High-resolution biomarker discovery: Moving from large-scale proteome profiling to quantitative validation of lead candidates

Diverse proteomic techniques based on protein MS have been introduced to systematically characterize protein perturbations associated with disease. Progress in clinical proteomics is essential for personalized medicine, wherein treatments will be tailored to individual needs based on patient stratification using noninvasive disease monitoring procedures to reveal the most appropriate therapeutic targets. However, breakthroughs await the successful development and application of a robust proteomic pipeline capable of identifying and rigorously assessing the relevance of multiple candidate proteins as informative diagnostic and prognostic indicators or suitable drug targets involved in a pathological process. While steady progress has been made toward more comprehensive proteome profiling, the emphasis must now shift from in depth screening of reference samples to stringent quantitative validation of selected lead candidates in a broader clinical context. Here, we present an overview of the emerging proteomic strategies for high-throughput protein detection focused primarily on targeted MS/MS as the basis for biomarker verification in large clinical cohorts. We discuss the conceptual promise and practical pitfalls of these methods in terms of achieving higher dynamic range, higher throughput, and more reliable quantification, highlighting research avenues that merit additional inquiry.     

Initial high beta operation of the HBT-EP Tokamak

HBT-EP is a new research tokamak designed and built to investigate passive and active feedback techniques to control MHD instabilities. In particular, HBT-EP will be able to test techniques to control fast MHD instabilities occurring at high Troyon-normalized beta, _N Ba/I_p [Tm/MA], since it is equipped with a thick, close-fitting, and adjustable conducting shell. The major goals of the initial operation of HBT-EP have been the achievement of high beta operation (_N 3) using only ohmic heating and the observation of MHD instabilities. By using a unique fast startup technique, we have successfully achieved these goals. A variety of MHD phenomena were observed during the high beta operation of HBT-EP. At modest beta (_N 2), discharges have been maintained for more than 10 msec, and these discharges exhibit saturated resistive instabilities. When _N approaches 3, major disruptions occur preceded by oscillating, growing precursors. During start-up, one or more minor disruptions are usually observed. A 1-D transport code has been used to simulate the evolution of the current profile, and these early minor instabilities are predicted to be double tearing modes. The simulation also reproduces the observed high beta operation when saturated neo-Alcator energy confinement scaling is assumed.     

Efficient worst-case data structures for range searching

In this paper we investigate the worst-case complexity of range searching: preprocess N points in k-space such that range queries can be answered quickly. A range query asks for all points with each coordinate in some range of values, and arises in many problems in statistics and data bases. We develop three different structures for range searching in this paper. The first structure has absolutely optimal query time (which we prove), but has very high preprocessing and storage costs. The second structure we present has logarithmic query time and O(N ¹⁺²) preprocessing and storage costs, for any fixed >0. Finally we give a structure with linear storage, O(N ln N) preprocessing and O(N ) query time.Research in this paper has been supported partially under Office of Naval Research contract N000014-76-C-0373, USA, and by the Austrian Federal Ministry for Science and Research     

On generators and generative capacity of EOL forms

Summary In this paper we study the generative capacity of EOL forms from two different points of view. On the one hand, we consider the generative capacity of special EOL forms which one could call linear like and context free like, establishing the existence of a rich variety of non-regular sub-EOL language families. On the other hand, we propose the notion of a generator L of a language family We mean by this that any synchronized EOL system generating L generates — if understood as an EOL form — all languages of . We characterize the generators of the family of regular languages, and prove that other well known language families do not have generators.Partially supported under NSE Research Council of Canada, grant No. A-7700     

Variation in the local motion statistics of real-life optic flow scenes

Optic flow motion patterns can be a rich source of information about our own movement and about the structure of the environment we are moving in. We investigate the information available to the brain under real operating conditions by analyzing video sequences generated by physically moving a camera through various typical human environments. We consider to what extent the motion signal maps generated by a biologically plausible, two-dimensional array of correlation-based motion detectors (2DMD) not only depend on egomotion, but also reflect the spatial setup of such environments. We analyzed the local motion outputs by extracting the relative amounts of detected directions and comparing the spatial distribution of the motion signals to that of idealized optic flow. Using a simple template matching estimation technique, we are able to extract the focus of expansion and find relatively small errors that are distributed in characteristic patterns in different scenes. This shows that all types of scenes provide suitable motion information for extracting ego motion despite the substantial levels of noise affecting the motion signal distributions, attributed to the sparse nature of optic flow and the presence of camera jitter. However, there are large differences in the shape of the direction distributions between different types of scenes; in particular, man-made office scenes are heavily dominated by directions in the cardinal axes, which is much less apparent in outdoor forest scenes. Further examination of motion magnitudes at different scales and the location of motion information in a scene revealed different patterns across different scene categories. This suggests that self-motion patterns are not only relevant for deducing heading direction and speed but also provide a rich information source for scene structure and could be important for the rapid formation of the gist of a scene under normal human locomotion.     

A symbolic summation approach to Feynman integral calculus

Given a Feynman parameter integral, depending on a single discrete variable N$N$ and a real parameter ε$\epsilon$, we discuss a new algorithmic framework to compute the first coefficients of its Laurent series expansion in ε$\epsilon$. In a first step, the integrals are expressed by hypergeometric multi-sums by means of symbolic transformations. Given this sum format, we develop new summation tools to extract the first coefficients of its series expansion whenever they are expressible in terms of indefinite nested product–sum expressions. In particular, we enhance the known multi-sum algorithms to derive recurrences for sums with complicated boundary conditions, and we present new algorithms to find formal Laurent series solutions of a given recurrence relation.     

Reduced order optimization for model predictive control using principal control moves

In order to reduce the computational complexity of model predictive control (MPC) a proper input signal parametrization is proposed in this paper which significantly reduces the number of decision variables. This parametrization can be based on either measured data from closed-loop operation or simulation data. The snapshots of representative time domain data for all manipulated variables are projected on an orthonormal basis by a Karhunen-Loeve transformation. These significant features (termed principal control moves, PCM) can be reduced utilizing an analytic criterion for performance degradation. Furthermore, a stability analysis of the proposed method is given. Considerations on the identification of the PCM are made and another criterion is given for a sufficient selection of PCM. It is shown by an example of an industrial drying process that a strong reduction in the order of the optimization is possible while retaining a high performance level.