT FROM AUTHOR]

Gag-specific cytotoxic T lymphocytes (CTLs) exert strong suppressive pressure on human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. However, it has remained unclear whether they can actually contain primary viral replication. Recent trials of prophylactic vaccines inducing virus-specific T-cell responses have indicated their potential to confer resistance against primary SIV replication in rhesus macaques, while the immunological determinant for this vaccine-based viral control has not been elucidated thus far. Here we present evidence implicating Gag-specific CTLs as responsible for the vaccine-based primary SIV control. Prophylactic vaccination using a Gag-expressing Sendai virus vector resulted in containment of SIVmac239 challenge in all rhesus macaques possessing the major histocompatibility complex (MHC) haplotype 90-120-Ia. In contrast, 90-120-Ia-positive vaccinees failed to contain SIVs carrying multiple gag CTL escape mutations that had been selected, at the cost of viral fitness, in SIVmac239-infected 90-120-Ia-positive macaques. These results show that Gag-specific CTL responses do play a crucial role in the control of wild-type SIVmac239 replication in vaccinees. This study implies the possibility of Gag-specific CTL-based primary HIV containment by prophylactic vaccination, although it also suggests that CTL-based AIDS vaccine efficacy may be abrogated in viral transmission between MHC-matched individuals. [ABSTRACT FROM AUTHOR]

Although it is clear that the CD45 tyrosine phosphatase is required for efficient T-cell activation and T-cell development, the factors that regulate CD45 function remain uncertain. Previous data have indicated that there is an association of CD45 with CD4 and the T-cell receptor (TCR) complex controlled by the variable ectodomain of CD45 and, following activation, by high- and low-potency peptides. This suggests that controlling substrate access to CD45 may be an important regulatory mechanism during T-cell activation. In the present study we have examined the role of the transmembrane adapter-like molecule CD45-associated protein (CD45-AP) in regulating the association of CD45 with CD3/TCR and lck, and in regulating primary CD4+ T-lymphocyte activation. In CD4+ T cells from CD45-AP-deficient mice, coimmunoprecipitation of CD45 with the CD3/TCR complex, in addition to lck, is significantly reduced compared with wild-type T cells. Functionally, this correlates with a decreased proliferative response, a decrease in interleukin (IL)-2 production, and a decrease in calcium flux upon stimulation with a low-potency altered peptide ligand. However, the response of CD45-AP-deficient T cells to stimulation with a high-avidity agonist peptide was largely intact, except for a modest decrease in IL-2 production. These data suggest that CD45-AP promotes or stabilizes the association of CD45 with substrates and regulates the threshold of T-cell activation. [ABSTRACT FROM AUTHOR]

PHoM is a software package in C++ for finding all isolated solutions of polynomial systems using a polyhedral homotopy continuation method. Among three modules constituting the package, the first module StartSystem constructs a family of polyhedral-linear homotopy functions, based on the polyhedral homotopy theory, from input data for a given system of polynomial equations f(x)=0. The second module CMPSc traces the solution curves of the homotopy equations to compute all isolated solutions of f(x)=0. The third module Verify checks whether all isolated solutions of f(x)=0 have been approximated correctly. We describe numerical methods used in each module and the usage of the package. Numerical results to demonstrate the performance of PHoM include some large polynomial systems that have not been solved previously. [ABSTRACT FROM AUTHOR]

Presents a study that examined mutations of human pancreatic cancers in the K-ras oncogene. Background on pancreatic adenocarcinoma; Analysis of the activation of various downstream targets by Ras; Roles of several mitogen-activated protein kinase pathways in cell survival and proliferation.